PRESENTED BY LINDA MOSE Clinical features of infections

. PRESENTED BY LINDA MOSE

� Clinical features of infections of the nervous system depend upon the location of the infection ( in the meninges or in the brain/spinal cord parenchyma), the causative agent (ie bacterial infections, viral infections, slow virus and prion infections, parasitic infections, fungal infections) and whether the infection is acute or chronic.

� Bacterial CNS infections may occur as: ◦ Meningitis ◦ Parenchymal bacterial infections ◦ An infection of the central nervous system may primarily affect its coverings, which is called meningitis. It may affect the brain parenchyma, called encephalitis, or affect the spinal cord, called myelitis. A patient may have more than one affected area, and if all are affected, the patient has "meningoencephalomyelitis". The nervous system may also suffer from localized pockets of infection. Within the brain or spinal cord there may be an abscess, and outside them there may be an epidural abscess or subdural empyema.

� Meningitis is inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. � The inflammation may be caused by infection with viruses, bacteria, or other microorganisms, and less commonly by certain drugs. � Meningitis can be life-threatening because of the inflammation's proximity to the brain and spinal cord; therefore the condition is classified as a medical emergency.

MECHANISM ANATOMY � The meninges comprise three membranes that, together with the cerebrospinal fluid, enclose and protect the brain and spinal cord (the central nervous system). � The pia mater is a very delicate impermeable membrane that firmly adheres to the surface of the brain, following all the minor contours. � The arachnoid mater (so named because of its spider-web -like appearance) is a loosely fitting sac on top of the pia mater. � The subarachnoid space separates the arachnoid and pia mater membranes, and is filled with cerebrospinal fluid. � The outermost membrane, the dura mater, is a thick durable membrane, which is attached to both the arachnoid membrane and the skull.

MECHANISM OF INFECTION AND INFLAMMATION � � � In bacterial meningitis, bacteria reach the meninges by one of two main routes: through the bloodstream or through direct contact between the meninges and either the nasal cavity or the skin. In most cases, meningitis follows invasion of the bloodstream by organisms that live upon mucous surfaces such as the nasal cavity. This is often in turn preceded by viral infections, which break down the normal barrier provided by the mucous surfaces. Once bacteria have entered the bloodstream, they enter the subarachnoid space in places where the blood-brain barrier is vulnerable—such as the choroid plexus. Direct contamination of the cerebrospinal fluid may arise from indwelling devices, skull fractures, or infections of the nasopharynx or the nasal sinuses that have formed a tract with the subarachnoid space; occasionally, congenital defects of the dura mater can be identified.

� The large-scale inflammation that occurs in the subarachnoid space during meningitis is not a direct result of bacterial infection but can rather largely be attributed to the response of the immune system to the entrance of bacteria into the central nervous system. � When components of the bacterial cell membrane are identified by the immune cells of the brain (astrocytes and microglia), they respond by releasing large amounts of cytokines, hormone-like mediators that recruit other immune cells and stimulate other tissues to participate in an immune response. � The blood-brain barrier becomes more permeable, leading to "vasogenic" cerebral edema (swelling of the brain due to fluid leakage from blood vessels).

� Large numbers of white blood cells enter the CSF, causing inflammation of the meninges, and leading to "interstitial" edema (swelling due to fluid between the cells). � In addition, the walls of the blood vessels themselves become inflamed (cerebral vasculitis), which leads to a decreased blood flow and a third type of edema, "cytotoxic" edema. � The three forms of cerebral edema all lead to an increased intracranial pressure; together with the lowered blood pressure often encountered in acute infection, this means that it is harder for blood to enter the brain, and brain cells are deprived of oxygen and undergo apoptosis (automated cell death).

SIGNS AND SYMPTOMS � � � � Headache Fever Meningismus – nuchal rigidity Obtundation - greatly reduced consiousness level Photophobia Phonophobia Vomiting and nausea Meningococcal rash Altered mental state/confusion Drowsiness Convulsions Coma In children symptoms may not be characterisitc and one may report irritability, bulging anterior fontanelle in children < 6 months, cold extremeties, inactivity, refusal to feed

