Lecture Outline: infections of the central nervous system

Bacterial infectionsBacterial infections• Tuberculosis• Leprosy• Neurosyphilis• Lysteriosis• Bacterial meningitis• Brain abscessViral infectionsViral infections• Viral meningitis• Herpes simplex encephalitis• Rabies• Poliomyelitis• Progressive multifocal leukoencephalopathyProtozoal infectionsProtozoal infections• ToxoplasmosisFungal infectionsFungal infections• Cryptococcal meningitisParasitesParasites• Neurocysticercosis

CT: Neurocysticercosis

Bacteria can grow in the cerebrospinal fluid in the subarachnoid space of the CNS. Meningitis: Inflammation of meninges. Bacterial infection involving the leptomeninges

within the subarachnoid space.Infection of leptomeninges Skull or backbone fractures Medical procedures Along peripheral nerves Blood or lymph Encephalitis: Inflammation of the brain.

•Depending on the duration of symptoms, meningitis may be classified as acute or chronic:•Acute meningitis evolution of symptoms within hours to several days, Acute meningitis (<1 d) is almost always a bacterial infection. Expedient diagnosis is essential. •Patients with acute bacterial meningitis may decompensate very quickly and so they require emergency care, including antimicrobial therapy, ideally within 30 minutes of emergency department (ED) presentation.•Chronic meningitis has an onset and duration of weeks to months. The duration of symptoms of chronic meningitis is characteristically at least 4 weeks. •Most bacterial meningitis is not acute. Approximately 75% of patients with bacterial meningitis present subacutely with symptoms beginning several days prior. •Chronic symptoms lasting longer than 1 week suggest meningitis caused by some viruses as well as tuberculosis, syphilis, fungi (especially cryptococci).

•Three major pathways exist by which an infectious agent bacteria, virus, fungus, or parasites gain access to the CNS •From this site, the organism invades the submucosa by circumventing host defenses (eg, physical barriers, local immunity, phagocytes/macrophages) and gains access to the CNS by (1) invasion of the bloodstream (ie, bacteremia, viremia, fungemia, parasitemia) and subsequent hematogenous seeding of the CNS, which is the most common mode of spread for most agents (eg, meningococcal, cryptococcal, syphilitic, and pneumococcal meningitis); (2) a retrograde neuronal (ie, olfactory and peripheral nerves) pathway or (3) direct contiguous spread (ie, sinusitis, otitis media, congenital malformations, trauma, direct inoculation during intracranial manipulation). •Bacteria from the maternal genital tract colonize the neonate after rupture of membranes, and specific bacteria, such as group B streptococci (GBS), enteric gram-negative rods, and Listeria monocytogenes, can reach the fetus transplacentally and cause infection•Once pathogens enter the subarachnoid space, an intense host inflammatory response is triggered by lipoteichoic acid and other bacterial cell wall products produced as a result of bacterial lysis. This response is mediated by the stimulation of macrophage-equivalent brain cells that produce cytokines and other inflammatory mediators. This resultant cytokine activation then initiates several processes that ultimately cause damage in the subarachnoid space, culminating in neuronal injury and apoptosis.

•Mortality/Morbidity•Morbidity and mortality depend on pathogen, patient's age and condition, and severity of acute illness.•Despite advances in care for patients with bacterial meningitis, the overall case fatality remains steady at approximately 10-30%.•Bacterial meningitis was uniformly fatal before the antimicrobial era. With the advent of antimicrobial therapy, the overall mortality rate from bacterial meningitis has decreased but remains alarmingly high approximately 25%. •Among the common causes of acute bacterial meningitis, the highest mortality rate is observed with pneumococcus. The reported mortality rates for each specific organism are 19-26% for S pneumoniae meningitis,• 3-6% for H influenzae meningitis, •3-13% for N meningitides meningitis

Sex•Male infants have a higher incidence of gram-negative neonatal meningitis male-to-female ratio is 3:1.

Age•Very young individuals (infants and young children) and elderly individuals (>60 y) are more predisposed to the infection.•Newborns are at highest risk for acute bacterial meningitis. After the first month of life, the peak incidence is in infants aged 3-8 months.

The classic presentation of meningitis includes the triad fever, sever neck stiffness/rigidity, called meningismus, and change in mental status (eg, lethargy, confusion, irritability, delirium, and coma)Signs of meningeal irritation are observed in only approximately 50% of patients with bacterial meningitis, and their absence certainly does not rule out meningitis.• Kernig sign: flex patients hip to a 90° angle and then attempting passively straighten the leg at the knee produces pain in the hamstrings and resistance to further extension. Should present bilaterally to support the meningitis diagnosis.• Brudzinski sign: is positive if the patients hips and knees flex automatically when the examiner flexes the patients neck while the patient is supine.• Nuchal rigidity: Resistance to passive flexion of the neck is also a sign.• Headache-Exacerbation of existing headache by repeated horizontal movement of the head, at a rate of 2-3 times per second, may also suggest meningeal irritation. • Cranial nerve palsies may be observed as a result of increased ICP or the presence of exudates encasing the nerve roots.• Nuchal rigidity (generally not present in children <1 y or in patients with altered mental status)• Fever and chills• Photophobia• Vomiting• Prodromal upper respiratory infection (URI) symptoms (viral and bacterial)• Seizures (30-40% in children, 20-30% in adults)• Papilledema is present in only one third of meningitis patients with increased ICP; it takes at least several hours to develop.

Brudzinski Sign of Meningitis:

Kernig’s Sign of Meningitis:

Systemic findings upon physical examination may provide clues to the etiology.o Skin findings range from a nonspecific blanching, erythematous, maculopapular rash to a petechial or purpuric rash, most characteristic of meningococcal meningitis. Commonly affects the trunk and extremities.

Symptoms in infantsCardinal signs of meningitis (eg, fever, vomiting, stiff neck) are rarely present. For neonatal meningitis, these signs are the exception, rather than the rule.• Lethargy and/or change in level of alertness• Poor feeding and/or vomiting• Respiratory distress• Bulging fontanelle • Paradoxic irritability (ie, quiet when stationary, cries when held)• High-pitched cry• Hypotonia• Approximately 6% of affected infants and children show signs of disseminated intravascular coagulopathy and endotoxic shock. These signs are indicative of a poor prognosis.

Meningitis is caused by the following pathogens in each age group:• Beyond the neonatal period, the 3 most common organisms that cause acute bacterial meningitis are Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b (Hib).

• Neonates - Group B or D streptococci, nongroup B streptococci, Escherichia coli, and L monocytogenes

• Infants and children -H influenzae (48%), S pneumoniae (13%), and N meningitidis

• Adults -S pneumoniae, (30-50%), H influenzae (1-3%), N meningitidis (10-35%), gram-negative bacilli (1-10%), staphylococci (5-15%), streptococci (5%), and Listeria species (5%)

Etiology of neonatal meningitisoBacteria are often acquired from the maternal vaginal flora. oEarly onset group B streptococcal meningitis occurs during the first 7 days of life, a consequence of maternal colonization and the absence of protective antibody in the neonate; it is often associated with obstetric complications. The disease is seen most often in premature or low birth weight babies. Pathogens are acquired before or during the birth process.

Etiology of meningitis in infants and children: In children older than 4 weeks, S pneumoniae and N meningitidis are the most common etiologic agents. H influenzae type b has essentially disappeared in countries where the conjugate vaccine is routinely used.oMost deaths occur within 24 hours of hospital admission in patients who have features associated with poor prognosis (eg, hypotension, shock, neutropenia, extremes of ages, petechiae and purpura of <12 h duration, disseminated intravascular coagulopathy, acidosis, presence of organism in WBC on peripheral smear, low erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], serogroup C disease).

S pneumoniae meningitisoS pneumoniae are lancet-shaped, gram-positive diplococcic, 84 serotypes.oIt is a common colonizer of the human nasopharynx (5-10% of healthy adults and 20-40% of healthy children). oPresently, it is the most common bacterial cause of meningitis, accounting for 47% of cases. oChildren of any age may be affected, but incidence and severity are highest in very young and elderly persons.

N meningitidis meningitisoN meningitis is a gram-negative diplococcus that is carried in the nasopharynx of otherwise healthy individuals. It initiates invasion by penetrating the airway epithelial surface. oPresently, it is the leading cause of bacterial meningitis in children and young adults, accounting for 59% of cases. oMost cases occur in infants aged 6-12 months; a second lower peak occurs among adolescents. A petechial or purpuric rash frequently is seen. oMost deaths occur within 24 hours of hospital admission in patients who have features associated with poor prognosis (eg, hypotension, shock, neutropenia, extremes of ages, petechiae and purpura of <12 h duration, disseminated intravascular coagulopathy, acidosis, presence of organism in WBC on peripheral smear, low erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], serogroup C disease).

H influenzae type b meningitiso H influenzae type b is a gram-negative rod frequently found as part of the normal flora in the upper respiratory tract. o H influenzae meningitis occurs primarily in children who have not been immunized with H influenzae type b vaccine, with 80-90% of the cases occurring in children aged 1 month to 3 years o Its isolation in adults suggests the presence of an underlying medical disorder, including paranasal sinusitis, otitis media, alcoholism, CSF leak following head trauma.o Since the implementation of the HIB vaccine, the carriage rates for the B strain have decreased from 2-4% to less than 1%o Current mortality rates are less than 5%. Most fatalities occur during the first few days of the illness.o It can spread from one individual to another by airborne droplets or direct contact with secretions.

General guidelines The cornerstone in the diagnosis of meningitis is examination of the CSF.Bacterial meningitis is a medical emergency. A firm diagnosis is usually made when bacteria are isolated from the cerebrospinal fluid (CSF) and evidence of meningeal inflammation is demonstrated by increased pleocytosis, elevated protein level, and low glucose level in the CSF.

Measure the opening pressure and send the fluid for cell count (and differential count), chemistry (ie, CSF glucose and protein), and microbiology (ie, Gram stain and cultures).The opening pressure of CSF should be measured in older children. Similarly, the color of the CSF (eg, turbid, clear, bloody) should be recorded.

The bacterial meningitis score :Positive cerebrospinal fluid Gram stainCSF absolute neutrophil count greater than or equal to 1000 cells/mcLCSF protein greater than or equal to 80 mg/dLPeripheral blood absolute neutrophil count greater than or equal to 10000 cells/mcLHistory of seizure before or at the time of presentation

The opening pressure (reference range is 80-200 mm H2O) may be elevated, suggesting some form of increased ICP from cerebral edema.•If the spinal fluid is not crystal clear, administer treatment immediately without waiting for the results of CSF tests.•CT scan of the brain may be performed prior to lumbar puncture in some patient groups with a higher risk of herniation. •A lumbar puncture (LP) may be contraindicated in some of the following conditions brain abscess, brain tumors or other cause of raised intracranial pressure, and occasionally infection at the lumbar puncture site- •Risk of cerebral herniation complicating lumbar puncture performed to diagnose acute bacterial meningitis. perform CT examinations performed before a lumbar puncture. An LP “removes the stopper from below, thus adding to the effects of the compression from above.”

Infants and childrenMany children receive antibiotics before definitive diagnosis is made. As a rule, a few doses of oral antimicrobial agents, or even a single injection of an antibiotic, do not significantly alter CSF findings, including bacterial cultures, especially in patients with H influenzae type b disease.

• Examination of the CSF in patients with acute bacterial meningitis reveals the characteristic neutrophilic pleocytosis (usually hundreds to a few thousand, with >80% PMN cells). In some cases of L monocytogenes meningitis (25-30%), a lymphocytic predominance may occur. Low CSF WBC count (<20 cells/µL) in the presence of a high bacterial load suggests a poor prognosis.• The opening pressure (reference range is 80-200 mm H2O) may be elevated, suggesting some form of increased ICP from cerebral edema.• The CSF glucose (reference range is 40-70 mg/dL) is less than 40 mg/dL in 60% of patients. Obtain a simultaneous blood glucose determination for comparison purposes. Some patients may have elevated blood sugar levels as a result of underlying diabetes mellitus, and the predictive value of the CSF and blood sugar ratio may not be accurate in these circumstances.• The CSF protein (reference range is 20-50 mg/dL) is usually elevated.

