Mmsc Oscar Module 2

8/22/2019 Mmsc Oscar Module 2

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MMSc PROGRAM

INSTRUCTIONS

Type the details in the respective columns.

Objective Specific Clinical assessment report(OSCAR)

Module - 2

Title: _____________DR __________________Name of the Author: ____MATIN AHMAD KHAN_______________

Program/Specialization: ____MMScHIV Medicine ___________

Year of Study: _________2013 ________________

Serial No 1 :Skills to be learnt :Diagnosis and management of meningitis presenting as global cerebralsyndromes in HIV infected patients

Hands on Training :.Assist in the management of 5 patients with chronic meningitis and write downthe subjective objective assessment and planning till dischargeTasks : How will you differentiate TB meningitis, Bacterial meningitis, Syphilitic meningitis and

cryptococcal meningitis and HAND by CSF analysis? How will you manage these conditions? What

are the complications you look for?

Ans : Diagnosis and management of meningitis presenting as global cerebral syndromes in

HIV infected patients

DIAGNOSISDifferent forms ofmeningitis are associated with HIV infection which can be diagnosed by their presentation ,CSF Analysis , Antigen testing and Brain Imaging

They may be classified as follows, according to the etiologic agent:

Cryptococcal Tuberculous Syphilitic Listeria species Lymphomatous Aseptic

Chronic meningitis or episodes of acute meningitis for which no cause is found can occur at any time during the

course of AIDS. In addition, although individuals who are HIV seropositive are at increased risk for thedevelopment of certain types of meningitis, evidence suggests that they are also more likely than the general

population to develop community-acquired bacterial or viral meningitides.

Meningitis is multifactorial in patients with HIV or AIDS. Besides specific pathogens, autoimmune processes

and HIV itself have been implicated in the development of HIV-associated meningitis.Aseptic meningitis may be caused by HIV-1 itself. An early form of aseptic, HIV-associated meningitis

develops within days to weeks after HIV infection.

The appearance of meningitis due to cryptococcosis, coccidioidomycosis, histoplasmosis, or other fungalinfections is an AIDS-defining event and occurs typically in patients with very low CD4

+lymphocyte counts.

Medications such as nonsteroidal anti-inflammatory drugs (NSAIDs), trimethoprim-sulfamethoxazole, and

intravenous immunoglobulin (IVIG) are often overlooked as possible causes of HIV-associated meningitis.The prognosis in patients with HIV-associated meningitis depends on the etiology of meningitis and the stage of

HIV infection. Patients with aseptic meningitis, a diagnosis of exclusion, have a good prognosis and do not
http://emedicine.medscape.com/article/232915-overviewhttp://emedicine.medscape.com/article/211316-overviewhttp://emedicine.medscape.com/article/211316-overviewhttp://emedicine.medscape.com/article/232915-overview


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require any specific treatment. Cryptococcal meningitis once had a mortality of 20%, but this may now be as

low as 6%, owing to more aggressive therapy.Higher mortality rates correlate with the following:

Poor mental status High cerebrospinal fluid opening pressure at presentation (present in about two thirds of patients) Positive CSF India ink test Extra-CNS manifestations Higher fungal burdens, in fungal meningitis Cytomegalovirus ventriculoencephalitis (often causes death within weeks to months)

PRESENTATION :In general, symptoms and signs typically associated with meningitis are less likely to occur in HIV-seropositive

individuals than in the general population. This probably reflects the different organisms involved and thedifferences in immune responses.

Physical examination can reveal malaise, photophobia, headache, nuchal rigidity, fever, and cranial

neuropathies. Less common findings are confusion, somnolence, and personality changes.

Cryptococcal meningitis can occur acutely, with severe headache, change in mental status, fever, nuchalrigidity, and focal signs, or with a subacute course of malaise and headache without stiff neck over several

weeks.

Surprisingly, a study from China published in 2012 found a lower mortality in HIV-infected patients than in

HIV-uninfected patients with cryptococcal meningitis. The reason for decreased mortality in the HIV-infectedpopulation was determined to be low intensity of inflammation and effective surgical cerebrospinal fluid

drainage for increased intracranial pressure.

Cytomegaloviral infection usually presents as ventriculoencephalitis, with possible meningeal involvement,while aseptic HIV-associated meningitis appears as a mononucleosis-like illness and in rare cases is associated

with encephalitis.

Differential diagnosisThe differential diagnosis of HIV-associated meningitis includes chronic paroxysmal hemicrania,

meningococcal meningitis, migraine headache, neurosyphilis, and staphylococcal meningitis. Other problems to

be considered include lymphomatous meningitis; bacterial meningitis, which often occurs in conjunction with

sepsis; and cytomegalovirus ventriculoencephalitis, which usually results in a change in mental status that

evolves over several weeks and can be misdiagnosed as HIV-associated dementia.In patients receiving highly active antiretroviral therapy (HAART) who have a syndrome of relapsing-remitting

meningitis with negative cultures and atypical signs and symptoms, consider immune reconstitutioninflammatory syndrome (IRIS). This is regarded as an overactive response of a newly reconstituted immune

system to infectious agents already present in the patient when the therapy is started.