� The stiff neck that occurs in meningitis is often striking--it is really stiff, almost boardlike, but not so painful as it is stiff. The stiffness is caused by reflex spasm of the neck muscles due to traction on inflamed cervical nerve roots. It is greatest with flexion, less with extension or rotation. Of course, a lot of older people have necks that are quite stiff due to osteoarthritis, and if they have a fever, this may occasionally lead to diagnostic concern for meningitis. Usually their necks are stiff with both rotational and flexion/extension movement. Associated with the stiff neck are two other classic "meningeal signs", the signs of Kernig and Brudzinski's sign is involuntary flexion of the hip and knee when the examiner flexes the patient's neck. Kernig's sign is limitation of straightening of the leg with the hip flexed. Meningeal signs occur not only in infectious meningitis, but in subarachnoid hemorrage and chemical meningitis. Unfortunately, meningismus occurs only in about 50% of cases of bacterial meningits, so the sign is neither highly specific nor highly sensitive

CAUSES � � � The types of bacteria that cause bacterial meningitis vary by age group. In premature babies and newborns up to three months old, common causes are group B streptococci (subtypes III which normally inhabit the vagina and are mainly a cause during the first week of life) and those that normally inhabit the digestive tract such as Escherichia coli (carrying K 1 antigen), Klebsiella and Proteus species. Listeria monocytogenes (serotype IVb) may affect the newborn and occurs in epidemics. Older children are more commonly affected by Neisseria meningitidis (meningococcus), Streptococcus pneumoniae (serotypes 6, 9, 14, 18 and 23) and those under five by Haemophilus influenzae type B. In adults, N. meningitidis and S. pneumoniae together cause 80% of all cases of bacterial meningitis, with increased risk of L. monocytogenes in those over 50 years old.

� Recent trauma to the skull gives bacteria in the nasal cavity the potential to enter the meningeal space. � Similarly, individuals with a cerebral shunt or related device (such as an extraventricular drain or Ommaya reservoir) are at increased risk of infection through those devices. In these cases, infections with staphylococci are more likely, as well as infections by pseudomonas and other Gram-negative bacilli. � The same pathogens are also more common in those with an impaired immune system. � In a small proportion of people, an infection in the head and neck area, such as otitis media or mastoiditis, can lead to meningitis. � Recipients of cochlear implants for hearing loss are at an increased risk of pneumococcal meningitis.

� Tuberculous meningitis, meningitis due to infection with Mycobacterium tuberculosis, is more common in those from countries where tuberculosis is common, but is also encountered in those with immune problems, such as AIDS. � Recurrent bacterial meningitis may be caused by persisting anatomical defects, either congenital or acquired, or by disorders of the immune system. � Anatomical defects allow continuity between the external environment and the nervous system. The most common cause of recurrent meningitis is skull fracture, particularly fractures that affect the base of the brain or extend towards the sinuses and petrous pyramids.

Aseptic � The term aseptic meningitis refers loosely to all cases of meningitis in which no bacterial infection can be demonstrated. � This is usually due to viruses, but it may be due to bacterial infection that has already been partially treated, with disappearance of the bacteria from the meninges, or by infection in a space adjacent to the meninges (e. g. sinusitis). � Endocarditis (infection of the heart valves with spread of small clusters of bacteria through the bloodstream) may cause aseptic meningitis. � Aseptic meningitis may also result from infection with spirochetes, a type of bacteria that includes Treponema pallidum (the cause of syphilis) and Borrelia burgdorferi (known for causing Lyme disease).

Streptococcus pneumoniae � � � This organism is now the most common cause of bacterial meningitis in all age groups except newborns. It is a Gram-positive coccus that occurs in pairs. It has an external polysaccharide capsule that determines its serotype. Serotype is important for vaccine creation and epidemiology, but is not routinely performed on clinical isolates, and does not guide antibiotic therapy. The nasopharynx is the primary site of pneumococcal colonization. Spread is from person to person through droplets, so there is an increased chance of spread in day care centers, barracks and prisons. The organism may spread to the meninges through local extension from an infected sinus or middle ear infection. Because it colonizes the nasopharynx this strain is common when meningitis occurs as a consequence of ENT procedures or of chronic CSF leak. Major risk factors for meningitis with this organism are: splenectomy, diabetes mellitus, liver disease, alcoholism, CSF leak, terminal complement deficiency, and pneumococcal pneumonia.

� Treatment and prevention For many years, S. pneumoniae was reliably sensitive to penicillin. Meningitis caused by these strains responds to meningitis doses of penicillin, ampicillin, cefotaxime, or ceftriaxone. � In recent years, penicillin-resistant strains have become common. � These strains remain susceptible to the third generation cephalosporins ceftriaxone and cefotaxime. � Vancomycin plus Rifampicin � Chlormaphenicol � Like pneumococcal pneumonia, meningitis can be prevented with pneumococcal conjugate vaccine.