Bacterial Meningitis Viral Meningitis* Fungal Meningitis**

Pressure

5-15 cm H2 O

Increased Normal or mildly increased Normal or mildly increased in TB. May be increased in fungal. AIDS patients with cryptococcal meningitis have increased risk of blindness, death unless maintained at <30 cm.

Cell countpreterm: 0-25term: 0-22>6 months: 0-5mononuclearcells/mm3

No cell count result can exclude bacterial meningitis. Typically thousands of PMNs, but may be less dramatic or even normal (classically, in very early meningococcal meningitis and in extremely ill neonates). Lymphocytosis with normal CSF chemistries seen in 15-25%, especially when cell counts <1000 or if partially treated. Approximately 90% of patients with ventriculoperitoneal shunts have CSF WBC count >100 cells/mm3 are infected; CSF glucose usually normal, and organisms are less pathogenic. Cell count and chemistries normalize slowly (over days) with antibiotics.

Usually <500 cells, nearly 100% mononuclear. Up to 48 hours, significant PMN pleocytosis may be indistinguishable from early bacterial meningitis; this is particularly true with eastern equine encephalitis. Presence of nontraumaticRBCs in 80% of HSV meningoencephalitis, although 10% have normal CSF results

Hundreds of mononuclear cells

Microno organisms

Gram stain 80% effective. Inadequate decolorization may mistake H influenzae for gram-positive cocci. Pretreatment with antibiotics may affect stain uptake, causing gram-positive organisms to appear gram negative and decrease culture yield on average 20%.

No organism India ink 80-90% effective for fungi; AFB stain 40% effective for TB (increase yield by staining supernate from at least 5 cc CSF)

Glucoseeuglycemia: >50% serumhyperglycemia: >30% serum wait 4 h after glucose load

Decreased Normal Sometimes decreased. Aside from fulminant bacterial meningitis, the lowest levels of CSF glucose are seen in TB, primary amebic meningoencephalitis, neurocysticercosis

Proteinpreterm: 65-150term: 20-170>6 months: 15-45mg/dL

Usually >150, may be >1000 Mildly increased Increased; >1000 with relatively benign clinical presentation suggestive of fungal disease

Table 1. Comparison of CSF Findings by Type of Organism

• CSF Gram stain permits rapid identification of the bacterial cause in 60-90% of patients with bacterial meningitis. The presence of bacteria is 100% specific, but the sensitivity for detection is variable. The likelihood of detection is higher in the presence of a higher bacterial concentration and diminishes with prior antibiotic use.• CSF bacterial cultures yield the bacterial cause in 70-85% of cases. The yield diminishes significantly in patients who have received antimicrobial therapy. In these cases, some experts advocate the use of a CSF bacterial antigen assay. This is a latex agglutination technique that can detect the antigens of HIB, S pneumoniae, N meningitidis, E coli K1, and S agalactiae. Its theoretical advantage is the detection of the bacterial antigens even after microbial killing, as is observed following antibacterial therapy. Others, however, have shown that it may not be better than the Gram stain. It is specific (a positive result indicates a diagnosis of bacterial meningitis), but a negative finding on bacterial antigen test does not rule out meningitis (50-95% sensitivity).• Obtain blood cultures and appropriate cultures from possible sites of infection. Obtain these promptly and prior to the administration of an antibacterial agent. The utility of these cultures is most evident in cases when the performance of a lumbar puncture is delayed by the need for head imaging (risk for herniation in a patient with focal neurologic deficit or coma) and when antimicrobial therapy is rightfully initiated before the lumbar puncture and neuroimaging tests.

Acute viral meningitis • The CSF picture of acute viral meningitis is different from the CSF picture of bacterial meningitis.• The opening pressure is usually within the reference range.• The CSF cell count is usually in the few hundreds (100-1000 cells/µL) with a predominance of lymphocytes. Some cases of echovirus, mumps, and HSV meningitis may produce a neutrophilic picture early in the course of disease.• The CSF glucose level is usually within the reference range, but some cases of LCM, HSV, mumps, and polio may cause low CSF glucose levels.• CSF protein levels may be within the reference range but are usually elevated.• PCR assay

Cryptococcal meningitis • The definitive diagnosis usually relies on the demonstration of the specific fungal pathogen in the CSF.• The CSF is characterized by a lymphocytic pleocytosis (10-200 lymphocytes), a reduced glucose level, and an elevated protein level.• The CSF opening pressure may be elevated at times, suggesting increased ICP. • The CSF picture of other fungal meningitis is similar to the CSF picture of cryptococcal meningitis, usually with lymphocytic pleocytosis.

Tuberculosis meningitis • The CSF of patients with tuberculosis meningitis is characterized by a predominantly lymphocytic pleocytosis, usually in the hundreds.• The opening CSF pressure is usually elevated.• A characteristic hypoglycorrhagia (glucose <40 mg/dL) is present, and the protein level is usually elevated, especially if a CSF block is present.• The demonstration of the acid-fast bacilli in the CSF is difficult and usually requires a large volume of CSF.• Meningeal biopsy, with the demonstration of caseating granulomas and acid-fast bacilli on the smear, may prove useful because it has a higher yield than the CSF acid-fast bacilli smear.• The culture for Mycobacterium usually takes several weeks and may delay definitive diagnosis.• PCR• The need for mycobacterial growth in cultures remains because this offers the advantage of performing drug susceptibility assays.

Lumbar puncture o Elevated opening pressure correlates with increased risk of morbidity and mortality in bacterial and fungal meningitis.o Take tube #1 to chemistry lab for glucose and protein.o Take tube #2 to hematology lab for cell count with differential.o Take tube #3 to microbiology and immunology lab for Gram stain, bacterial culture, acid-fast bacillus (AFB) stain and tuberculosis (TB) cultures, India ink stain and fungal cultures, CIE, VDRL, and cryptococcal antigen, if indicated.o Hold tube #4 for repeat cell count with differential, if needed (or for other subsequent studies not initially ordered).o Research correlates CSF cytokines in children with bacterial meningitis.

NeonatalInitiate treatment as soon as bacterial meningitis is suspected. Ideally, blood and cerebrospinal fluid (CSF) cultures should be obtained before antibiotics are administered.

Fluid and electrolyte managementBy prescribing the correct type and volume of fluid, the risk of development of brain edema can be minimized. The child should receive fluids sufficient to maintain systolic blood pressure at around 80 mm Hg, urinary output of 500 mL/m2/d, and adequate tissue perfusion. Although care to avoid SIADH is important, underhydrating the patient and risk of decreased cerebral perfusion are equally concerning as well.

Traditionally, initial antimicrobial treatment consists of ampicillin and an aminoglycoside combination (ampicillin and cefotaxime also appropriate).As per the 2004 Infectious Diseases Society of America (IDSA) practice guidelines for bacterial meningitis, the combination of vancomycin and either ceftriaxone or cefotaxime is recommended for those with suspected bacterial meningitis, with targeted therapy based upon susceptibilities of isolated pathogens. This combination provides adequate coverage for most penicillin-resistant pneumococci and beta-lactamase resistant H influenzaetype b.

Once the pathogen has been identified and antimicrobial susceptibilities determined, the antibiotics may be modified for optimal targetted treatment.

One of the major contributors to the morbidity associated with bacterial meningitis is the severity of inflammation. Decreased inflammation, reduction in cerebral edema and intracranial pressure, and lessening brain damage with use of dexamethasone.As a result, the IDSA guidelines recommend the use of adjunctive dexamethasone in cases of H influenzae type b meningitis to be initiated 10-20 minutes prior to or at least concomitant with the first antimicrobial dose at 0.15 mg/kg q6h for 2-4 days.

Bacteria Susceptibility Antibiotic(s)Duration

(Days)

S pneumoniae Penicillin MIC <0.1 mg/L Penicillin G 10-14

MIC 0.1-1 mg/L Ceftriaxone or cefotaxime

MIC >2 mg/L Ceftriaxone or cefotaxime

Ceftriaxone MIC >0.5 mg/L Ceftriaxone or cefotaxime plus vancomycin or rifampin

H influenzae Beta-lactamase-negative Ampicillin 7

Beta-lactamase-positive Ceftriaxone or cefotaxime

N meningitidis ... Penicillin G or ampicillin 7

L monocytogenes ... Ampicillin or penicillin G plus an aminoglycoside

14-21

S agalactiae ... Penicillin G plus an aminoglycoside, if warranted

14-21

Enterobacteriaceae ... Ceftriaxone or cefotaxime plus an aminoglycoside

21

P aeruginosa ... Ceftazidime plus an aminoglycoside

21

Table.Specific Antibiotics and Duration of Therapy for Patients With Acute Bacterial Meningitis

•Neurosyphilis is caused by the bacteria spirochaete Treponema pallidum. •Infects the brain and spinal cord. •Occurs in persons with untreated syphilis 10 - 20 years after they are first infected.

Incidence•Before the advent of antibiotics, typically 25-35%

Neurosyphilis in HIV• Neurosyphilis is now most common in patients with HIV infection. •In the AIDS population up to 1-3% of patients are positive to cerebrospinal fluid (CSF) Veneral Disease Research Laboratory (VDRL) tests. Without therapy, 5-10% of patients develop clinical evidence of neurosyphilis. •The classically described time intervals from infection to symptom onset of 20 and 25-30 years for, respectively, general paresis and tabes dorsalis appear to be shortened in HIV-infected patients.

. •The CNS manifestations of syphilis can be broadly classified into meningeal and parenchymal. Meningeal manifestations range from the acute and more subtle and chronic forms of meningitis and meningoencephalitis up to the formation of circumscribed masses. These gummas are composed, similarly to those in all other sites in the body, of granulation tissue surrounded by mononuclear epithelial and fibroblastic cells and, intracranially, usually located over the cerebral convexities, adherent to both dura and brain parenchyma. •Parenchymal manifestations include two types of vasculitis, respectively Heubner's and Nissl's endarteritis, the former affecting large and medium-sized arteries with resultant irregular luminal narrowing and ectasia, the latter primarily involving small vessels in which a luminal narrowing occurs as a consequence of intense proliferation of endothelial and adventitial cells. Vascular neurosyphilis may present with focal neurological deficits as a consequence of arterial occlusion.

•CSF examination: An abnormal leukocyte cell count, protein level, or glucose level•Demonstrated reactivity to Venereal Disease Research Laboratory (VDRL) antibody testOther tests include:•Fluorescent treponemal antibody absorption•Rapid plasma reagin •Treponema pallidum particle agglutination assay •Cerebral angiogram •Head CT or MRI scan

Imaging findings include meningeal enhancement and small infarcts or foci of ischaemia with a predilection for the basal ganglia and the middle cerebral artery regions, revealed in the subacute phase by areas of contrast enhancement. Cerebral atrophy is a frequent accompaniment. Gummas are visible as mass lesions, with nodular or ring enhancement, at the brain surface.

•Syphilitic meningitis. Acute syphilitic meningitis usually occurs within the first few weeks to the first few years of infection; 10% of cases are diagnosed at the time of the secondary-stage syphilis rash. Patients present with headache, stiff neck, nausea, and vomiting, meningeal irritation, Argyll Robertson pupil (miotic pupil not reactive to light but reactive to accommodation is pathognomonic), and cranial nerve abnormalities, especially the optic nerve, facial nerve and the vestibulocochlear nerve. Rarely, it affects the spine instead of the brain, causing focal muscle weakness or sensory loss.

•Meningovascular syphilis occurs 10 or more years (average, 7 years) after the primary syphilis infection. Meningovascular syphilis can be associated with prodromal symptoms lasting weeks to months before focal deficits are identifiable. Prodromal symptoms include unilateral numbness, paresthesias, upper or lower extremity weakness, headache, vertigo, insomnia, and psychiatric abnormalities such as personality changes. The focal deficits initially are intermittent or progress slowly over a few days-seizures and paraplegia. However, it can also present as an infectious arteritis and cause an ischemic stroke. Angiography may be able to demonstrate areas of narrowing in the blood vessels or total occlusion.