In IRIS, patients who are on antiretroviral therapy develop symptoms that are consistent with an infectious or

inflammatory condition and that cannot be explained by a new or a previous infection or by the side effects ofthe therapy. It has been proposed that IRIS is due to an imbalance of CD8

+/CD4

+cells.

In rare cases, metastatic CNS lymphoma can appear as meningitis.CSF ANALYSIS

CSF analysis facilitates the diagnosis of specific HIV-related etiologies and the assessment of other nonHIV-

associated causes. CSF findings include the following: Meningitis at seroconversion and cryptogenic meningitis Cytomegalovirus (CMV) ventriculoencephalitis Cryptococcal meningitis

Sometimes, Cryptococcus neoformans is incidentally found in the CSF.

An asymptomatic form of meningitis is found in one third of patients in whom CSF is examined for other

reasons (eg, headache).

Meningitis at seroconversion and cryptogenic meningitis

CSF reveals the following at this stage:

Elevated protein and mononuclear pleocytosis Normal glucose level


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Cytomegalovirus ventriculoencephalitis

The following CSF characteristics are seen with this condition:

Polymorphonuclear pleocytosis (common) Low to normal glucose level Normal to high protein levels

Polymerase chain reaction (PCR) is more sensitive than culture in detecting CMV. In 2 studies, PCR hadessentially 100% sensitivity in histologically proven CMV and was positive in 4 samples that had negative

culture results.

Cryptococcal meningitis(Fungal Meningitis)In one study of patients with AIDS, 26% of patients with cryptococcal meningitis had normal CSF findings;

40% had high protein levels, low glucose levels, and pleocytosis; and 55% had fewer than 10 lymphocytes/mL.

The CSF may have a clear or turbid appearance in cryptococcal meningitis. Variable mononuclear pleocytosis isobserved, and the white blood cell (WBC) count may be over 20 x 10

9/L. A high CSF opening pressure is

present in about two thirds of patients and is a poor prognostic sign.

CSF cultures are the criterion standard in diagnosing cryptococcal meningitis, but weeks and several specimens

may be needed to obtain a positive result. Results of the India ink test are supportive of the diagnosis if positive,but they do not exclude the diagnosis if they are negative

Cryptococcal antigen is present several weeks before overt signs of meningitis develop; therefore, its detection

provides an opportunity to catch infection early, and, hence, screening persons with HIV for cryptococcal

infection when they access health care can identify asymptomatic infected patients, allowing for prompttreatment and prevention of death.

[2]This can be used as a point-of-care assay and serve as a cost-effective

screening.

Test results for serum and CSF cryptococcal antigen may be positive in cryptococcal meningitis. The initialdiagnostic sensitivity of cryptococcal CSF antigen is 94.1%, followed by the serum antigen of 93.6%; however,

this tool is unreliable in assessing point of discontinuation of antifungal therapy, at least among patients who are

HIV positive.The latex agglutination test for cryptococcal polysaccharide antigen in the serum is highly sensitive and specific

in the diagnosis of infection with C. neoformans and a positive serum cryptococcal antigen titer of greater than

1:8 is as presumptive evidence of cryptococcal infection. Such patients should be evaluated for possible

meningeal involvement. Culture ofC. neoformans from any body site should also be regarded as significant and

is an indication for further evaluation and initiation of therapy.Bacterial meningitis

Acute bacterial meningitis is an infrequent complication of HIV infection. HIV-positive patients are atconsiderable increased risk for pneumococcal infection. However, pneumonia is the most common

manifestation of this predisposition, and although bacteremia is common, meningitis is not commonly seen in

the developed world. In contrast, bacterial meningitis is much more common in HIV-infected patients in the

developing world . The limited available data suggests that HIV infected patients are also at slightly increasedrisk for invasive infections withNeisseria meningitidis compared to the general population; however

meningococcal meningitis and septicemia remain infrequent. Neurosyphilis can also complicate HIV infection.

Central nervous system involvement in syphilis may occur at any time after initial infection. In particular,

syphilitic meningitis may be seen within the first few weeks of infection or as a primary presenting symptom.

Meningeal and meningovascular involvement may be suggested by changes in mental status, auditory or othercranial nerve dysfunction, ocular abnormalities, signs of meningeal irritation (meningismus), or stroke. CSF

findings consistent with neurosyphilis include elevated protein and elevated white blood cell count. A reactiveVDRL test on CSF is very specific for neurosyphilis but quite insensitive, so clinical judgment must be used in

making the diagnosis. Treatment of choice for neurosyphilis is intravenous administration of aqueous crystalline

penicillin-G (12 to 24 million units) daily for 14 days. Ceftriaxone may be an alternative.The most important bacterial cause of meningitis in patients with AIDS is tuberculosis Worldwide, tuberculosis

is the most common opportunistic complication of HIV infections and accounts for considerable morbidity. In

the developed world, there is considerable overlap among groups at high risk for TB and HIV including thosewho are homeless, housed in institutions, injection drug users, or living in urban areas where TB rates are high.