Hemophilus influenzae � H. influenzae is a small (1 -2 micrometer diameter) Gram-negative coccobacillus. � Strains causing meningitis in children almost all have an outer capsule, but non-meningitiscausing strains do not. � The organism colonizes the upper respiratory tract of humans, who are its only natural host. � Spread occurs through respiratory droplets or by direct contact with respiratory secretions. � Risk factors for meningitis include head trauma, neurosurgery, paranasal sinusitis, otitis media and CSF leak.

� Treatment and prevention H. influenzae meningitis can be prevented by use of H. influenzae conjugate vaccine. � As with S. pneumoniae, beta-lactam and ampicillin-resistant strains are increasingly found, but resistance to ceftriaxone or cefotaxime are rare, and these are the drugs of choice. � Chlormaphenicol may also be used

Listeria monocytogenes � Listeria monocytogenes is a facultatively anaerobic Gram- positive rod. � The organism can be found in human feces, unpasteurized milk, cheeses, and other foods. � Most cases are sporadic, and contaminated food is the source of infection. � It may be difficult to diagnose clinically, because compared to other meningitides meningeal signs are less frequent, there is a lower CSF WBC count, less neutrophilic predominance, and lower protein. � Cranial nerve dysfunction may occur, and there are occasional cases of brainstem encephalitis. � Listeria monocytogenes is a common cause of meningitis in infants less than 1 month old, and is also common in adults greater than 60 years old. Risk factors include pregnancy, advanced age, and immunosuppression.

Treatment and prevention � Listeria monocytogenes remains sensitive to penicillins, and ampicillin is the antibiotic of choice, but treatment must be prolonged--3 or 4 weeks. � Trimethoprim-sulfamethoxasole is an alternative for the penicillin-allergic patient. � Gentamicin can also be used in combination with ampicillin. � Listeriosis results from food-borne transmission, so proper food handling measures markedly reduces infection risk.

Group B streptococcus � This is the most common meningitis in infants less than 1 month of age (70% of cases). � Transmission to the neonate usually occurs from mothers colonized by group B streptococcus in the genital tract. � In adults, group B streptococcal infection is often nosocomial. Treatment and prevention Beta-lactam-resistant strains of group B streptococcus have not emerged. � Treatment is with penicillin and ampicillin. � Neonatal meningitis can be prevented by therapies aimed at reducing maternal birth canal colonization, or by Caesarian section.

Neisseria meningitidis � � � Neisseria meningitidis is an encapsulated Gram-negative organism that appears in pairs on Gram stain. It commonly colonizes the nasopharynx, and can spread rapidly from person to person through respiratory droplets. N. meningitidis often occurs in epidemics among persons living in close quarters like dormitories or barracks. The course of the illness is usually rapid and dramatic. A petechial rash on the trunk and lower body may coalesce into purpura, which is a sign of disseminated meningococcemia and disseminated intravascular coagulation. Distal extremity necrosis may also occur. Treatment is effective and the disease usually occurs in immunocompetent patients. It is common to have non-lethal complications such as cutaneous scars, amputation, hearing loss, and renal injury. As with other encapsulated organisms, asplenia is a risk factor for infection.

Treatment and prevention � � � Penicillin-resistant strains are uncommon, so drugs of choice are penicillin or ampicillin. Ceftriaxone or cefotaxime response is also excellent. A polysaccharide vaccine has been available for a number of years and routinely recommended for all adolescents, such as college freshmen or military recruits. It has also been useful in patients with risk factors such as asplenia. Since 2005 a conjugate vaccine has been available. Close contacts of patients have a significantly increased risk of contracting infection, so antimicrobial prophylaxis is recommended for household members, day care contacts, and others. This should be done within 24 hours after exposure because secondary disease occurs within several days. One dose of ciprofloxacin or ceftriaxone is an alternative, and ceftriaxone can be given to pregnant patients.