•General paresis (dementia paralytica) is a severe manifestation of neurosyphilis. It is a chronic dementia that ultimately results in death in as little as 2-3 years. General paresis can occur between 3-30 years after infection, mostly in patients >40 years. Other clinical signs include: delusions, alterations of personality, memory loss and speech difficulties, and associated with a general hypereflexitivity and with the Argyll Robertson pupil. Pathology: General paresis appears to be the result of diffuse parenchymal damage associated with chronic meningoencephalitis. Imaging of the brain usually shows atrophy. Direct spirochete invasion of the neural tissue causing neuronal degeneration, astrocytic proliferation, and meningitis. Resultant degenerative and sclerotic changes produce a thickened dura matter, chronic subdural hematoma, cortical cell atrophy, and astrocyte proliferation. The frontal lobes are disproportionately affected.

General paresis pathology

•Tabes dorsalis Clinical signs include vision loss, loss of reflexes and loss of sense of vibration, spastic gait, and impaired balance, pains in the limbs or abdomen, failure of muscle coordination, and bladder disturbances and is the reflection of a myelopathy characterized by atrophic, degenerated, and demyelinated dorsal nerve roots and posterior spinal columns. Tabes dorsalis can occur anywhere from 5 -50 years after initial syphilis infection, usually in persons aged 25-40. Both direct invasion by the spirochete and an immunologenic reaction may occur, producing degenerative and sclerotic changes in the posterior nerve root fibres of the spinal cord, spinal ganglia cells, long fibers of the posterior columns of the spinal cord, optic nerves and oculomotor nuclei.

•Gumma A soft, non-cancerous growth resulting from the tertiary stage of syphilis. It is a form of granuloma.

•Meningovascular syphilis responds promptly to treatment with penicillin G. Treatment of general paresis and tabes dorsalis is far less successful. iv or sc for 10 - 14 days. Combined with Oral Probenecid x4/day.•Non-pregnant individuals who have severe allergic reactions to penicillin may be effectively treated with oral tetracycline or doxycycline. •Ceftriaxone may be considered as an alternative therapy. •Follow-up includes clinical evaluation (blood tests and lumbar punctures for CSF fluid analysis) at 1 to 2 weeks followed by clinical and serologic evaluation at 3, 6, 9, 12, and 24 months after treatment.

PrognosisThis is considered a life-threatening complication of syphilis. Prognosis can change based on the type of neurosyphilis and how early in the course of the disease people with neurosyphilis get diagnosed and treated. Individuals with asymptomatic neurosyphilis or meningeal neurosyphilis usually return to normal health. People with meningovascular syphilis, general paresis, or tabes dorsalis usually do not return to normal health, although they improve.

Ceftriaxone

Viral Meningitis• Viral meningitis is inflammation of the leptomeninges as a manifestation of CNS infection.

Viral meningitis syn. aseptic meningitis.• In uncomplicated viral meningitis, the clinical course is usually self-limited, with complete

recovery in 7-10 days. However, when the viral pathogen causes a more involved meningoencephalitis or meningomyelitis, the course can be significantly more protracted.

• Partially untreated bacterial meningitis in particular can present similarly to viral meningitis-devastating outcomes if misdiagnosed.

Causes• Enteroviruses account for more than 85% of all cases of viral meningitis. • Herpes family viruses: HSV-1, HSV-2, VZV, EBV, CMV, and human herpesvirus 6 collectively

cause approximately 4% of cases of viral meningitis, with HSV-2 being the most common offender.

• Lymphocytic choriomeningitis virus• Adenovirus• Measles• Mumps

Viral Meningitis

Pathophysiology• Viral pathogens may gain access to the CNS via 2 main

routes: hematogenous or neural. • Multiple host defenses (local and systemic immune

responses, skin and mucosal barriers, and the blood-brain barrier) prevent viral inoculum from causing clinically significant infection.

Mortality/Morbidity• Excluding the neonatal period, the mortality rate

associated with viral meningitis is less than 1%; the morbidity rate is also low.

Viral Meningitis-Clinical Manifestations• The classically taught triad of meningitis consists of fever, nuchal rigidity, and

altered mental status.• Upon presentation, most patients report fever, headache, irritability, nausea,

vomiting, stiff neck, rash, or fatigue within the past 18-36 hours.• Nuchal rigidity or other signs of meningeal irritation (Brudzinski or Kernig sign)

may be seen in more than half of patients but is generally less severe than in bacterial meningitis. Pediatric patients, especially neonates, tend not to exhibit nuchal rigidity on examination.

• The neonate may exhibit hypotonia, irritability, and poor feeding. • Some viruses cause rapid onset of the above symptoms, while others manifest

as nonspecific viral prodromes, such as malaise, myalgia, and upper respiratory symptoms. In many cases, symptoms have a biphasic pattern; the nonspecific flu-like symptoms and low-grade fever precede neurologic symptoms by approximately 48 hours. With the onset of neck stiffness and headache, the fever usually returns.

Viral Meningitis-Clinical Manifestations• Headache is common and is characteristically severe.• Photophobia is relatively common but may be mild. Phonophobia may also be

present.• Seizures occur occasionally and are usually from the fever, although the involvement

of brain parenchyma (encephalitis) should be considered. • Other signs of specific viral infection can aid in diagnosis:• Pharyngitis and pleurodynia in enteroviral infections• Skin manifestations, such as zoster eruption in VZV, maculopapular rash from measles

and enteroviruses, vesicular eruption by herpes simplex, and herpangina in coxsackievirus A infections.

• Pharyngitis, lymphadenopathy, and splenomegaly suggest Epstein-Barr virus infection.• Immunodeficiency and pneumonia should suggest adenovirus, cytomegalovirus , or

HIV as the causative agent.• Parotitis and orchitis can occur with mumps• Gastroenteritis and rash occur with most enteroviral infections.

Viral Meningitis-Diagnosis• CT scan usually is performed prior to LP to rule out intracranial hematoma, mass

effect, or obstructive hydrocephalus. • PCR testing for viral DNA. • The following are some CSF characteristics used to support the diagnosis of viral

meningitis:• Cells: Pleocytosis with WBC counts in the range of 50 to >1000 x 109/L of blood has

been reported in viral meningitis. Mononuclear cell predominance is the rule, but PMNs may comprise the majority of cells in the first 12-24 hours; the cell count usually is then dominated by lymphocytes in the classic CSF pattern of viral meningitis. This helps to distinguish viral from bacterial meningitis, which has a much higher cell count and a predominance of PMNs in the cell differential; this is by no means an absolute rule, however.

• Protein: CSF protein level usually is only slightly elevated, but can range from being normal to as high as 200 mg/dL.

• Glucose: Normal in most cases.• Culture, Gram stain, and acid-fast stain

Viral Meningitis-Treatment• Mostly supportive-Rest, hydration, antipyretics, and pain or anti-

inflammatory medications. The most important decision is whether to initiate antimicrobial therapy empirically for bacterial meningitis while waiting for the cause to be identified. Patients with signs and symptoms of meningoencephalitis should receive acyclovir early to possibly curtail HSV encephalitis.

• Enteroviruses and HSV are both capable of causing viral septic shock in newborns and infants. In these young patients, broad-spectrum antibacterial coverage and acyclovir should be instituted as soon as the diagnosis is suspected.

• Seizures should be treated immediately with IV anticonvulsants such as lorazepam, phenytoin, midazolam, or a barbiturate.

T1-weighted MRI of brain demonstrates diffuse enhancement of the meninges in viral meningoencephalitis.

Herpes Simplex EncephalitisHerpes simplex encephalitis (HSE) occurs as 2 distinct entities:• In children older than 3 months and adults, oral herpes, HSV-1 is

responsible for virtually all cases.• In neonates, the usual cause is herpes simplex virus type 2 (HSV-2),

genital herpes which is acquired at the time of delivery.Frequency• Herpes simplex encephalitis is the most common cause of

sporadic lethal encephalitis, occurring in about 1 person per 250,000-500,000 population per year.

Mortality/Morbidity• Before the availability of IV acyclovir the mortality rate of herpes

simplex encephalitis in untreated patients is 70%.

Herpes Simplex Encephalitis-Pathophysiology

• Brain infection is thought to occur by means of direct neuronal transmission of the virus from a peripheral site to the brain via the trigeminal or olfactory nerve. The herpes virus preferentially involves the temporal lobe and orbital surfaces of the frontal lobes. Herpes viruses cause a hemorrhagic necrosis and inflammatory infiltrates.

Destruction of inferior frontal and anterior temporal lobes – necrotizing inflammation

Herpes Simplex Encephalitis-Clinical Manifestations• Herpes simplex encephalitis (HSE) is an acute or subacute illness, causing both general

and focal signs of cerebral dysfunction:• Fever (90%)• Headache (81%)• Psychiatric symptoms (71%)• Seizures (67%)• Vomiting (46%)• Focal weakness (33%)• Memory loss (24%)• Alteration of consciousness (97%)• Hemiparesis (38%)• Cranial nerve defects (32%)• Visual field loss (14%)• Papilledema (14%)

Herpes Simplex Encephalitis-Diagnosis• No pathognomonic clinical findings reliably distinguish HSE from other neurological disorders with similar presentations

(eg, non-HSV encephalitis, brain abscess, tumor). Confirmation of the diagnosis depends on the identification of HSV in the CSF by means of a polymerase chain reaction (PCR) or on the identification of HSV in brain tissue by means of brain biopsy. The diagnosis of HSE should be considered in any patient with a progressively deteriorating level of consciousness, fever, abnormal CSF findings, and focal neurological abnormalities in the absence of any other causes.

Serologic analysis• Serologic evaluation of blood or CSF may be useful for retrospective diagnosis, but it has no role in the acute diagnosis and

treatment of patients.CSF analysis• Patients with herpes simplex encephalitis (HSE) typically have mononuclear pleocytosis of 10-500 WBCs/µL (average, 100

WBCs/µL).• As a result of the hemorrhagic nature of the underlying pathologic process, the RBC count may be elevated (10-500

RBCs/µL).• Protein levels are elevated to the range 60-700 mg/dL (average, 100 mg/dL).• Glucose values may be normal or mildly decreased (30-40 mg/dL).• In about 5-10% of patients, especially children, initial CSF results may be normal.• However, on serial examinations, the cell counts and protein values increase.• Viral cultures of CSF are rarely positive and should not be relied on to confirm the diagnosis.Polymerase chain reaction • PCR analysis of CSF for the detection of HSV DNA has virtually replaced brain biopsy as the criterion standard for diagnosis.

Herpes Simplex Encephalitis-Treatment• Empiric treatment of patients with suspected HSE is recommended pending confirmation of

the diagnosis because acyclovir, the drug of choice, is relatively nontoxic and because the prognosis for untreated HSE is poor.

• The treatment of choice for herpes simplex encephalitis (HSE) is acyclovir. Through a series of in vivo reactions catalyzed by viral and host cellular enzymes, acyclovir is converted to acyclovir triphosphate, a potent inhibitor of HSV DNA polymerase, without which viral replication cannot occur. Human cells are not affected.

• Acyclovir has relatively few serious adverse effects. The drug is excreted by the kidney, and the dose should be reduced in patients with renal dysfunction. Crystal-induced nephropathy may occur if the maximum solubility of free drug is exceeded. Risk factors for this are intravenous administration, rapid infusion, dehydration, concurrent use of nephrotoxic drugs, underlying renal disease, and high doses. The risk of renal toxicity is reduced by adequately hydrating the patient (eg, 1 mL fluid per day for each 1 mg/d of acyclovir).

• Gastrointestinal disturbances, headache, and rash are among the more frequent adverse reactions. Acyclovir is considered appropriate for serious infections during pregnancy.

• Since most relapses occur within 3 months of completing an initial course of intravenous acyclovir, then a prolonged oral course.

Herpes Simplex Encephalitis-Neuroimaging• Typically, T2-weighted MRI reveals hyperintensity corresponding to edematous

changes in the temporal lobes, inferior frontal lobes, and insula, with a predilection for the medial temporal lobes. Foci of hemorrhage occasionally can be observed on MRI.

T2–weighted MRI image in a 62-year-old woman with confusion and herpes encephalitis shows T2 hyperintensity involving the right temporal lobe.

Top Image: Axial diffusion-weighted image reveals restricted diffusion in the left medial temporal lobe consistent with herpes encephalitis. This patient also had a positive result on polymerase chain reaction assay for herpes simplex virus, which is both sensitive and specific. In addition, the patient had periodic lateralized epileptiform discharges on electroencephalogram, which supports the diagnosis of herpes encephalitis.