In urban areas where coinfection with TB and HIV is more common, there is also an increased risk of


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acquisition of multiple-drug-resistant TB (MDR TB), particularly among individuals previously treated with

antimycobacterial drugs.The clinical manifestations of TB depend in part on the degree of immunosuppression in the patient. When the

patients are still relatively immunocompetent, with CD4 lymphocyte counts > 200 cell/mm3

, pulmonary disease

is most common. However, disseminated infection is more likely to ensue with more advanced

immunodeficiency. The sites most frequently involved are the central nervous system (tuberculous meningitis),the reticuloendothelial system (lymph nodes, spleen, liver, bone marrow), or bone (vertebral bodies). However,

virtually any other organ can be infected during hematogenous dissemination. Tuberculous meningitis may

present clinically with fever, headache, mental-status changes, or focal neurologic deficits. Analysis of thecerebrospinal fluid usually shows an elevated serum protein, low glucose, and a lymphocytic pleocytosis.

Identification of the organism in the CSF is unusual although cultures are typically positive within 2-3 weeks.

Blood cultures may also be positive, especially in the setting of disseminated infection

Other causes of meningiti sOpportunistic viral meningitis is rare. In contrast, meningitis can be a presentation of acute infection with HIV

itself ). The clinical manifestations of symptomatic primary HIV infection are myriad and most often include

the acute onset of fever, generalized lymphadenopathy, pharyngitis, erythematous maculopapular rash.Headache is common and probably represents meningeal involvement in many cases. However it is rarely

severe enough to prompt evaluation that includes a lumbar puncture. Aseptic meningitis with a lymphocytic

pleocytosis is most commonly seen when CSF is analyzed. More severe neurologic manifestations including

encephalitis, the Guillain-Barr syndrome, facial palsy, cauda equina syndrome, brachial neuritis, andperipheral neuropathy may occur, demonstrating the neurotropism of HIV. These manifestations usually recover

completely as the acute syndrome resolves.

One final consideration in meningitis in patients with HIV infection is that it might be drug induced. Severalcases of aseptic meningitis due to trimethoprim/sulfamethoxazole have been described The presentation is one

of acute meningitis with lymphocytic pleocytosis on CSF analysis. Resolution is prompt when the drug is

stopped.One of the really important things that we struggle with in making a diagnosis of HAND is finding the

appropriate patients from a screening test. A screening test is essential for primary providers to

have to find patients who potentially could have HIVassociated neurocognitive disorder.

There is the HIV dementia scale, developed by Dr. McArthur, actually, and it has a diagnostic accuracy of over

80% percent. There is a current app for it available on the iTunes, under Hopkins HIV, and its simple for non-neurologists to perform. It requires about two minutes. When making a diagnosis of HAND,

neuropsychological testing is required, according to the 2007 American Academy of Neurology guidelines.Our patient had a classic pattern of executive dysfunction, including problems with planning, organization,

multitasking, and mental flexibility, as well as with psychomotor speed and less severe impairments in memory

and inattention. Typically for a diagnosis of HAND, CSF is not required. It was done in this case, however, and

the CSF viral load was actually undetectable.BRAIN IMAGING

Findings on brain imaging may be nonspecific because of concurrent nonmeningitic neurologic complications

of HIV, such as atrophy in cases of AIDS dementia/HIV encephalopathy.

Ependymal enhancement is seen with CMV ventriculoencephalitis.

CT or MRI scans of patients with tuberculous meningitis may show parenchymal mass lesions (tuberculomas);there are conflicting data on the prevalence of tuberculomas and other pathological changes that represent an

inflammatory response in HIV-infected patients

MANAGEMENTMeningitis in patients with HIV disease is most frequently due to opportunistic infections. Thus, predictions

center on the likelihood of controlling opportunistic infection. The best way to prevent opportunistic infectionsis to give effective antiretroviral therapy - the future epidemiology of opportunistic infections is inextricably

linked with the effectiveness of future antiretroviral treatment

Drugs of choice include ganciclovir for CMV ventriculoencephalitis and amphotericin B for cryptococcalmeningitis.


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In cases of cryptococcal meningitis, initially treat patients with amphotericin B(0.7-1 mg/kg/day)

with flucytosine for 2 weeks, followed by fluconazole 400 mg orally daily for 10 weeks. High-doseamphotericin B with flucytosine and high-dose fluconazole with flucytosine have been tried in patients with

cryptococcal meningitis with promising results.

In a randomized study that compared 1 mg/kg versus 0.7 mg/kg of amphotericin B in HIV-infected patients

with cryptococcal meningitis, the higher dose was more rapidly fungicidal; side effects were comparable.Patients in both arms of the study also received flucytosine, 25 mg/kg 4 times daily.

Because amphotericin B treatment is not available in many centers in developing countries, oral therapy is an

important alternative. Results of a randomized trial suggest that a 2-week course of high-dose fluconazole (1200mg/day) combined with flucytosine (100 mg/kg/day) is the optimal oral therapy for cryptococcal meningitis.