Presumptive therapy for bacterial meningitis Age Major pathogens Antibiotics less than 3 months group B strep. ampicillin E. coli + cefotaxime L. monocytogenes S. pneumoniae 3 months to 50 years S. pneumoniae N. meningitidis H. influenzae (now rare in USA) 3 rd generation cephalosporin (1) + vancomycin (2)

Pathogen-specific therapy for bacterial meningitis Organism Drug of choice (1) Second choice if allergic Duration of therapy group B streptococci penicillin G or ampicillin vancomycin 14 - 21 days 3 rd generation chloramphen H. influenzae 7 - 10 days cephalospori icol n L. monocytoge nes ampicillin + gentamycin trimethoprim 14 - 21 days sulfamethox asole N. penicillin G chloramphen

TUBERCULOUS MENINGITIS � � � M tuberculosis is an aerobic gram-positive rod that stains poorly because of its thick cell wall that contains lipids, peptidoglycans, and arabinomannans. Mycobacteria vary in appearance from spherical to short filaments, which may be branched. Although they appear as short to moderately long rods, they can be curved and frequently are seen in clumps. Individual bacilli generally are 0. 5 -1 µm in diameter and 1. 5 -10 µm long. They are nonmotile and do not form spores. One of the distinct characteristics of mycobacteria is their ability to retain dyes within the bacilli that usually are removed from other microorganisms by alcohols and dilute solutions of strong mineral acids such as hydrochloric acid. This ability is attributed to a waxlike layer composed of long-chain fatty acids, the mycolic acids, in their cell wall. As a result, mycobacteria are termed acid-fast bacilli. The mechanisms by which neurovirulence may occur are unknown.

TUBERCULOUS MENINGITIS The development of TBM is a 2 -step process. Mycobacterium tuberculosis bacilli enter the host by droplet inhalation, the initial point of infection being the alveolar macrophages. � Localized infection escalates within the lungs, with dissemination to the regional lymph nodes to produce the primary complex. � During this stage, a short but significant bacteremia is present that can seed tubercle bacilli to other organs in the body. � In persons who develop TBM, bacilli seed to the meninges or brain parenchyma, resulting in the formation of small subpial or subependymal foci of metastatic caseous lesions. These are termed Rich foci, after the original pathologic studies of Rich and Mc. Cordick. �

� The second step in the development of TBM is an increase in size of a Rich focus until it ruptures into the subarachnoid space. � The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement. � Tubercles rupturing into the subarachnoid space cause meningitis. � Those deeper in the brain or spinal cord parenchyma cause tuberculomas or abscesses. � While an abscess or hematoma can rupture into the ventricle, a Rich focus does not.

�A thick gelatinous exudate infiltrates the cortical or meningeal blood vessels, producing inflammation, obstruction, or infarction. � Basal meningitis accounts for the frequent dysfunction of cranial nerves (CNs) III, VI, and VII, eventually leading to obstructive hydrocephalus from obstruction of basilar cisterns. � Subsequent neurological pathology is produced by 3 general processes: adhesion formation, obliterative vasculitis, and encephalitis or myelitis.

� Tuberculomas are conglomerate caseous foci within the substance of the brain, as shown in the image below. � Centrally located, active lesions may reach considerable size without producing meningitis. � Under conditions of poor host resistance, this process may result in focal areas of cerebritis or frank abscess formation, but the usual course is coalescence of caseous foci and fibrous encapsulation (ie, tuberculoma).

SIGNS AND SYMPTOMS � Clinical features resemble those of other bacterial meningitis and include: headache; vomiting; low-grade fever; lassitude; depression; confusion; behavioural change � Signs include: meningism (may be absent); oculomotor palsies; papilloedema; depression of conciousness level; focal hemisphere signs

DIAGNOSIS � Diagnosis requires high index of suspicion with careful inquiry into history and physical findings. � CSF studies can be conducted ie MCS, ZN stain � Cranial CT scan

TREATMENT � First-line therapy includes INH, RIF, PZA, SM, and ethambutol. � Second-line therapy includes ethionamide, cycloserine, PAS, aminoglycosides, capreomycin, and thiacetazone. � Potential new agents include oxazolidinone and isepamicin. Fluoroquinolones useful in the treatment of TBM include ciprofloxacin, and levofloxacin. � Because of the intensity of the inflammatory and fibrotic reactions at the meningeal site, adjunctive corticosteroids, in addition to standard antituberculous therapy, is recommended in TM.

�PARENCHYMAL INFECTIONS BACTERIAL

CEREBRAL ABSCESSES Etiology � Abscesses may arise by spread from an intracranial infection such as mastoiditis, but usually are spread to brain through the blood stream. Hematogenous spread from heart or lungs is most common. Congential heart disease with right to left shunting, pulmonary A-V fistulas, bronchiectasis, and lung abscess are all risk factors. Bacterial endocarditis is usually only a minor risk factor for brain abscess. � Streptococcus viridans is the most commonly isolated organism, but abscesses are usually polymicrobial, and Staphylococcus aureus, hemolytic Streptococcus, Enterobacteriaciae, Bacteroides and other anaerobes, are also common. In immunocompromised patients, fungal or Toxoplasma gondii abscesses may occur.