Bottom Image: Coronal T2-weighted image reveals hyperintensity in the left temporal lobe (arrows) in a distribution similar to the restricted diffusion abnormality seen in the previous image. This finding is typical for herpes encephalitis. In patients with HHV6 infection, one series noted that in addition to mesial temporal lobe abnormality, abnormal T2 hyperintensity has been seen in the insular and inferior frontal region, which may suggest the diagnosis. There are felt to be 2 typical imaging appearances: one seen in older adults involves T2 hyperintensity confined to the medial temporal lobe; in young adults, a more varied pattern has been described that includes foci of restricted diffusion with an otherwise normal magnetic resonance, diffuse cortical necrosis, or small focal regions of abnormal T2 hyperintensity.

Poliomyelitis• Greek polio (gray) and myelon (marrow, indicating the spinal cord)• Humans are the only know reservoir for poliovirus, a member of the

Picoviridae, enterovirus group. • Poliovirus transmission now primarily occurs in the Indian subcontinent, the

Eastern Mediterranean and Africa.• Person-to-person spread occurs predominantly via the fecal-oral route.• Poliovirus is highly infectious and may be present in the stool up to 6 weeks;

seroconversion in susceptible household contacts of children is nearly 100% and for adults >90%.

• Enhanced potency trivalent oral poliovirus vaccine (OPV) containing attenuated strains of all 3 serotypes of poliovirus. Effective immunity (99% after 3 doses).

Poliomyelitis-clinical manifestations• Incubation period 6-20 days.• 95% of all polio infections are asymptomatic even though infected persons shed virus in stool and

are contagious.• Abortive Poliomyelitis- Occurs in 4-8% of infections. Minor illness, no CNS infection, complete

recovery in one week. Sore throat, fever, nausea, vomiting, abdominal pain, constipation-influenza like illness indistiguisable from other enteric viral illnesses.

• Nonparalytic aseptic meningitis- Usually occurring several days after a prodrome similar to minor illness. Symptoms stiff neck, leg and back, deep muscle pain, and sometimes areas of hyperesthesia (increased sensation) and paresthesia (altered sensation), typically last 2-10 days followed by complete recovery.

Poliomyelitis-clinical manifestationsThree types of paralytic polio are described:• Spinal polio (79%) asymmetric paralysis usually involving the legs• Bulbar polio (2%) weakness of the mucles innervated by cranial nerves• Bulbospinal polio (19%) combination• Postpolio Syndrome-Occurs 30-40 years after paralytic poliomyelitis, when patients note seemingly increased

weakness.

• Flaccid paralysis-Occurs in <1% of polio infections. Paralytic symptons typically begin 1-10 days after the prodromal symptoms. Initially sever muscle aches and spasms are seen with significant menigumus and a Kerning sign. Evolves into a flaccid paralysis with diminished muscle stretch reflexes. No sensory or cognitive loss occurs. Weakness and paralysis present 12 months after onset is usually permanent.

Diagnosis Poliovirus isolation from the pharynx or stool. Neutralizing Ab present early at high levels. CSF shows increased WBC

and protein. Differential diagnosis-Asymmetric weakness distribution and CSF findings help to differentiate it from Gullain-Barre

syndrome

Treatment Physical therapy is the most important part of treatment of paralytic polio during convalescence. The ideal strategy

with polio is clearly to prevent it by immunization against poliovirus.

PoliomyelitisPathophysiologyThe virus enters via the oral route and multiplies in the intestinal mucosa lymphoid tissues in the pharynx, it is usually present in the throat and stool before clinical onset. Within 1 week of clinical onset little virus exists in the throat, but it continues to be excreted in the stool for several weeks. The virus invades the local lymphoid tissue, enters the blood stream and then infects the CNS. Viral replication in the anterior horn cells of the spinal cord and the brainstem motor neuron cells results in cell destruction and paralysis.

Rabies Virus (Rhabdovirus)Introduction Rabies is a viral disease that causes acute encephalitis. It is zoonotic, most commonly by a bite

from an infected animal. The rabies virus travels to the brain by following the peripheral nerves. The incubation period of the disease is usually a few months in humans, depending on the distance the virus must travel to reach the central nervous system. Once the rabies virus reaches the central nervous system and symptoms begin to show, the infection is effectively untreatable and usually fatal within days.

DiagnosisDemonstration of anti-rabies glycoprotein Ab in serum or CSF.

Prognosis In unvaccinated humans, rabies is almost invariably fatal if post-exposure

prophylaxis is not administered prior to the onset of severe symptoms. Death ordinarily occurs within three to five days after the onset of symptoms due to cardiac or respiratory failure.

Incidence• Rabies is common in Asia, especially in India, where up to 50,000 die each year.

Some parts of America and Africa, have it. Greenland and many countries in Europe have rabies in their animal populations. Although most of Scandinavia, as well as Japan, Australia and New Zealand are practically Rabies-Free!

Rabies Virus (Rhabdovirus)

In the unvaccinated individual rabies evolves in three stages: The Prodomal Phase - the lead up over a period of 2 -3 days. The patient may have a fever,

vomiting and loss of appetite, anxiety, often with pain and parenthesias at the bite site. The autonomic nervous system is affected, this manifests itself as copious salivation and sadness.

The Anger Stage-The patient will appear restless and irritable and display signs of aggression. May appear disorientated and may develop seizures. This stage lasts for about 2 - 4 days.

The Paralytic Stage- Two to 10 days after the prodrome, the encephalitic form presents with agitation, autonomic instability, delirium, seizures, rigidity, severe pharynx spasms, stridor, hydrophobia and aerophobia. The paralytic (20%) form presents with progressive paralysis until death. Paralysis develops, usually beginning at the wound site. The production of large quantities of saliva and tears coupled with an inability to speak or swallow are typical during the later stages of the disease, in which the patient has difficulty swallowing because the throat and jaw become slowly paralyzed. Hydrophobia- shows panic when presented with liquids to drink, and cannot quench his or her thirst.

Rabies Virus (Rhabdovirus)-Signs and symptoms

Patient with rabies, 1959

Treatment after exposure, known as post-exposure prophylaxis (PEP), is highly successful in preventing the disease if administered promptly, generally within ten days of infection. Thoroughly washing the wound as soon as possible with soap and water for approximately five minutes is very effective at reducing the number of viral particles. If available, a virucidal antiseptic such as povidone-iodine, iodine tincture, aqueous iodine solution or alcohol (ethanol) should be applied after washing. Exposed mucous membranes such as eyes, nose or mouth should be flushed well with water.One dose of human rabies immunoglobulin (HRIG) and four doses of rabies vaccine over a fourteen day period. The immunoglobulin dose should not exceed 20 units per kilogram body weight. As much as possible of this dose should be infiltrated around the bites, with the remainder being given by deep intramuscular injection at a site distant from the vaccination site. The first dose of rabies vaccine is given as soon as possible after exposure, with additional doses on days three, seven and fourteen after the first. Patients who have previously received pre-exposure vaccination do not receive the immunoglobulin, only the post-exposure vaccinations on day 0 and 2.

Rabies Virus (Rhabdovirus)-Treatment

Brain and spine Tuberculosis• Tuberculous meningitis: tuberculosis infection of the meninges. It is the most common form

of CNS tuberculosis.• Causative agent: Mycobacterium tuberculosis is an aerobic gram-positive rod. • CNS tuberculosis most commonly occurs in those infected with HIV and those from South East

Asia where TB is still endemicFrequency The World Health Organization (WHO) estimates that one third of the world's population is

infected by M. tuberculosis.

Clinical ManifestationsTuberculous meningitis progresses rapidly with headache, fever, tremor, and cranial nerve deficts

(esp CN-IV palsy). Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and tetraparesis. Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels . Visual findings-Papilledema is the most common visual effect of TBM.

• The clinical picture in primary spinal meningitis is often characterized by myelopathy, with radicular pain and progressive paraplegia or tetraplegia.

Brain and spine Tuberculosis-PathophysiologyDiagnosis• Diagnosis of TB meningitis is made by analysing

cerebrospinal fluid collected by lumbar puncture. A spider-web clot in the collected CSF is characteristic of TB meningitis, but is a rare finding.

• Culture for M. tuberculosis takes 2 weeks. More than half of cases of TB meningitis cannot be confirmed microbiologically, and these patients are treated on the basis of clinical suspicion only before the diagnosis is confirmed.

• PCR

Brain and spine TuberculosisTreatment• The treatment of TB meningitis is isoniazid, rifampicin, pyrazinamide and

ethambutol for two months, followed by isoniazid and rifampicin alone for a further ten months. Corticosteroids are always used in the first six weeks of treatment when cerebral edema, subarachnoid block, or both occur.

• Treatment must be started as soon as there is a reasonable suspicion of the diagnosis. Treatment must not be delayed while waiting for confirmation of the diagnosis.

Mortality/Morbidity• Death follows within weeks in untreated CNS tuberculosis. Mortality is

greatest at the extremes of age 20% at <5 years of age and 60% at>50 years or if illness has been present more than 2 months (80%)

Tuberculous meningitis -Clinical Manifestations• Tuberculous meningitis progresses rapidly with headache, fever,

meningismus, and cranial nerve deficts (esp CN-IV palsy). Focal cerebral or cerebellar deficts are followed by altered sensorium and coma.

Visual findings• Papilledema is the most common visual effect of TBM. In children,

papilledema may progress to primary optic atrophy and blindness resulting from direct involvement of the optic nerves and chiasma by basal exudates (ie, opticochiasmatic arachnoiditis).

• In adults, papilledema may progress more commonly to secondary optic atrophy, provided the patient survives long enough.

• Apart from papilledema, fundus examination occasionally reveals a retinal tuberculoma or a small grayish-white choroidal nodule, highly suggestive of TB. These lesions are believed to be more common in miliary TB than in other forms of TB.

Neurologic findings• Cranial neuropathies, most often involving CN VI, may be noted. CNs III, IV, VII,

and, less commonly, CNs II, VIII, X, XI, and XII, also may be affected.• Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and

tetraparesis.• Tremor is the most common movement disorder seen in the course of TBM. In a

smaller percentage of patients, abnormal movements, including choreoathetosis and hemiballismus, have been observed, more so in children than adults. In addition, myoclonus and cerebellar dysfunction have been observed. Deep vascular lesions are more common among patients with movement disorders.

• Vasculitis with resultant thrombosis and hemorrhagic infarction may develop in vessels that traverse the basilar or spinal exudate or lie within the brain substance. Eventually, fibrinoid degeneration within small arteries and veins produces aneurysms, multiple thrombi, and focal hemorrhages, alone or in combination.

Tuberculous meningitis-Clinical Manifestations

Tuberculous meningitis-Pathophysiology• Many of the symptoms, signs, and sequelae of tuberculous meningitis (TBM) are the result of an immunologically directed inflammatory reaction to the infection. The development of TBM is a 2-step process. M. 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 McCordick.

• 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.

T1 w MRI IMAGE

Tuberculoma is the round gray mass in the left corpus callosum. The red meninges on the right are consistent with irritation and probable meningeal reaction to tuberculosis.

Tuberculomas are conglomerate caseous foci within the substance of the brain. 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).

Tuberculous meningitis-Pathophysiology

Tuberculous spinal meningitis-Clinical manifestions• Tuberculous spinal meningitis may manifest as an acute, subacute, or chronic

form.• The clinical picture in primary spinal meningitis is often characterized by

myelopathy, with progressive ascending paralysis, eventually resulting in basal meningitis and associated sequelae.

• In some cases with acute onset, in addition to variable constitutional symptoms, patients develop acute paraplegia with sensory deficits and urinary retention. The clinical picture often mimics transverse myelitis or Guillain-Barré syndrome.

• The subacute form is often dominated by myeloradiculopathy, with radicular pain and progressive paraplegia or tetraplegia.

• A less virulent chronic form might mimic a very slowly progressive spinal cord compression or a nonspecific arachnoiditis.

• The dorsal cord seems to be affected most commonly, followed by the lumbar and the cervical regions.