The combination proved more fungicidal than fluconazole alone and had a tolerable side-effect profile

Treatment should be administered in consultation with an infectious disease specialist.

Recurrence

Cryptococcal meningitis may recur after treatment. Without maintenance therapy, 50-70% of patients relapsewithin 1 year.

The rate decreases to 2-7% in patients treated with long-term fluconazole.

CMV ventriculoencephalitis also may recur.

Follow-up CareFollow-up care in patients with CMV meningitis includes the following drugs and dosages:

Ganciclovir500 mg PO q4h or 1 g PO tid for life Foscarnet 90-120 mg/kg IV daily for life

In cryptococcal meningitis, maintenance therapy should be continued with fluconazole 200 mg/day. Lifelong

secondary prevention may be required. Consideration might be given to discontinuing secondary antifungal

prophylaxis in selected patients who have responded well to highly active antiretroviral therapy (HAART), with12-18 months of successful suppression of HIV viral replication.

Symptomatic increased intracranial pressure should be treated with repeated lumbar punctures.

Patients with mild disease, pancytopenia, renal insufficiency, or abnormalities in electrolytes (potassium,

magnesium) may be treated with fluconazole 200 mg twice daily for 8-10 weeks.

Untreated, cryptococcal meningitis is fatal. In patients with AIDS, amphotericin B (0.7 mg/kg IV) given for 2weeks followed by fluconazole 400 mg PO for a further 8 weeks is associated with the best outcome to date in

prospective trials with a mortality of less than 10% and a mycologic response of approximately 70% Thisregimen is also reasonable for treatment of meningitis in other circumstances. Concomitant use of flucytosine,

100 mg/kg/day in four divided doses, with amphotericin B may be considered. Flucytosine does not improve

immediate outcome, but may decrease the risk of relapse. The combination of fluconazole, 400-800 mg /day

with flucytosine and liposomal formulations of amphotericin B are options for patients unable to tolerate theusual formulation of amphotericin B

Clinical deterioration in patients with meningitis may be due to increased intracranial pressure, which may be

diagnosed by a raised opening pressure of the CSF. A recent study in patients with AIDS showed a strong

correlation between mortality in the first two weeks after diagnosis, and the baseline opening pressure. All

patients with cryptococcal meningitis should have the opening pressure measured when a lumbar puncture isperformed, and strong consideration should be given to reducing such pressure (by repeated lumbar punctures, a

lumbar drain or a shunt) if the opening pressure is high (>25 cm of water).Cryptococcal meningitis in AIDS requires lifelong suppressive therapy unless the immunosuppression is

reversed Fluconazole, 200 mg daily, is the suppressive treatment of choice. Fluconazole, in dosages ranging

from 400 mg weekly to 200 mg daily, and itraconazole, 100 mg twice daily, are very effective in preventinginvasive cryptococcal infections, especially in HIV-positive patients with CD4 counts < 50-100 cells/mm

3.)

However, because of the relative infrequency of invasive fungal infections, antifungal prophylaxis does not

prolong life and is not routinely recommended.Other fungi rarely involve the meninges.Histoplasma capsulatum meningitis can occasionally be an additional

feature of disseminated histoplasmosis. Candida species may also rarely cause meningitis. Although mucosal
http://reference.medscape.com/drug/fungizone-amphotericin-b-conventional-amphotericin-b-deoxycholate-342582http://reference.medscape.com/drug/flucytosine-342589http://reference.medscape.com/drug/diflucan-fluconazole-342587http://reference.medscape.com/drug/cytovene-ganciclovir-342619http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614http://reference.medscape.com/drug/cytovene-ganciclovir-342619http://reference.medscape.com/drug/diflucan-fluconazole-342587http://reference.medscape.com/drug/flucytosine-342589http://reference.medscape.com/drug/fungizone-amphotericin-b-conventional-amphotericin-b-deoxycholate-342582


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candidiasis is very commonly a feature of HIV infection, systemic candidiasis is rare and usually is a very late

complication of AIDS. Neutropenic patients and those using intravenous drugs are at greater risk for invasivecandidiasis, including candida meningitis. The clinical features, and CSF findings are similar to cryptococcal

infection.

Untreated, tuberculous meningitis progresses relentlessly and is uniformly fatal. Treatment of tuberculosis

requires use of an adequate number of active antituberculous drugs for a prolonged duration. Treatment shouldbe guided by antimycobacterial drug-susceptibility testing. Initial isolates and isolates recovered from those

who relapse or for whom therapy fails should be tested for susceptibility to antituberculous drugs. In HIV-

positive patients, issues of therapy are also complicated by the potential requirement for antiretroviral therapy.Many of the more potent antiviral agents, such as the protease inhibitors and non-nucleoside reverse

transcriptase inhibitors have significant interactions with rifamycins, which are critically important in the

treatment of tuberculosis Concomitant usage of potent antiretroviral therapy and anti-tuberculous therapyrequires expert management and should follow published guidelines

Management of tuberculosis is further complicated by the emergence of resistance to treatment as a significant

factor. In 1998, 8% of TB isolates recovered from patients in the United States were resistant to at least

isoniazid, and 1.1% were resistant to at least isoniazid and rifampin . Development of resistance has beenassociated with poor adherence to therapy, failure to recognize drug resistance leading to a delay in initiation of

appropriate treatment, and the use of ineffective treatment regimens.