Symptoms and signs � Headache � Focal neurologic deficits � Fever, chills and other signs of infection usually do not occur � Papilledema (with increased ICP) � Nausea, vomiting (with increased ICP)

Diagnosis � Focal neurologic deficit or seizure suggests focal brain lesion � The patient may have a risk factor for abscess, such as: ◦ ◦ congenital heart disease with right to left shunt bacterial endocarditis lung abscess or bronchiectasis paranasal sinusitis � Contrast-enhanced CT or MRI may show a ringenhancing lesion or lesions and surrounding brain edema � If the diagnosis is in doubt, a stereotaxic brain biopsy will confirm that the lesion is an abscess

Cerebrospinal fluid � Lumbar puncture is not usually performed because abscess creates an intracranial mass with edema, so there is a risk of brain herniation. � If the abscess is well-encapsulated, protein may be increased, but cell counts are usually low and cultures are usually negative, so the diagnostic usefulness of LP is limited even if the physician is bold enough to do it.

Treatment � If the abscess is small and not causing severe neurologic deficit, presumptive antibiotic therapy can be given--usually a combination regimen that covers both aerobic and anaerobic organisms is needed. � If the abscess grows or fails to resolve, then surgery will be needed for diagnosis and drainage.

SUBDURAL EMPYEMA � Subdural empyema is a collection of pus in the subdural space, usually arising by direct spread from an intracranial infection such as sinusitis, osteomyelitis of the skull vault or middle ear disease. � Signs and symptoms are like those of brain abscess, but seizures are especially common, and treatment essentially always requires surgical drainage. � Diagnosis – cranial CT scan or MRI

SPINAL EPIDURAL ABSCESS Spinal epidural abscess produces a rapid-onset spinal cord syndrome. � Infection usually haematogenous � The most common cause is S. aureus. Symptoms � Fever � Back pain � Limb weakness or sensory changes � Bowel or bladder dysfunction � Symptoms are those of spinal cord dysfunction: weakness, sensory changes, bladder or bowel dysfunction. In the case of epidural abscess, localized back pain and fever are very common. Signs � Signs are those of spinal cord dysfunction: paraparesis, sensory level, hyporeflexia or hyperreflexia with extensor plantar responses, loss of anal reflexes, loss of anal tone and loss of bulbocavernosus reflex. . �

Diagnosis � Characteristic signs and symptoms. � MRI of the spine at the level suggested by the clinical exam. � LP is contraindicated in spinal epidural abscess because: 1) by needling the abscess you may seed the CSF with bacteria, causing a meningitis, 2) you may precipitate spinal block, with immediate complete paraplegia.

� Spinal epidural abscess is a medical emergency because loss of function can be prevented by prompt surgical drainage of the abscess, but if diagnosis or treatment is delayed until paraplegia occurs, recovery is very poor. � Appropriate antibiotic therapy is essential.

TETANUS � � � Tetanus, also called lockjaw, is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, obligate anaerobic bacterium Clostridium tetani. Infection generally occurs through wound contamination and often involves a cut or deep puncture wound. Neonatal through infection of umbilical stump when childbirth occurs under unhygienic conditions. Spores germinate and bacilli multiply in anaerobic conditions which occurs in areas of tissue necrosis and low oxygen tension. Exotoxin has affinity for motor nerve endings and motor nerve cells. Anterior horn cells affected after toxin has passed into blood stream ands their involvement results in rigidity and convulsions.

Symptoms occur 2 days to several weeks after injury and include: � Trismus – spasm of masseter muscles, causing difficulty in opening the mouth and in chewing, hence the term ‘lockjaw’. � Tonic rigidity involving facial muscles, neck and trunk. � Risus sardonicus – contraction of frontalis and muscles at the angles of the mouth. � Opisthotonous � Board like abdominal wall � Convulsions

� Repeated convulsions may lead to death of patient from exhaustion, asphyxia or aspiration pneumonia. � Autonomic involvement may cause CVS complications such as hypertension. Other symptoms include elevated temperature, sweating, and episodic rapid heart rate. Diagnosis � Usually on clinical grounds as it is rarely possible to isolate organism from original locus of entry

Mild tetanus Mild cases of tetanus can be treated with: � Tetanus immunoglobulin IV or IM, � metronidazole IV for 10 days, � diazepam, � tetanus vaccination Severe tetanus Severe cases will require admission to intensive care. In addition to above: � human tetanus immunoglobulin injected intrathecally (increases clinical improvement from 4% to 35%) � tracheostomy and mechanical ventilation for 3 to 4 weeks, � magnesium, as an intravenous (IV) infusion, to prevent muscle spasm, � diazepam as a continuous IV infusion, � the autonomic effects of tetanus can be difficult to manage (alternating hyper- and hypotension, hyperpyrexia/hypothermia) and may require IV labetalol, magnesium, clonidine, or nifedipine.