T2-weighted magnetic resonance image of the thoracic spinal cord of a patient with 2 hyperintense intramedullary tuberculomas.

Brain and spine Tuberculosis-Neuroimaging

• In the tuberculous process, the spinal meninges may be involved, owing to the spread of infection from intracranial meningitis, primary spinal meningitis in isolation as a result of a tuberculous focus on the surface of the cord rupturing into the subarachnoid space, or transdural extension of infection from caries of the spine.

• Pathologically, a gross granulomatous exudate fills the subarachnoid space and extends over several segments. Vasculitis involving arteries and veins occurs, sometimes resulting in ischemic spinal cord infarction.

• The earliest lesion in the vertebra is invariably due to hematogenous spread, often involving the body of the vertebra near an intervertebral disk. The intervertebral disk is almost always involved with the spread of the disease to the adjacent vertebra and eventually along the anterior or posterior longitudinal ligaments or through the end plate. Soon, a cold abscess develops, either as a paraspinal abscess in the dorsal and lumbar regions or as a retropharyngeal abscess in the cervical region. As the disease progresses, increasing decalcification and erosion result in progressive collapse of the bone and destruction of intervertebral disks, involving as many as 3-10 vertebrae in one lesion, resulting in kyphosis. The abscess may rupture intraspinally, resulting in primary spinal meningitis, hyperplastic peripachymeningitis, intraspinal abscess, or tuberculoma.

Tuberculous spinal meningitis -Pathophysiology

Tuberculous spondylitis-Clinical manifestions• Tuberculous spondylitis is also known as Pott disease or spinal caries.• In regions where the disease is endemic, such as Asia and Africa, this condition

still accounts for 30-50% of all cases of compressive myelopathy resulting in paraplegia. Spinal TB also accounts for approximately 50% of all bone and joint TB cases.

• In the lumbar region, tuberculous spondylitis may result in a psoas abscess that often calcifies.

• It usually runs a subacute or a chronic course, with back pain and fever and variable neurological deficits.

• Spondylitis can also result in various symptoms, including local and radicular pain, limb motor and sensory loss, and sphincter disturbances.

• Eventually, complete spinal cord compression with paraplegia, the most dreaded complication, may supervene.

Brain and spine Tuberculosis-Diagnosis• Diagnosis of TB meningitis is made by analyzing cerebrospinal fluid collected

by lumbar puncture. The CSF usually has a high protein, low glucose and a raised number of lymphocytes. Acid-fast bacilli are sometimes seen on a CSF smear, but more commonly, M. tuberculosis is grown in culture. A spider-web clot in the collected CSF is characteristic of TB meningitis, but is a rare finding.

• Culture for M tuberculosis; takes 2 weeks (50-80% of known cases of TBM yield positive results). More than half of cases of TB meningitis cannot be confirmed microbiologically, and these patients are treated on the basis of clinical suspicion only before the diagnosis is confirmed..

• Polymerase chain reaction (PCR): Results imply that PCR can provide a rapid and reliable diagnosis of TBM, although false-negative results potentially occur in samples containing very few organisms.

• Differential diagnosis: Cryptococcal antigen and herpes antigen testing; Syphilis serology

T2-weighted magnetic resonance image of a patient with a tuberculoma in the right parietal lobe.

Brain and spine Tuberculosis-Neuroimaging

Brain and spine Tuberculosis-Treatment• The treatment of TB meningitis is isoniazid, rifampicin, pyrazinamide and

ethambutol for two months, followed by isoniazid and rifampicin alone for a further ten months. Corticosteroids are always used in the first six weeks of treatment when cerebral edema, subarachnoid block, or both occur.

• Treatment must be started as soon as there is a reasonable suspicion of the diagnosis. Treatment must not be delayed while waiting for confirmation of the diagnosis.

Surgical Care• Hydrocephalus occurs as a complication in about a third of patients with TB

meningitis and will require placement of a ventriculoperitoneal shunt.• Mortality/Morbidity• Death follows within weeks in untreated CNS tuberculosis. Mortality is greatest

at the extremes of age 20% at <5 years of age and 60% at>50 years or if illness has been present more than 2 months (80%)

Progressive multifocal leukoencephalopathy • PML is caused by reactivation of the endemic JC papovavirus

(polyomavirus). As many as 90% of healthy individuals have serum antibodies to this virus, but less than 10% show any evidence of ongoing viral replication.

• Progressive multifocal leukoencephalopathy (PML) occurs almost exclusively in AIDS patients.

• As many as 90% of healthy individuals have serum antibodies to this virus, but less than 10% show any evidence of ongoing viral replication.

• At present, PML develops in as many as 5% of all patients with AIDS-PML is an AIDS-defining illness.

Progressive multifocal leukoencephalopathy Pathology • Multiple demyelinative lesions are generally

located in the cerebral white matter. Spinal cord involvement is rare.

This sliced fixed brain shows multiple isolated or confluent gray demyelinative foci. Atrophy may be present.

Progressive multifocal leukoencephalopathy-Pathology-demyelinative foci

Progressive multifocal leukoencephalopathy Mortality/Morbidity• In the pre-HAART (Highly Active Antiretroviral therapy- three to four anti-

virals taken in combination) era, the prognosis of PML was dismal, with death occurring within 4-6 months after diagnosis.

Clinical Manifestations• Present with rapidly progressive focal symptoms including behavioral, speech,

cognitive impairment, hemiparesis, and visual impairment. Focal signs tend to be related to posterior brain (eg, occipital lobes).

• Late in the course abnormalities may progress to quadriparesis, cortical blindness, profound dementia and coma.

Diagnosis• PCR• Brain biopsy has a sensitivity of 74-92% and a specificity of 92-100%.• CSF cell count and chemistry usually normal

Contrast-enhanced T1-weighted MRI demonstrates a hypointense lesion predominantly in a subcortical, left frontoparietal location. Note the characteristic absence of enhancement and lack of mass effect.

PML-Neuroimaging

Fluid-attenuated inversion recovery (FLAIR) MRI shows a PML lesion with improved contrast after the suppression of cerebrospinal fluid signal intensity.

PML-Neuroimaging

Nonenhanced CT of the head shows a hypoattenuating lesion in the subcortical white matter. Note the characteristic scalloped lateral margin.

PML-Neuroimaging

Fluid-attenuated inversion recovery (FLAIR) images in a patient with HIV infection presenting with visual defects, aphasia, and balance problems. Patchy, confluent, and hyperintense lesions are seen in the left occipitotemporoparietal lobes in the subcortical and periventricular white matter. The patient's clinical and radiologic features suggested progressive multifocal leukodystrophy, though cerebrospinal fluid results for the JC virus were negative.

PML-Neuroimaging

Neuro-Cyptococcosis Cryptococcal meningitis -a leading cause of infectious morbidity and mortality in patients with AIDS.

Among AIDS/HIV subjects, cryptococcal meningitis is the second (1st being tuberculous meningitis) most common cause of opportunistic neuro-infection. Cryptococcal meningitis occurs in non-HIV patients who are immunodeficient due to diabetes, cancer, solid organ transplants, chemotherapeutic drugs, hematological malignancies etc and rarely in healthy individuals with no obvious predisposing factors.

Cryptococcal meningitis is the most common form of fungal meningitis and is caused by Cryptococcus neoformans . C. neoformans is Soil fungus associated with pigeon and chicken droppings. Seroypes A and D and AD hybrids are globally responsible for 98% of all cryptococcal infections in patients with AIDS.

Cryptococcus neoformans

Neuro-Cyptococcosis-Pathogenesis The fungus enters the human body through inhalation into the lungs. In the alveoli, the yeasts come

into contact with alveolar macrophages, which elicit an inflammatory response. This pulmonary infection is often asymptomatic but the organism may disseminate to other organs depending on the immune status of the individual. The cerebrospinal fluid is an ideal site for infection as it lacks complements and immunoglobulins.

Neuro-Cyptococcosis-Clinical manifestationsCryptococcal meningitis commonly presents as chronic or subacute meningitis.

Patients often present with severe unbearable headache with or without fever that is often severe enough to interfere with day-to-day activities. Headache may be accompanied by vomiting and at times, there can be transient visual obscurations due to raised intracranial tension. In some instances, severe headache almost mimics headache associated with subarachnoid hemorrhage. The exact mechanism for such severe headache is not known, but it may due to meningeal involvement / raised intracranial tension / or sino-venous thrombosis. Seizures are seen in < 8% of cases. Examination is usually unremarkable except for papilledema. Neck stiffness is seen in only 30% of the cases. One third of the patients can have disseminated infection with the involvement of the lungs, kidney or skin. A careful search for cutaneous cryptococcal lesions can be rewarding in some cases of suspected cryptococcal meningitis. Cranial neuropathies, especially of the lower cranial nerves, affecting one or more cranial nerves (II, VII, VIII, IX, X, XII) occur in isolated cases secondary to basal arachnoiditis or due to hydrocephalus.

Neuro-Cyptococcosis-Pathology

Opaque thick fibrotic CSF obstruction - hydrocephalus. Gelatinous material within the subarachnoid space and small cysts within the parenchyma ("soap bubbles“) Specially in the basal ganglia.

The nature and duration of treatment for cryptococcal infection is based on the immunity of the host and anatomic sites of involvement. For immunocompetent individuals with cryptococcal meningitis, the standard therapy consists of amphotericin B 0.7-1.0 mg/kg/day along with 5-flucytosine 100 mg/kg/day for 6-10 weeks. An alternative to this regimen is amphotericin B 0.7-1.0 mg/kg/day plus 5-flucytosine 100 mg/kg/day for two weeks, followed by fluconazole 400mg/day for a minimum of ten weeks. Fluconazole "consolidation" therapy may be continued for as long as 6-12 months, depending on the clinical status of the patient. For patients with HIV infection and cryptococcal meningitis, induction therapy with amphotericin B 0.7-1.0 mg/kg/day plus 5-flucytosine 100 mg/kg/day is given for two weeks, followed by fluconazole 400mg/day for a minimum of ten weeks. After ten weeks of therapy, the fluconazole dosage may be reduced to 200 mg/day, depending on the clinical status of the patient.  Fluconazole should be continued for life or at least up to the time the CD4+ count reaches 350/cmm.

Neuro-Cyptococcosis-Treatment

Elevated intracranial pressure occurs in up to 75% of the patients with cryptococcal meningitis and is an important contributor to mortality and morbidity. Treated aggressively-percutaneous lumbar drainage or ventriculoperitoneal shunting or acetazolamide. In patients with normal baseline opening pressure (< 200 mm H 2 O), a repeat lumbar puncture should be performed two weeks after the initiation of therapy to exclude elevated pressure and to evaluate culture status.

PrognosisThe majority of the patients with cryptococcal meningitis improve with adequate therapy. Mortality is seen in about 10% of the cases while morbidity is unusual. Mortality is more common in HIV-positive individuals.

Neuro-Cyptococcosis-Treatment

T2 MRI Multicystic form of cerebral cryptococcosis: lesions in basal ganglia and cerebellum 

Neuro-Cyptococcosis-Neuroimaging

T2 W MRI Small cystic lesions in basal ganglia 

Neuro-Cyptococcosis-Neuroimaging

CNS cryptococcosis: brain MRI findings (A) Axial T2 sequence showing bilateral pseudocysts as hyperintensities (arrowheads) predominantly involving the basal ganglia. The pseudocysts are thick walled and septated with a proteinaceous content depicted by their relative hyperintensity compared to CSF. (B) Post-gadolinium MRI sequences showing little to no enhancement of the cysts or surrounding parenchyma.

Neuro-Cyptococcosis-Neuroimaging

NocardiosisNocardiosis is an acute, subacute, or chronic infectious disease that occurs in cutaneous, pulmonary, and disseminated forms. Disseminated nocardiosis may involve the brain or meninges, usually from a pulmonary focus. Most persons with disseminated nocardiosis have underlying immunocompromising disease or are receiving immunosuppressive therapy.

PathophysiologyMembers of the genus Nocardia are aerobic actinomycetes that are ubiquitous saprophytes in soil, decaying organic matter, and water. Nocardia asteroides is responsible for most cases of Nocardia disease among humans.

High-power microscopic appearance of Nocardia. 