Initial therapy for uncomplicated TB in whom potent antiretroviral therapy is not started should include at least

four drugs: isoniazid, rifampin, pyrazinamide, and either ethambutol or streptomycin Tuberculous meningitisshould be treated for at least 12 months. The role of concomitant corticosteroids is uncertain Although some

studies suggest that steroids may reduce acute mortality, especially in children, there are limited data available

on their use in HIV-infected patients.Unusual clinical manifestations have also been described in patients receiving potent antiretroviral therapy. In

the first few months after starting antiretroviral therapy, patients may experience apparent worsening of their

tuberculosis with increased fever, pleural effusions, enlarging lymph nodes (especially mediastinal). In patientswith meningitis, cerebritis and space-occupying lesions on scans has also been described. This paradoxical

worsening is probably immune-mediated, does not imply failure of anti-TB treatment, and may respond to

corticosteroids.

The mainstay of management of HAND is antiretroviral therapy, and this is especially important

Unfortunately, there are no currently approved adjunctive therapies for HAND. There have beenmultiple treatment trials that have been unsuccessful, but research is still ongoing.

Typically, we recommend nonpharmacologic therapies that are helpful for other forms of cognitive impairment.These include things like cognitive behavioral therapy, aerobic exercise, a Mediterranean diet, increased activity

levels, and were always careful to point out that the management of HAND involves a multidisciplinary team.

We worknot only with the patient, but also the patients family social workers and psychiatry for a

multidisciplinary approach.

Q How will you differentiate TB meningitis, Bacterial meningitis, Syphilitic meningitis

and cryptococcal meningitis and HAND by CSF analysis? How will you manage these

conditions? What are the complications you look for?

Ans :Meningitis is an inflammation of the leptomeninges and underlying subarachnoidcerebrospinalfluid (CSF) The inflammation may be caused by infection with viruses, bacteria, other micro-organisms, or

non-infective causes.

Viral meningitis is more common and usually more benign than bacterial meningitisbut all cases of suspectedmeningitis should be managed as though having bacterial meningitis, until proven otherwise. Meningococcal

disease is the leading infectious cause of death in early childhood. It presents as bacterial meningitis (15% of

cases), septicaemia (25% of cases), or as a combination of the two presentations (60% of cases).Epidemiology
http://www.patient.co.uk/search.asp?searchterm=CEREBROSPINAL+FLUID+ANALYSIShttp://www.patient.co.uk/search.asp?searchterm=CEREBROSPINAL+FLUID+ANALYSIShttp://www.patient.co.uk/search.asp?searchterm=VIRAL+MENINGITIShttp://www.patient.co.uk/search.asp?searchterm=BACTERIAL+MENINGITIShttp://www.patient.co.uk/search.asp?searchterm=BACTERIAL+MENINGITIShttp://www.patient.co.uk/search.asp?searchterm=VIRAL+MENINGITIShttp://www.patient.co.uk/search.asp?searchterm=CEREBROSPINAL+FLUID+ANALYSIShttp://www.patient.co.uk/search.asp?searchterm=CEREBROSPINAL+FLUID+ANALYSIS


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Meningitis occurs in people of all age groups, but infants, young children and the elderly are morepredisposed to meningitis

Viral meningitis is the most common cause. The epidemiology of bacterial meningitis in the UK has changed dramatically over a period of two

decades following the introduction of vaccines to controlHaemophilus influenzaetype b, serogroup C

meningococcus and pneumococcal disease.

There is currently no licensed vaccine against serogroup B meningococcus, which is now the mostcommon cause of bacterial meningitis (and septicaemia) in those aged 3 months to 16 years.

Risk factors Patients with CSF shunts or dural defects (eg staphylococcal). Patients having spinal procedures (eg spinal anaesthetics) are at increased risk andPseudomonasspp.

may then be the cause.

Other risk factors include bacterial endocarditis,diabetes mellitus, alcoholism and cirrhosis, intravenousdrug abuse, renal insufficiency, adrenal insufficiency, malignancy (increased risk of listerial

infection),hypoparathyroidism, thalassaemia major and cystic fibrosis.

Splenectomy and sickle cell disease increase the risk of meningitis secondary to encapsulated organisms Crowding (eg military recruits and college students) increases the risk of outbreaks ofmeningococcal

meningitis.

Causes Neonates: group B streptococci,Listeria monocytogenes,Escherichia coli. Infants and young children:H. influenzae type b, if younger than 4 years and unvaccinated;Neisseria

meningitidis,Streptococcus pneumoniae.

Adults and older children: S. pneumoniae,H. influenzae type b,N. meningitidis, Gram-negative bacilli,staphylococci, streptococci andL. monocytogenes.

Elderly and immunocompromised:S. pneumoniae,L. monocytogenes, tuberculosis(TB), Gram-negativeorganisms.