PREVENTION � Unlike many infectious diseases, recovery from naturally acquired tetanus does not usually result in immunity to tetanus. This is due to the extreme potency of the tetanospasmin toxin; even a lethal dose of tetanospasmin is insufficient to provoke an immune response. � Tetanus can be prevented by vaccination with tetanus toxoid. The CDC recommends that adults receive a booster vaccine every ten years, and standard care practice in many places is to give the booster to any patient with a puncture wound who is uncertain of when he or she was last vaccinated, or if he or she has had fewer than 3 lifetime doses of the vaccine.

NEUROSYPHILLIS Neurosyphilis is an infection of the brain or spinal cord. It occurs in persons with untreated syphilis many years after they are first infected. Causes Neurosyphilis is caused by Treponema pallidum, the bacteria that cause syphillis. It occurs about 10 - 20 years after a person is first infected with syphilis. Not everyone who has syphilis will develop this complication. There are four different forms of neurosyphilis: � Asymptomatic � General paresis(general paralysis of the insane) � Meningovascular � Tabes dorsalis Asymptomatic neurosyphilis occurs before symptomatic syphilis.

symptoms Abnormal walk (gait) � Blindness � Confusion � Dementia � Depression � Headache � Incontinence � Inability to walk � Irritability � Loss of muscle function � Mental decline � Paralysis � Poor concentration � Seizures � Stiff neck � Tremors � Visual disturbances � Weakness, numbness of lower extremities Note: There may be no symptoms �

EXAMS AND TESTS Signs include: � Abnormal reflexes � Muscle atrophy � Muscle contractions Blood tests can be done to detect substances produced by thebacteria that cause syphilis. The oldest test is the VDRL test. Other tests include: � Fluorescent treponemal antibody absorption (FTA-ABS) � Rapid plasma reagin (RPR) � Treponema pallidum particle agglutination assay (TPPA) In neurosyphilis, it is important to test the spinal fluid for signs of syphilis.

Tests to look for problems with the nervous system may include: � Cerebral angiogram � Head CT scan � Lumbar puncture ("spinal tap") and a cerebrospinal fluid analysis ( CSF fluid analysis) � MRI scan of the brain, brainstem, or spinal cord

Treatment � Penicillin is used to treat neurosyphilis. The medicine may be given in various ways. � It may be injected into a vein every day for 10 14 days. � You may take probenecid by mouth 4 times a day, combined with daily muscle injections -both for 10 - 14 days. � Further courses of penicillin given if symptoms not releived or in case of clinical progression or CSF shows presence of active disease(elevated cell count-lymphocytic, elevated protein count 0. 5 -1 g/l and increased gammaglobulin fraction.

LYME DISEASE � Lyme disease is a bacterial illness caused by a bacterium called a "spirochete. " The actual name of the bacterium is Borrelia burgdorferi. � Lyme disease is spread by hard ticks(ixodid) when they bite the skin, which permits the bacterium to infect the body. � Lyme disease is not contagious from an affected person to someone else. � Lyme disease can cause abnormalities in the skin, joints, heart, and nervous system.

stage 1: Early localized infection � Common bullseye rash pattern associated with Lyme disease � erythema chronicum migrans (also erythema migrans or EM), occurs at the site of tick bite 3 to 30 days after bite � Patients can also experience flu-like symptoms such as headache, muscle soreness, fever, and malaise. Lyme disease can progress to later stages even in patients who do not develop a rash. Stage 2: Early disseminated infection � Erythema chronicum migrans may develop at sites across the body that bear no relation to the original tick bite. borrelial lymphocytoma, a purplish lump may develops on the ear lobe, nipple, or scrotum. Other discrete symptoms include migrating pain in muscles, joint, and tendons, and heart palpitations and dizziness caused by changes in heartbeat. � Acute neurological problems, appear in 15% of untreated patients These include facial or Bell's palsy, as well as meningitis. Radiculoneuritis causes shooting pains that may interfere with sleep as well as abnormal skin sensations. Mild encephalitis may lead to memory loss, sleep disturbances, or mood changes.