NocardiosisDiagnosisBrain biopsy is the most reliable diagnostic technique if the diagnosis cannot be made by evaluation of pulmonary or skin lesion.

Nocardiosis-Clinical manifestations •CNS nocardiosis is detected in 20-40% of disseminated nocardial infections. CNS nocardiosis manifests as a slowly progressive mass lesion, with a host of specific neurologic findings related to the specific location of the abscess.

•In two thirds of patients with CNS nocardiosis, clinical findings indicate abscess with or without meningitis, including fever, headache, stiff neck, altered consciousness and/or altered mental status, personality changes, or various localizing neurologic findings.

Brain MRI scan in a patient with nocardial brain abscess.

Nocardiosis-Treatment  

Sulfonamides have long been the first-line antimicrobial therapy for nocardiosis. Among the sulfonamides, sulfadiazine is generally preferred because of its CNS and CSF penetration. Alternative parenteral therapies include meropenem, third-generation cephalosporins (cefotaxime or ceftriaxone), and , alone or in combination. Meropenem plus amikacin (synthetic aminoglycoside) may be the preferred regimen. Surgery-Needle aspiration or surgical excision needed in most.Relapse common

Mortality/Morbidity•Cure rates with appropriate therapy are approximately 100% in skin and soft-tissue infections.•Ninety percent of pleuropulmonary infections can be cured with appropriate therapy.•The cure rate in disseminated nocardiosis falls to 63%, while only half of patients with brain abscess can be cured with therapy.

sulfadiazine meropenem amikacin

Listeriosis is a bacterial infection caused by a gram-positive, motile bacterium, Listeria monocytogenes. Listeriosis is relatively rare and occurs primarily in newborn infants, elderly patients, and patients who are immunocompromised.

Epidemiology Incidence in 2004–2005 was 2.5–3 cases per million population, where pregnant women

accounted for 30% of all cases. Of all nonperinatal infections, 70% occur in immunocompromised patients.

Etiology Listeria monocytogenes is ubiquitous in the environment. The main route of acquisition of

Listeria is through the ingestion of contaminated food products. Listeria has been isolated from raw meat, dairy products, vegetables, and seafood. Soft cheeses, unpasteurized milk and unpasteurised pâté are potential dangers.

Diagnosis In CNS infection cases, Listeria monocytogenes can often be cultured from the blood, and

always cultured from the CSF. There are no reliable serological or stool tests.

Listeriosis

There are four distinct clinical syndromes: Infection in pregnancy: Listeria can proliferate asymptomatically in the vagina and uterus. If the

mother becomes symptomatic, it is usually in the third trimester. Symptoms include fever, myalgias, arthralgias and headache. Miscarriage, stillbirth and preterm labor are complications of this infection. Symptoms last 7-10 days.

Neonatal infection (granulomatosis infantisepticum): There are two forms. One, an early-onset sepsis, with Listeria acquired in utero, results in premature birth. Listeria can be isolated in the placenta, blood, meconium, nose, ears, and throat. Another, late-onset meningitis is acquired through vaginal transmission, although it also has been reported with caesarean deliveries.

Central nervous system (CNS) infection: Listeria has a predilection for the brain parenchyma, especially the brain stem, and the meninges. It can cause cranial nerve palsies, encephalitis, meningitis, meningoencephalitis and abscesses. Mental status changes are common. Symptoms of meningitis are headache, stiff neck, confusion, loss of balance, and convulsions. Seizures occur in at least 25% of patients.

Gastroenteritis: L. monocytogenes can produce food-borne diarrheal disease, which typically is noninvasive. The median incubation period is 21 days, with diarrhea lasting anywhere from 1–3 days. Patients present with fever, muscle aches, gastrointestinal nausea or diarrhea, headache, stiff neck, confusion, loss of balance, or convulsions.

Listeriosis-Clinical manifestations

Treatment Bacteremia should be treated for 2 weeks, meningitis for 3 weeks, and brain

abscess for at least 6 weeks. Ampicillin generally is considered antibiotic of choice; gentamicin is added frequently for its synergistic effects. Overall mortality rate is 20–30%; of all pregnancy-related cases, 22% resulted in fetal loss or neonatal death, but mothers usually survive.

Listeriosis

Cysticercosis, is an infection which results from the ingestion of the eggs of the pork tapeworm, Taenia solium. The eggs are usually found in fecally-contaminated water or food. Autoinfection as a result of the entry of eggs into stomach due to retroperistalsis or as a result of accidental ingestion of eggs from the host's own feces due to contaminated hands is also possible. The incubation period ranges from months to over ten years. Neurocysticercosis, is when the brain or spinal cord is affected by the larval stage of T. solium (cysticercus) , neurocysticercosis is the most common helminthic (tapeworm) infestation to affect the CNS worldwide and is the prime cause of acquired epilepsy.

Neurocysticercosis

T. Solium adult worm stage

In the case of cysticerci in the brain parenchyma, four major stages have been classified: In stage 1, immature cysts appear within 1–4 weeks during which the oncosphere lodges to the

brain and finally expands into a cyst. It is mainly asymptomatic, although flu-like illness, rare seizures, rare increased intracranial pressure from massive infestation has been recorded.

In stage 2, the cysticerci become mature and viable about 2 months after egg ingestion. The cyst possesses a protoscolex with the cyst bladder and causes no or minimal surrounding inflammation or edema. The cysticerci also down-regulate host cellular immunity. Stage 2 cysts are also asymptomatic, and can persist for more than 10 years.

Stage 3 is typified by colloid or degenerating cysts with thick cystic fluid, thickened capsule, and appear two to 10+ years after the cyst becomes mature. The cyst no longer prevents a host immune response and its antigens leak from the bladder wall. The intense inflammation is provoked around the degenerating cyst. Most patients bearing stage 3 develop clinical signs and symptoms such as seizures, occasional focal neurological signs, headaches, nausea, vomiting, lethargy from increased intracranial pressure and altered mental status.

At stage 4, the cyst is calcified. The surrounding inflammation drops since the dead cyst no longer produces foreign antigens. Common clinical features includes persistent non-provoked seizures although most of the patients are asymptomatic.

Neurocysticercosis-Pathophysiology

IncidenceNCC is endemic in Central and South America, sub-Saharan Africa, and in some regions of

the Far East, including the Indian subcontinent, Indonesia, and China, reaching an incidence of 3.6% in some regions. It is rare in Eastern and Central Europe, in North America (with the exception of Mexico), and in Australia, Japan, and New Zealand, as well as in Israel and in the Muslim countries of Africa and Asia. NCC is the most common parasitic infection of the CNS. Approximately 2.5 million people worldwide carry the adult tapeworm, and many more are infected with cysticerci.

Race Subcutaneous cysticercosis is more common in Asian populations than in other peoples of other areas of endemic disease.

Age Peak incidence is between ages 30 and 40 years.

MorbidityThe racemose form of NCC, which appears macroscopically as groups of cysticerci, often in

clusters that resemble bunches of grapes, located in the subarachnoid space, is associated with poor prognosis and elevated mortality rate (over 20%).

Neurocysticercosis

In meningeal cysticercosis, cysticerci often do not develop into typical cysts, and become racemose, lacking a scolex and becoming lobes in thin-walled bladders. These cysts increase and slowly leak their antigen into the subarachnoid CSF producing meningitis and can further develop into arachnoiditis, which may lead to obstructive hydrocephalus, cranial nerve involvement, intracranial hypertension, arterial thrombosis and stroke. In intraventricular cysticercosis, the cysts occur in the lateral, third or fourth ventricles which may be asymptomatic or if they block the flow of CSF, they may cause increased intracranial pressure. Because the larvae are relatively large, they may lodge in the subarachnoid space, ventricles, or brain tissue. Cysts in the subarachnoid space may result in chronic meningitis, cysts in the ventricular system may lead to obstruction hydrocephalus, and cysts in the cerebrum may mimic brain tumors.

Neurocysticercosis-Pathophysiology

NCC is a pleomorphic disease, although it sometimes produces no clinical manifestation. This pleomorphism is due to variations in the locations of the lesions, the number of parasites, and the host's immune response.

•Many patients are asymptomatic; others report vague symptoms such as headache or dizziness. •The onset of symptoms is usually subacute to chronic, with the exception of seizures, which present in an acute fashion. Patients

may present with the following:Epilepsy Epilepsy is the most common presentation (70%) and is also a complication of the disease. NCC is the leading cause of adult-onset epilepsy and is probably one of the most frequent causes of childhood epilepsy in the

world. Seizures secondary to NCC may be generalized or partial. Simple and complex partial seizures may be associated with the

presence of a single lesion. Generalized seizures are usually tonic-clonic; this is thought to be related to the presence of multiple lesions. However, irritation of focal cortical tissue by one of the lesions most probably leads to focal onset with secondary generalization. Myoclonic seizures also have been described.

Headache Chronic headaches associated with nausea and vomiting (simulating migraines) Headaches associated with intracranial hypertension and indicative of hydrocephalus Intracranial hypertension Most often, intracranial hypertension is due to obstruction of cerebrospinal fluid (CSF) circulation caused by basal or ventricular

cysticercosis. It may also result from large cysts displacing midline structures, granular ependymitis, arachnoiditis, or the so-called cysticercotic encephalitis caused by the inflammatory response to a massive infestation of cerebral parenchyma with cysticerci.

These patients may have seizures and deterioration of their mental status, mainly due to the host's inflammatory reaction as an exaggerated response to the massive infestation.

Neurocysticercosis-Clinical Manifestations

Strokes Ischemic cerebrovascular complications of NCC include lacunar infarcts and large cerebral infarcts due to occlusion or vascular damage. Hemorrhage also can occur, and has been reported as a result of rupture of mycotic aneurysms of the basilar artery. Strokes may be responsible for the following signs and symptoms: paresis or plegias, involuntary movements, gait disturbances, or paresthesias.

Neuropsychiatric disturbances• These range from poor performance on neuropsychological tests to severe dementia.• These symptoms appear to be related more to the presence of intracranial hypertension than to the number or location of parasites in the brain.

Diplopia: This is a result of intracranial hypertension or arachnoiditis producing entrapment or compression of cranial nerves III, IV, or VI.

Hydrocephalus Ten to thirty percent of patients with NCC develop communicating hydrocephalus due to inflammation and fibrosis of the arachnoid villi or inflammatory

reaction to the meninges and subsequent occlusion of the foramina of Luschka and Magendie. Noncommunicating hydrocephalus may be a consequence of intraventricular cysts. Other forms of neurocysticercosis

Intrasellar neurocysticercosis: Patients present with ophthalmologic and endocrinologic manifestations mimicking those of pituitary tumors.

Spinal NCC: This is rare. Spinal NCC may be either intramedullary or extramedullary. The latter is the most frequent and is responsible of symptoms of spinal dysfunction such as radicular pain, weakness, and paresthesias. Intramedullary presentation may cause paraparesis, sensory deficits with a level, and sphincter disturbances.

Ocular cysticercosis: This occurs most commonly in the subretinal space. Patients may present with decreased visual acuity, visual field defects, or monocular blindness.

Neurocysticercosis-Clinical Manifestations

Neurocysticercosis-Neuroimaging

CT scans showing different phases of neurocysticercosis.Top left: CT scan showing many calcifications and active cysts with scolices in both hemispheres.Top right: T1-weighted MRI showing 2 active cysts with the scolex in their interior (vesicular phase).Bottom left: Postcontrast CT scan showing a ring-enhancing cyst (colloidal phase) on left.Bottom right: Proton density-weighted MRI showing a thick capsule with adjacent scolex and perilesional edema (colloidal phase).

Neurocysticercosis-Neuroimaging

Neuroimaging in neurocysticercosis. Cysticercotic encephalitis.Left: Contrast-enhanced CT scan showing multiple, small, nodular, and annular areas of abnormal enhancement in brain parenchyma.Right: Gadolinium-enhanced T1-weighted MRI showing hyperintense lesions.