Hospital-acquired and post-traumatic meningitis (may often be multidrug-resistant),Klebsiellapneumoniae,E.coli,Pseudomonas aeruginosa,Staphylococcus aureus.

N. meningitidis: usually local outbreaks among young adults; there is increased incidence in late winteror early spring. Meningococcal meningitis is endemic in parts of Africa, India and other developingnations. Periodic epidemics occur in sub-Saharan Africa as well as among religious pilgrims travelling

to Saudi Arabia for the Hajj.

Syphilis and TB are rare causes but are increasing in association with HIV infection.Neonatal meningitis

See also separate general articles Congenital, Perinatal and Neonatal Infection.

Neonates are at greater risk of meningitis. Risk factors for the development of meningitis include lowbirthweight (below 2,500 g), premature delivery, premature rupture of membranes, traumatic delivery,

fetal hypoxia and maternal peripartum infection.

Intrapartum prophylactic antibiotics in pregnant mothers who carry, or who are at risk of colonising,group B streptococci, have been effective in reducing the risk of neonatal group B streptococcal

meningitis. Caesarean section reduces the risk of transmission of herpes simplex virus (HSV). The initial presentation is usually nonspecific with features including raised or unstable temperature,

respiratory distress, episodes of apnoea and bradycardia, hypotension, feeding difficulty, irritability and

reduced activity.[4

]

Meningitis should therefore be considered and included in the urgent investigations of any acutely illneonate.

In developed countries, the rate of mortality from bacterial meningitis among neonates has decreased butthere has not been a significant decrease in long-term complications such as cerebral palsy, learningdisability, seizures and hearing impairment.
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Mortality following HSV infection of the central nervous system is 15%. HSV-1 and HSV-2 have thesame risk of mortality but HSV-2 is more often associated with long-term complications such ascerebral palsy, mental retardation, seizures, microcephaly and visual impairment.

Aseptic meningitis

CSF has cells but is Gram-stain negative and no bacteria can be cultured on standard media. Causes include:

Partly treated bacterial meningitis. Viral infection, eg mumps, echovirus, Coxsackievirus, HSV[3] and herpes zoster virus,

HIV, measles, influenza, arboviruses.

Fungal infection: fungal meningitis is rare, but can be life-threatening. People with immunodeficiency(eg AIDS, leukaemia, immunosuppressant medication) are at higher risk. Fungal causes of meningitis

include infection withCryptococcus,Histoplasma andCoccidioides species.

Parasites, eg eosinophilic meningitis caused by angiostrongyliasis. Other possible causative organisms include atypical TB, syphilis, Lyme disease,leptospirosis, listeriosis

and brucellosis.

Kawasaki's disease. Mollaret's meningitis.

Non-infective meningitis

Meningeal inflammation can be caused by meningeal infiltration by:

Malignant cells (leukaemia, lymphoma, other tumours). Chemical meningitis (intrathecal drugs, contaminants). Drugs (non-steroidal anti-inflammatory drugs (NSAIDS), trimethoprim). Sarcoidosis. Systemic lupus erythematosus. Behet's disease.

Presentation

.Invasive meningococcal disease :Invasive meningococcal disease may present with septicaemia, meningitis or a combination of both. A

generalised petechial rash, beyond the distribution of the superior vena cava, or a purpuric rash in any location,

in an ill child, is strongly suggestive of meningococcal septicaemia and should lead to urgent treatment and

referral to secondary care.

The following features in an ill child should prompt consideration of a diagnosis of invasivemeningococcal disease: petechial rash, altered mental state, cold hands and feet, extremity pain,

fever, headache, neck stiffness, skin mottling.

Meningococcal meningitis and/or septicaemia may also present with capillary refill time more than 2seconds, unusual skin colour and hypotension.

Meningococcal septicaemia without meningitis does not tend to present with stiff neck, back rigidity,bulging fontanelle, photophobia, Kernig's sign, Brudzinski's sign, paresis, focal neurological deficits orseizures.

Clinical presentation of meningitis may include Fever, headache. Stiff neck (generally not present in children under the age of one year or in patients with altered

mental state), back rigidity, bulging fontanelle (in infants), photophobia, opisthotonus (if severe). Altered mental state, unconsciousness, toxic/moribund state. Shock: signs of shock include tachycardia and/or hypotension, respiratory distress, altered

mental state and poor urine output.

Kernig's sign (pain and resistance on passive knee extension with hips fully flexed). Brudzinski's sign (hips flex on bending the head forward). Paresis, focal neurological deficits (including cranial nerve involvement and abnormal pupils). Seizures.

Viral meningitis may be clinically indistinguishable from bacterial meningitis but features may be moremild and complications (eg focal neurological deficits) less frequent. Any person presenting with

suspected meningitis should therefore be managed as having bacterial meningitis until proved otherwise.
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Classic symptoms are not evident in infants and also not often seen in the elderly. Some children and young people will present with mostly nonspecific symptoms or signs and the

conditions may be difficult to distinguish from other less important infections presenting in this way.