Stage 3: Late persistent infection � After several months, untreated or inadequately treated patients may go on to develop severe and chronic symptoms that affect many parts of the body, including the brain, nerves, eyes, joints and heart. Myriad disabling symptoms can occur, including permanent paraplegia in the most extreme cases. � Chronic neurologic symptoms occur in up to 5% of untreated patients. � A polyneuropathy that involves shooting pains, numbness, and tingling in the hands or feet may develop. � A neurologic syndrome called Lyme encephalopathy is associated with subtle cognitive problems, such as difficulties with concentration and short-term memory. These patients may also experience profound fatigue. � depression � fibromyalgia � Chronic encephalomyelitis, which may be progressive, can involve cognitive impairment, weakness in the legs, awkward gait, facial palsy, bladder problems, vertigo, and back pain. � In rare cases untreated Lyme disease may cause frank psychosis, which has been mis-diagnosed as schizophrenia or bipolar disorder. Panic attack and anxiety can occur, also delusional behavior, including somatoform delusions, sometimes accompanied by a depersonalization or derealization syndrome, where the person begins to feel detached from themselves or from reality. ]

diagnosis � � � Serological tests eg Western Blot and Elisa PCR Western blot, ELISA and PCR can be performed by either blood test via venipuncture or cerebrospinal fluid (CSF) via lumbar puncture. Though lumbar puncture is more definitive of diagnosis, antigen capture in the CSF is much more elusive; reportedly CSF yields positive results in only 10– 30% of patients cultured. The diagnosis of neurologic infection by Borrelia should not be excluded solely on the basis of normal routine CSF or negative CSF antibody analyses. New techniques for clinical testing of Borrelia infection have been developed, such as LTT-MELISA, which is capable of identifying the active form of Borrelia infection (Lyme disease). Others, such as focus floating microscopy, are under investigation. New research indicates chemokine CXCL 13 may also be a possible marker for neuroborreliosis.

management � Tick removal as early as possible Treatment � Antibiotics of choice are doxycycline (in adults), amoxicillin (in children), erythromycin (for pregnant women) and ceftriaxone, with treatment lasting 14 to 28 days. Alternative choices are cefuroxime and cefotaxime � Late diagnosed Lyme is treated with oral or IV antibiotics, frequently ceftriaxone for a minimum of four weeks. Minocycline is also indicated for neuroborreliosis for its ability to cross the bloodbrain barrier.

EXAMINATION OF CEREBROSPINAL FLUID COLLECTION AND TRANSPORT � Done by experienced medical officer or health worker. � Aseptic technique � Fluid usually collected from the subarachnoid space. � A sterile wide-bore needle is inserted btn the 4 th and 5 th lumbar vertebrae and CSF allowed to drip into two dry sterile containers – ie for culture and for biochemical tests. � No delays in delivering specimens to the laboratory so as not to interfere with chances of isolating pathogens.

LAB EXAMINATION OF CSF 1) Report appearance of the c. s. f. - clear, slightly turbid, cloudy or definately purulent (pus suggests acute pyogenic bacterial meningitis) - contains blood (may be due to traumatic tap or rarely haemorrhage to CNS) - contains clots ( indicates high protein conc. with increased fibrinogen as may occur in pyogenic meningitis or spinal constriction)in tbm spider web like clot seen- do ZN stain

2) Test the c. s. f. � Purulent or cloudy- make and examine a gram stained smear and issue report without delay. Culture the c. s. f. � Slightly cloudy or clear c. s. f. - perform a cell count, note any increase in white cells, presence of pus and lymphocytes. � If predominantly pus cells- gram stain, wet preparation, culture. � If predominantly lymphocytes, may indicate viral meningitis, TBM, cryptococcal meningitis or other conditions. Measure protein concentration and c. s. f glucose (normal in viral, reduced in TBM, very low in pyogenic meningitis). Do a wet preparation and examine for yeast cells and trypanosomes.

GRAM SMEAR � Required when the c. s. f contains pus cells. It should be the first investigation performed and reported when c. s. f appears purulent or cloudy. � A Gram smear may also provide useful info when c. s. f is unsuitable for cell counting or biochemical testing eg if traumatic tap or it contains clots. � Examine for pus cells, bacteria and reports presence of yeast cells.