Antihelminthic drugs (Albendazole or praziquantel) and corticosteroids or surgery. Surgical treatment includes direct excision of ventricular cysts, shunting procedures, and removal of cysts via endoscopy. In the case of brain parenchymal cysticercosis, treatment depends on the stage of cyst development. In immature cyst stage (stage 1), high-dose corticosteroids are administered to reduce the edema but antihelminthic drugs have been found to be harmful. Vesicular or viable cysts (stage 2) are often asymptomatic, and usually are not treated with antihelminthic drugs, while surgical removal of the cyst, along with albendazole is indicated in the colloid cyst stage (stage 3). No antihelminthic treatment is administered in dead calcified cysts stage (stage 4).

Neurocysticercosis-Management and Therapy

ToxoplasmosisToxoplasmosis is a parasitic disease caused by the protozoan Toxoplasma gondii. Up to one third of the world's human population is estimated to carry a Toxoplasma infection.

Clinical manifestationsFour major T. gondii clinical syndromes occur: congenital, ocular, lymphadenopathic, and severe neurologic or disseminated diseases.

Acute toxoplasmosisDuring acute toxoplasmosis, symptoms are often influenza-like: swollen lymph nodes, or muscle aches and pains that last for a month or more. Rarely, a patient with a fully functioning immune system may develop eye damage or nasal lesions from toxoplasmosis. After the first few weeks of infection have passed, the parasite rarely causes any symptoms in otherwise healthy adults. However, subjects with HIV/.AIDS or those who are pregnant, may become seriously ill. Infants infected via placental transmission may be born with either of these problems, or with nasal malformations. Acute toxoplasma infection can leads to psychotic symptoms similar to schizophrenia.

Latent toxoplasmosisIn most immunocompetent patients, the infection enters a latent phase, during which only bradyzoites are present, forming cysts in nervous and muscle tissue. Occurs in 50% of immunocompromised patients. Diffuse encephalitis, meningoencephalitis, or focal cerebral mass lesions are common presentations in patients with AIDS or HIV with toxoplasmosis.

Toxoplasmosis-TransmissionToxoplasma eggs are shed in cat feces. After their release in the soil, these eggs require 24 hours to become infectious. Cats excrete the pathogen in their faeces for a number of weeks after contracting the disease, generally by eating an infected rodent. Intermediate hosts (dogs, rodents, food animals, and humans) become contaminated by ingesting Toxoplasma eggs. In the soil, the eggs can remain infectious for more than 1 year. Ingestion of raw or partly cooked meat, especially pork, lamb, or venison containing Toxoplasma cysts. Infection prevalence in countries where undercooked meat is traditionally eaten has been related to this transmission method. Oocysts may also be ingested during hand-to-mouth contact after handling undercooked meat, or from using knives, utensils, or cutting boards contaminated by raw meat. Pregnancy precautionsCongenital toxoplasmosis is a special form in which an unborn child is infected via the placenta. A positive antibody titer indicates previous exposure and immunity and largely ensures the unborn baby's safety. A simple blood draw at the first pre-natal doctor visit can determine whether or not the woman has had previous exposure and therefore whether or not she is at risk.

ToxoplasmosisDiagnosisThe indirect fluorescent Ab test measuring IgG Ab is the most widely used diagnostic tool. Detection of T. gondii in human blood samples may be also achieved by using the PCR.

Treatment Acute•Pyrimethamine (antimalarial) 4-6 weeks•Sulfadiazine -in combination with pyrimethamine.•Clindamycin •Cotrimoxazole or spiramycin-used for pregnant women to prevent the infection of their child.Latent•In latent toxoplasmosis, the cysts are immune to these treatments, as the antibiotics do not reach the bradyzoites in sufficient concentration.•Atovaquone - used to kill Toxoplasma cysts in AIDS patients. •Clindamycin - in combination with atovaquone

Pyrimethamine

spiramycin

Atovaquone

Clindamycin

Toxoplasmosis-Pathology

CNS toxoplasmosis, which has a propensity for involvement of the basal ganglia.

T2-weighted coronal magnetic resonance image at the level of the insulae in a patient with human immunodeficiency virus infection and central nervous system toxoplasmosis. The image shows large, bilateral hyperintense lesions (almost symmetrically placed on either side of the third ventricle and/or lateral ventricle) (arrows). Note the slight mass effect on the right lateral ventricle (V).

Toxoplasmosis-Neuroimaging

T1-weighted axial brain magnetic resonance image at the level of the basal ganglia in a 24-year-old man with human immunodeficiency virus infection. The image shows hypointense lesions in the region of the thalami (arrows) caused by toxoplasmosis.

Toxoplasmosis-Neuroimaging

T1-weighted gadolinium-enhanced magnetic resonance image at the level of the fourth ventricle in a 32-year-old patient with human immunodeficiency virus infection. The image shows a peripheral, right frontoparietal ring-enhancing lesion (arrow). The patient presented with a solitary space-occupying lesion, which was confirmed to be secondary to toxoplasmosis.

Toxoplasmosis-Neuroimaging

T1-weighted axial gadolinium-enhanced magnetic resonance images at 2 levels through the basal ganglia (same patient as in the previous image). These images show 2 complex, ring-enhancing lesions in the basal ganglia on the right, with surrounding notable white matter edema. This appearance is typical of central nervous system toxoplasmosis, which has the propensity for involvement of the basal ganglia.

Toxoplasmosis-Neuroimaging

Prion Related Diseases•The prion diseases are a large group of related neurodegenerative conditions, which affect both animals and humans. •Prion diseases are unique in that they can be inherited, they can occur sporadically, or they can be infectious. •These diseases all have long incubation periods but are typically rapidly progressive once clinical symptoms begin.

Disease Host MechanismKuru Human CannibalismSporadic CJD Human Spontaneous PrPC to PrPSc

conversion or somatic mutationIatrogenic CJD Human Infection from prion-containing

materialFamilial CJD Human Mutations in the PrP genevCJD Human Infection from BSEGSS Human Mutations in the PrP geneFFI Human D178N mutation in the PrP

gene, with M129 polymorphismSporadic fatal insomnia Human Spontaneous PrPC to PrPSc

conversion or somatic mutationScrapie Sheep Infection in susceptible sheepBSE Cattle Infection from contaminated

food

Table. Prion-Related Diseases, Hosts, and Mechanism of Transmission

  The infectious agent in the prion disease is composed mainly or entirely of an abnormal conformation of a host-encoded glycoprotein called the prion protein. PrPC is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein. PrP is found in most tissues of the body but is expressed at highest levels in the CNS, in particular in neurons. The replication of prions involves the recruitment of the normally expressed prion protein, which has mainly an alpha-helical structure, into a disease-specific conformation that is rich in beta-sheet, initiating a self-perpetuating vicious cycle. A unifying feature of all the prionoses is their neuropathology. These illnesses tend to affect the gray matter, producing neuronal loss affecting the cerebral hemispheres and cerebellum, gliosis, and characteristic spongiform change. In approximately 10% of patients with CJD, amyloid is present in the cerebellum or in the cerebral hemispheres.

Prion Related Diseases-Pathophysiology

Prion-related diseases. Spongiform change in prion disease. This section shows mild parenchymal vacuolation and prominent reactive astrocytosis.

  

TransmissionPrion diseases are transmitted naturally by peripheral routes, either orally or transcutaneously •Spread of prions to the CNS via lymphoid organs or hematogenic.•Prion diseases may spread by iatrogenic means. Hence, take care not to reuse EEG and/or electromyography (EMG) needles, surgical instruments that have been exposed to a patient with prion disease. The prion agent is remarkably resistant to inactivation; hence, routine sterilization procedures, such as autoclaving, are ineffective.•Ten percent of cases of CJD are familial, with an autosomal dominant pattern of inheritance linked to mutations in the PrP gene.FrequencyThe most common prion disease is CJD, with a uniform incidence of approximately 1 case per million population internationally. Familial forms of prion diseases, such as GSS and fatal familial insomnia (FFI), are much more rare. As of February 2006, 159 cases of definite or probable vCJD have been reported in the United Kingdom of which 153 persons have died.Mortality/MorbidityPrion-related diseases are relentlessly progressive and invariably lead to death.The mean duration of sporadic CJD is 8 months.vCJD has a slightly longer course, with a mean duration of 14 months.Familial CJD has a mean duration of 26 months, while GSS has the longest course, about 60 months.AgeThe mean age of onset of sporadic CJD is 62 years. vCJD occurs in younger patients, with a mean age of onset of 28 years.Familial CJD, GSS, and FFI have mean ages of onset ranging from 45-49 years.

Prion Related Diseases

  

CJDBy far the most common human prion disease is CJD, accounting for about 85% of all human prion disease. Clinically, CJD is characterized by a rapidly progressive dementia associated with myoclonic jerks, as well as a variable constellation of pyramidal, extrapyramidal, and cerebellar signs. The EEG findings typically show distinctive changes of high-voltage slow (1-2 Hz) and sharp wave complexes on an increasingly slow and low-voltage background.  

•Sporadic CJD is characterized by a rapidly progressive multifocal neurological dysfunction, myoclonic jerks, a terminal state of global severe cognitive impairment, and death in about 8 months.•About 40% of patients with sporadic CJD present with rapidly progressive cognitive impairment, 40% with cerebellar dysfunction, and the remaining 20% with a combination of both.•The clinical picture rapidly expands to include behavioral abnormalities, higher cortical dysfunction, cortical visual abnormalities, cerebellar dysfunction, and both pyramidal and extrapyramidal signs.•Almost all patients with sporadic CJD develop myoclonic jerks that involve either the entire body or a limb. These myoclonic jerks can occur spontaneously or can be precipitated by auditory or tactile stimulation.

Variant Creutzfeldt-Jakob disease (vCJD)A recent epidemic of a new prionosis has occurred; BSE has led to more then 160,000 cattle deaths in the United Kingdom. This new disease is thought to be caused by meat and bone meal dietary supplements to cattle that were contaminated with scrapie-infected sheep and other cattle with BSE. Extensive evidence suggests that BSE has also lead to a new type of CJD, called variant CJD.

Prion Related Diseases-Clinical Manifestations

  

Imaging StudiesMRI is an important imaging test. MRI may show hyperintense signals in the cortical ribbon, basal ganglia, and the thalamus on diffusion-weighted images (DWI) and fluid-attenuated inversion recovery (FLAIR) images. Two characteristic radiological signs have been described. The "hockey stick" sign, which refers to increased signal in the putamen and head of the caudate nucleus resembling a hockey stick, and the "pulvinar" sign, which corresponds to a usually bilaterally increased signal in the pulvinar thalamic nuclei. The latter sign has been found especially in patients with vCJD.Other Tests•Perform an EEG.During the course of sporadic CJD, most patients develop a characteristic picture on EEG with periodic or pseudoperiodic paroxysms of sharp waves or spikes on a slow background. These periodic complexes have a sensitivity and specificity of 67% and 87% respectively on a single EEG. However, if repeated recordings are obtained, more then 90% of patients show periodic EEG abnormalities.

0.5-1 Hz periodic sharp waves focally or diffusely.oIn vCJD, EEG does not show the typical changes observed in sporadic CJD, and findings often are normal.Perform lumbar puncture (LP) in all suspected cases.Check the opening pressure.Evaluate the cerebrospinal fluid (CSF) for cell count, protein, glucose, bacterial cultures, viral cultures, VDRL, cryptococcal antigen, and acid-fast bacilli (AFB).CSF is typically normal in sporadic CJD, although the CSF protein may be elevated slightly (but never >100 mg/dL).

Prion Related Diseases -Diagnosis

Shows characteristic signal changes of an MRI taken from a patient with sporadic CJD, using diffusion-weighted imaging (DWI). An abnormal signal is shown in both the basal ganglia (red arrows) and the cortical ribbon (yellow arrow).

 

 Alzheimer DiseaseCortical Basal Ganglionic DegenerationDementia in Motor Neuron DiseaseFrontal and Temporal Lobe DementiaHerpes Simplex EncephalitisHIV-1 Encephalopathy and AIDS Dementia ComplexHydrocephalusInherited Metabolic DisordersMulti-infarct DementiaMultiple System AtrophyNonherpes viral encephalitisDiffuse Lewy body diseaseChronic meningitisDementia as a paraneoplastic syndromeFamilial myoclonic dementiaLithium poisoning

TreatmentAll prion diseases are fatal; no effective treatment is available. Patients are currently provided symptomatic treatment. Hence, some patients with CJD who develop seizures should be administered antiepileptic drugs, while those with extrapyramidal symptoms should be administered anti-Parkinson drugs.