Children and young people with more specific symptoms and signs are more likely to have bacterial

meningitis or meningococcal septicaemia and the symptoms and signs may become more severe and

more specific over time

Approximately 25% of patients with bacterial meningitis present acutely within 24 hours of onset ofsymptoms. Other patients with bacterial meningitis and most patients with viral meningitis present with

subacute neurological symptoms developing over 1-7 days. Chronic symptoms lasting longer than oneweek suggest meningitis caused by some viruses as well as TB, syphilis or fungi.

Individual symptoms have low diagnostic accuracy. Absence of fever, neck stiffness, andaltered mental

status makes the diagnosis of meningitis much less likely. A study of children aged 16 years or younger withmeningococcal disease found that classical signs such as haemorrhagic rash, meningism and impaired

consciousness did not tend to appear until after 13 to 22 hours. However, more nonspecific features such as leg

pain, cold hands and feet and abnormal skin colour appeared much earlier with a median onset of 7-12 hours.

These earlier features are thus very important in early diagnosis and therefore earlier initiation of potentiallylife-saving treatment

Differential diagnosis

Other causes of pyrexia and severe infection. Intracranial abscess. Other causes of altered mental state and coma, egencephalitis, subarachnoid haemorrhage, brain

tumours.

InvestigationsInvestigations must not delay treatment.

Lumbar puncture

See separate article Lumbar Puncture (LP) and Cerebrospinal Fluid article for normal values and interpretation

of abnormal CSF findings.

LP is performed immediately provided there are no signs ofraised intracranial pressure(reducedconsciousness, very bad headache, frequent fits) or focal neurology. If there is any doubt of impending

brain herniation then a CT scan is usually performed first.

Samples of CSF are usually sent for Gram stain, Ziehl-Neelsen stain (TB), cytology, virology,glucose, protein, culture, rapid antigen screen or polymerase chain reaction (PCR) if available

and India ink for cryptococci.

CSF may be normal in the early stages of meningitis so the LP is usually repeated if symptomsand signs persist.

Other investigations

These are often also performed:

Blood cultures are usually sent before initiating antibiotic therapy. Blood glucose (to compare with CSF glucose). FBC, renal function tests Coagulation profile: especially ifdisseminated intravascular coagulation is suspected. CXR(lung abscess). Culture urine, nasal swabs and stool (virology). Perform whole blood real-time PCR testing (EDTA sample) forN. meningitidis to confirm a diagnosis

of meningococcal disease

CT scan is usually reserved for those with specific adverse clinical features or when an underlying causesuch as mastoiditis is suspected.

MRI can be extremely useful for detecting and monitoring the complications of meningitis. Other possible investigations:
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Serum cryptococcal antigen, especially if the baseline is known (less diagnostic than India inkand CSF cryptococcal antigen).

Serology of blood, urine, and CSF for specific bacterial antigens is occasionally recommended ifthere is diagnostic doubt or in patients with partially treated meningitis.

Serum test for syphilis ifneurosyphilis is suspected.The differentiation of TB meningitis, Bacterial meningitis, Syphilitic meningitis and

cryptococcal meningitis and HAND by CSF analysis of are tabulated as follows :

Cerebrospinal fluid (CSF) analysis - Meningitis

Normal values (CSF):

CSF opening pressure: 50180 mmH2O

Glucose: 4085 mg/dL.

Protein (total): 1545 mg/dL.

Lactate dehyrogenase: 1/10 of serum level.

Lactate: less than 35 mg/dL.

Leukocytes (WBC): 05/L (adults / children); up to 30/L (newborns).

Gram stain: negative.Culture: sterile.

Specific gravity: 1.0061.009.

Syphilis serology: negative.

Gross appearance: Normal CSF is clear and colorless.

Differential: 6070% lymphocytes; up to 30% monocytes

and macrophages; other cells 2% or less.

Bacterial Meningitis

Glucose (mg/dL): Normal to marked decrease. 250 mg/dL.WBCs (cells/L) >500 (usually > 1000). Early: May be < 100.

Cell differential: Predominance of Neutrophils (PMNs)

Culture: Positive

Opening Pressure Elevated

Fungal Meningitis(Cryptococcal Meningitis)

Glucose (mg/dL):


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WBCs (cells/L) Variable (10 -1000 cells/L) 40 mg/dL.)

Protein

(mg/dL)>45mg/dL (moderate increase)

WBCs

(cells/L)< 100 cells/L.

Cell

differential:Monocytes increased

Culture:

In non-HIV+ patients, a positive CSF VDRL alwaysindicates neurosyphilis, whereas a positive CSF

PCR for syphilis simply indicates that CSF invasion has

occurredHIV+ patients may have titers discordant from theirtrue disease state and therefore probably warrant

more aggressive treatment; they may also progress more

quickly than pts in the pre-HIV era

OpeningPressure

Usually normal or increased

HAND (HIV Associated Neuocognitive Disorders

Glucose(mg/dL):

Normal

Protein (mg/dL) (moderate to marked increase) 50 -500 mg/dL

WBCs

(cells/L)0 -15 cells/L) .