CULTURE � Culture the c. s. f when bacteria are seen in gram smear and or cells are present or protein concentration is raised. � CSF fluid must be cultured as soon as possible after collection. When delay is unavoidable keep fluid at 35 -37⁰C and not refridgerated. � Inoculate specimen on chocolate agar and blood agar. If gram positive diplococci seen in gram smear add an optochin disc to blood agar to assist in identification of S. Pneumoniae � Incubate in a CO₂ enriched atmosphere at 35 -37⁰C for upto 48 hours, checking for growth after overnight incubation. � In neonates, inoculate specimen also on Mac. Conkey agar and incubate aerobically at 35 -37⁰C overnight. - look for E. coli, Strep. agalactiae, Listeria monocytogenes and other bacteria causing neonatal meningitis

CELL COUNT � A white cell count with indication of whether cells are pus cells or lymphocytes is required when the c. s. f appears slightly cloudy or clear or when Gram stain does not indicate pyogenic meningitis. � Samples heavily blood stained or containing clots not suitable.

BIOCHEMICAL TESTING OF C. S. F. � Glucose must be measured within 20 minutes of collecting c. s. f. otherwise falsely low results will be obtained due to glycolysis. � Measured using colorimetric technique or Benedict’s reagent. � Total protein can be measured using a colorimetric technique or visual comparative technique. � Pandy’s test is a screening test which detects rises in c. s. f. globulin. Of value when not able to measure total c. s. f. protein

� ZIEHL NEELSEN SMEAR � Done in suspected TBM, raised c. s. f. lymphocyte count and low glucose and raised protein. � Presence of acid fast bacilli � When facilities for fluoresence microscopy are available, examination of an auramine stained smear is more sensitive in detecting AFB in c. s. f.

CSF findings in different forms of meningitis Type of meningitis Glucose Protein Cells Acute bacterial low high PMNs, often > 300/mm³ Acute viral normal or high mononuclear, < 300/mm³ Tuberculous low high mononuclear and PMNs, < 300/mm³ Fungal low high < 300/mm³ Malignant low high usually mononuclear

Typical CSF formulas Bacterial Viral Fungal Tuberculo us normal or high usually high WBC count 1, 000(cells/mm 10, 000 3) < 300 20 -500 50 -500 PMN (%) <20 <50 ~20 normal opening pressure >80 mononucl ear forms lymphocyt es RBC count (cells/mm 3) slight increase protein (mg/dl) very high normal (100 -500) high glucose < 40 usually < 40 normal

EARLY COMPLICATIONS OF MENINGITIS � � � The infection may trigger sepsis, a systemic inflammatory response syndrome of falling blood pressure, fast heart rate, high or abnormally low temperature and rapid breathing. Disseminated intravascular coagulation, the excessive activation of blood clotting, may cause both the obstruction of blood flow to organs and a paradoxical increase of bleeding risk. gangrene of limbs can occur. Severe meningococcal and pneumococcal infections may result in hemorrhaging of the adrenal glands, leading to Waterhouse. Friderichsen syndrome, which is often lethal. The brain tissue may swell, with increasing pressure inside the skull and a risk of swollen brain tissue getting trapped. This may be noticed by a decreasing level of consciousness, loss of the pupillary light reflex, and abnormal positioning. Inflammation of the brain tissue may also obstruct the normal flow of CSF around the brain (hydrocephalus).

LATE COMPLICATIONS � � Seizures may occur for various reasons; in children, seizures are common in the early stages of meningitis. Seizures may result from increased pressure and from areas of inflammation in the brain tissue. Focal seizures (seizures that involve one limb or part of the body), persistent seizures, lateonset seizures and those that are difficult to control with medication are indicators of a poorer long-term outcome. The inflammation of the meninges may lead to abnormalities of the cranial nerves, a group of nerves arising from the brain stem that supply the head and neck area and control eye movement, facial muscles and hearing, among other functions. Visual symptoms and hearing loss may persist after an episode of meningitis. Inflammation of the brain (encephalitis) or its blood vessels (cerebral vasculitis), as well as the formation of blood clots in the veins (cerebral venous thrombosis), may all lead to weakness, loss of sensation, or abnormal movement or function of the part of the body supplied by the affected area in the brain.

LATE COMPLICATIONS � Deafness � Epilepsy � Hydrocephalus � Cognitive deficits such as severe learning difficulty and severe behavioural disturbances � Blindness � Hemiplegia � Death may occur as an early or late complication

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