Prion Related Diseases-Differential Diagnoses

  

KuruSeveral different forms of prion disease exist. The first human prionosis to be described is called kuru. This is an illness of the Fore people living in the highlands of New Guinea that is thought to be linked to ritualistic cannibalism. Presumably, this illness originated with the consumption of an initial patient with sporadic CJD. Kuru was once the major cause of death among Fore women. Women had a greater tendency than men to develop kuru because it was part of the ritual cannibalism for women to eat the brains (and neural tissue has the highest dose of PrPSc). However, the disease has virtually disappeared with the end of cannibalistic rituals. Similar to scrapie, patients clinically present with difficulty walking and they develop progressive signs of cerebellar dysfunction. Death occurs approximately 1 year following onset of symptoms.

Gerstmann-Strãussler-Scheinker disease Patients with this illness present with a slowly progressive limb and truncal ataxia, as well as dementia.The prominent involvement of the brainstem often leads to symptoms suggestive of olivopontocerebellar degeneration. The pattern of inheritance is autosomal dominant and is caused by mutations of the PrP gene. The neuropathology of GSS is remarkable in that extensive and invariable amyloid deposition occurs, in addition to the typical spongiform change, gliosis, and neuronal loss. Interestingly, in several kindreds of GSS, extensive neurofibrillary tangle (NFT) formation is found. NFTs are an essential feature of Alzheimer disease, but are also observed in other neurodegenerative conditions.

Another variation of autosomal dominantly inherited human prionosis has been termed prion protein congophilic angiopathy (ie, prion protein cerebral amyloid angiopathy [PrP-CAA]), which is characterized by cerebral vessel amyloid deposition and the presence of NFT. Cerebral amyloid angiopathy (CAA) is also an essential feature of Alzheimer disease. Both these variants of prionoses further link the pathogenesis of Alzheimer disease and the prion-related diseases.

Other Prion Related Diseases

Tetanus, 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. As the infection progresses, muscle spasms develop in the jaw (thus the name "lockjaw") and elsewhere in the body.

Tetanus

Risus sardonicus is a highly characteristic, abnormal, sustained spasm of the facial muscles that appears to produce grinning. The name of the condition derives from the appearance of raised eyebrows and an open "grin" - which can appear malevolent to the lay observer - displayed by those suffering from these muscle spasms.

Opisthotonos (o-pis-to-ton-is)

The rough surface of rusty metal provides a prime habitat for a C. tetani endospore to reside, and the metal affords a means to puncture skin and deliver endospore into the wound. Tetanus begins when spores of C. tetani enter damaged tissue. The spores transform into rod-shaped bacteria and produce the neurotoxin tetanospasmin (aka tetanus toxin). It binds to the neuromuscular junction and then attaches to peripheral motor neuron nerve endings. It travels centrally up the nerve in by retrograde axonal transport to the anterior horn cells, where it enters adjacent spinal inhibitory interneurons, blocking inhibitory neurotransmitter release to the anterior horn cell. Damaged upper motor neurons can no longer inhibit lower motor neurons. This leads to the classic muscular hypertonia and muscle spasms.

Tetanus-Pathophysiology

The incubation period of tetanus may be up to several months but is usually about 8 days. In general, the further the injury site is from the CNS, the longer the incubation period.

Generalized tetanus is the most common type of tetanus, representing about 80% of cases. The generalized form usually presents with a descending pattern. The first sign is trismus, or lockjaw, and the facial spasms called risus sardonicus, followed by stiffness of the neck, difficulty in swallowing, and rigidity of pectoral and calf muscles. Other symptoms include elevated temperature, sweating, elevated blood pressure, and episodic rapid heart rate. Spasms may occur frequently and last for several minutes with the body shaped into a characteristic form called opisthotonos. Spasms continue for up to 4 weeks, and complete recovery may take months.Neonatal tetanus is a form of generalized tetanus that occurs in newborns. Infants who have not acquired passive immunity because the mother has never been immunized are at risk. It usually occurs through infection of the unhealed umbilical stump, particularly when the stump is cut with a non-sterile instrument. Neonatal tetanus is common in many developing countries and is responsible for about 14% (215,000) of all neonatal deaths, but is very rare in developed countries. In neonatal tetanus, symptoms usually appear from 4 to 14 days after birth, averaging about 7 days. Focal tetanus is an uncommon form of the disease, in which patients have persistent contraction of muscles at the wound site. The contractions may persist for many weeks before gradually subsiding. Focal tetanus is generally milder; only about 1% of cases are fatal, but it may precede the onset of generalized tetanus.Cephalic tetanus is a rare form of the disease, occasionally occurring with otitis media (ear infections) in which C. tetani is present in the flora of the middle ear, or following injuries to the head. There is involvement of the cranial nerves, especially in the facial area.

Tetanus-Treatment-Clinical Manifestations

Mild tetanus•Tetanus immunoglobulin IV or IM,•metronidazole IV for 10 days, antibiotic that decreases the number of bacteria but has no effect on the bacterial toxin. •diazepam,•tetanus vaccination

Severe tetanusSevere cases will require admission to intensive care. In addition to the measures listed above for mild tetanus:•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 (muscle relaxants) In extreme cases it may be necessary to paralyze the patient with curare-like drugs and use a mechanical ventilator.•the autonomic effects of tetanus can be difficult to manage (alternating hyper- and hypotension, hyperpyrexia/hypothermia) and may require IV labetalol, magnesium, clonidine, ornifedipine.In order to survive a tetanus infection, the maintenance of an airway and proper nutrition are required. An intake of 3500-4000 calories, and at least 150 g of protein per day, is often given in liquid form through a tube directly into the stomach (Percutaneous endoscopic gastrostomy), or through a drip into a vein (Total parenteral nutrition). This high-caloric diet maintenance is required because of the increased metabolic strain brought on by the increased muscle activity. Full recovery takes 4 to 6 weeks because the body must regenerate destroyed nerve axon terminals.

Tetanus-Treatment

Tetanus can be prevented by vaccination with tetanus toxoid. 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.

DiagnosisThere are no blood tests that can be used to diagnose tetanus. The diagnosis is based on the presentation of tetanus symptoms. The "spatula test" is a clinical test for tetanus that involves touching the posterior pharyngeal wall with a sterile, soft-tipped instrument, and observing the effect. A positive test result is the involuntary contraction of the jaw (biting down on the "spatula"), and a negative test result would normally be a gag reflex attempting to expel the foreign object.

Tetanus-Prevention

BotulismBotulism causes flaccid paralysis of muscles. It is caused by a neurotoxin, called

botulinum toxin, produced by the bacterium Clostridium botulinum (and rarely by C. butyricum and C. baratii). There are seven distinct neurotoxins (types A-G) that C. botulinum produces, but types A, B, and E (and rarely F) are the most common that produce the flaccid paralysis in humans. Botulism is not transmitted person to person.

Food-borne botulism is caused by eating foods that contain the botulinum neurotoxin.

Wound botulism is caused by neurotoxin produced from a wound that is infected with the bacteria C. botulinum.

Infant botulism occurs when an infant consumes the spores of the botulinum bacteria. The bacteria then grow in the intestines and release the neurotoxin.

Gram-positive, endospore-forming, obligate anaerobe

Botulism Pathophysiology botulinum toxin paralyzes the nerves so that the muscles cannot contract. This happens when the

neurotoxin enters nerve cells and eventually interferes with the release of acetylcholine so the nerve cannot stimulate the muscle to contract. Unless the nerve can regenerate a new axon that has no exposure to the neurotoxin, the interference at the neuromuscular junction is permanent.

Clinical Manifestations The classic symptoms of botulism include double vision, blurred vision, drooping eyelids, slurred

speech, difficulty swallowing, dry mouth, and muscle weakness. Constipation may occur. Examination may reveal that the gag reflex and the deep tendon reflexes like the knee-jerk reflex are decreased or absent.

Infants with botulism appear lethargic, weak, and floppy, feed poorly, become constipated, and have a weak cry and poor muscle tone. In infants, constipation is often the first symptom to occur.

These are all symptoms of the muscle paralysis that is caused by the neurotoxin. If untreated, these symptoms may progress to cause paralysis in various parts of the body, often seen as a descending paralysis of the arms, legs, trunk, and breathing muscles.

In food-borne botulism, symptoms generally begin 18-36 hours after eating a contaminated food, but they can occur as early as six hours or as late as 10 days afterward.

BotulismDiagnosis Differential diagnosis: Symptoms of other diseases, such as differential diagnosis Guillain-Barré syndrome ,

and myasthenia gravis can appear similar to those of botulism. The most direct way to confirm the diagnosis is to identify the botulinum neurotoxin in the patient's blood,

serum, or stool. This is done by injecting the patient's serum or stool into the peritoneal cavity of mice. An equal amount of serum or stool from the patient is treated with multivalent antitoxin and injected in other mice. If the antitoxin-treated serum- or stool-injected mice live while those injected with untreated serum or stool die, then this is a positive test for botulism and is called the mouse inoculation test. The bacteria can also be isolated from the stool of people with food-borne and infant botulism, but this is not a definitive test. However, stool cultures can help differentiate botulism from E. coli, Salmonella, and other infectious agents.

Treatment If diagnosed early, food-borne and wound botulism can be treated with an antitoxin that blocks the action

of neurotoxin circulating in the blood. The trivalent antitoxin (effective against three neurotoxins: A, B, and E). The antitoxin can prevent the disorder from worsening, but recovery still takes many weeks. Wounds should be treated, usually surgically, to remove the source of the toxin-producing bacteria. Infant botulism: immune globulins that can be given iv.

The respiratory failure and paralysis that occur with severe botulism may require a patient to be on a breathing machine (ventilator) for weeks and may require intensive medical and nursing care. After several weeks, the paralysis slowly improves as axons in the nerves are regenerated.

•Leprosy is a chronic infectious disease of skin and peripheral nerves.•World wide it is the most common cause of peripheral neuropathy•Mycobacterium leprae Acid-fast rod that grows best at 30°C.•Because of the distinct lifecycle of M. leprae, leprosy takes a very long time to manifest itself as disease after infection. The incubation time alone can be up to 5 years for the pathogen. It may even take up to 20 years for symptoms to appear.•Today leprosy is seen primarily in Asia, Africa, and Latin America•Prevalence of 1.3 million patients (70% from India)

Leprosy

Transmission by respiratory droplets and direct skin contact during close and frequent contact. Other routes: contact with armadillos (a reservoir in Texas), infected soil and tattooing.Diagnosis 3 cardinal diagnositic criteria:1.Anesthetic skin patches2.Thinkened nerves3.Acid-fast bacilli in skin smears

Leprosy

1.Paucibacillary (Tuberculoid)- <5 skin lesions and or 1 nerve is involved It is characterized by one or more hypopigmented skin macules and anaesthetic patches, where skin sensations are lost because of damaged peripheral nerves that have been attacked by the human host's immune cells.2.Multibacillary (midborderline or borderline)-Borderline leprosy is of intermediate severity and is the most common form. Skin lesions resemble tuberculoid leprosy but are more numerous and irregular; large patches may affect a whole limb, and peripheral nerve involvement with weakness and loss of sensation is common. 3.Multibacillary (Lepromatous)- >5 skin lesions and/or >2 nerves involved Multibacillary lepsory is characterized by lesions on the skin, nodules, thickened skin, and damage to the nasal passages. Disfiguring nodules over body; At its extreme, the loss of feeling prevents the adequate care of cuts or burns on extremities, which may lead to gangrenous infections and eventual amputation. Serious leprosy of the nasal passages can cause loss of the nose.

Leprosy-WHO classification criteria

•Multidrug treatment with antibiotic combination of rifampin, dapsone, and clofazimine is highly effective. Recurrence occurs with high bacterial loads and after 5 years of initial treatment. Severe neuronal damage responds to oral prednisone.•Thalidomide for severe erythema nodosum leprosum (an inflammatory complication of leprosy that results in painful skin lesions on the arms and legs and face) (teratogen-child bearing women).•Management- improve hygiene, injury prevention, reconstructive plastic surgery (nasal reconstruction)

Leprosy-Treatment

Necrotic erythema nodosum leprosum