Celldifferential:

Predominance of mononuclear cells , pleocytosis may beabsent in 65%

Culture: Negative

Opening

Pressure Normal

ManagementManagement includes supportive treatment (including fluids, antipyretics, antiemetics), treatment of the

causative organism and treatment of any complications, eg seizures, raised intracranial pressure. See also thearticles on specific infections for management of rarer causes of meningitis such as tuberculosis, fungi and

parasites.


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Management of viral meningitis

The general principles of management for all viral meningitis include supportive therapy, eg analgesia,antipyretics, nutritional support and hydration.

Enteroviral meningitis: usually self-limiting and no specific therapy is required unless thereis hypogammaglobulinaemia (immunoglobulins required).

Acicloviris considered beneficial in treating herpetic viral infections but only if given very early in thecourse of the infection, and evidence for benefit is limited. Intravenous aciclovir should be started

immediately if there is any suspicion ofherpes simplex encephalitis.

Gancicloviris effective forcytomegalovirus (CMV) infections but, because of toxicity, should bereserved for severe cases with positive CMV culture or when a congenital infection or an AIDS-related

infection is likely

Management of bacterial meningitis

Transfer any patient with suspected bacterial meningitis or suspected meningococcal septicaemia tosecondary care as an emergency.

Intramuscular or intravenous benzylpenicillin should be given before urgent transfer to hospital only ifthere is suspected meningococcal septicaemia with a non-blanching rash.

Benzylpenicillin should not be given if there is a history of anaphylaxis associated with penicillins or ifgiving antibiotics will delay urgent transfer to hospital.

If urgent transfer to hospital is not possible (eg remote locations or adverse weather conditions),antibiotics should be given to any person with suspected bacterial meningitis.

Management includes supportive treatment with analgesia, antipyretics, nutritional support andhydration.

Do not restrict fluids unless there is evidence of raised intracranial pressure or increased antidiuretichormone (ADH) secretion

The choice of antibiotics and the duration of therapy should be guided by the microbiological diagnosisbut initial 'blind' antibiotic therapy must be started immediately.

The National Institute for Health and Clinical Excellence (NICE) recommendation to children (over 3months old) is fordexamethasone to be given for suspected or confirmed bacterial meningitis as soon as

possible

Corticosteroids given to patients of all ages with bacterial meningitis have been shown to reduce hearingloss and neurological sequelae significantly, but there is no evidence that they reduce overall mortality

Choice of antibiotic is usually determined by local guidelines and close liaison with microbiologist.Initial 'blind' therapy:

Third-generation cephalosporin (cefotaxime orceftriaxone) is often used as empirical treatment beforeidentification of the causative organism.

Amoxicillin is often added if listeriosis is suspected.Meningitis caused by meningococci:

Benzylpenicillin or cefotaxime for at least 7 days are usually used. Rifampicin is usually prescribed for two days in order to eliminate nasopharyngeal carriage. Prevention of secondary case of meningococcal meningitis is usually with rifampicin orciprofloxacin.

Meningitis caused by pneumococci:

Usually treated with cefotaxime for 10-14 days. Benzylpenicillin may be given if the organism is penicillin-sensitive.

Meningitis caused by H. infl uenzaetype b:

Cefotaxime is given for at least 10 days. Rifampicin is usually given for four days prior to discharge for patients.

Meningitis caused by group B streptococci:

Benzylpenicillin and gentamicin, or cefotaxime alone are given for 14 days.Meningitis caused by listeriosis:

Amoxicillin and gentamicin for 10-14 days are usually given.
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Management of Fungal Meningitis

In cases of cryptococcal meningitis, initially treat patients with amphotericin B(0.7-1 mg/kg/day)with flucytosine for 2 weeks, followed by fluconazole 400 mg orally daily for 10 weeks. High-doseamphotericin B with flucytosine and high-dose fluconazole with flucytosine have been tried in patients

with cryptococcal meningitis with promising results.

In a randomized study that compared 1 mg/kg versus 0.7 mg/kg of amphotericin B in HIV-infectedpatients with cryptococcal meningitis, the higher dose was more rapidly fungicidal; side effects werecomparable. Patients in both arms of the study also received flucytosine, 25 mg/kg 4 times daily.

Because amphotericin B treatment is not available in many centers in developing countries, oral therapyis an important alternative. Results of a randomized trial suggest that a 2-week course of high-dose

fluconazole (1200 mg/day) combined with flucytosine (100 mg/kg/day) is the optimal oral therapy forcryptococcal meningitis. The combination proved more fungicidal than fluconazole alone and had a

tolerable side-effect profile Treatment should be administered in consultation with an infectious disease

specialist.

RecurrenceCryptococcal meningitis may recur after treatment. Without maintenance therapy, 50-70% of patients

relapse within 1 year.

The rate decreases to 2-7% in patients treated with long-term fluconazole.CMV ventriculoencephalitis also may recur.

Follow-up CareFollow-up care in patients with CMV meningitis includes the following drugs and dosages:

Ganciclovir500 mg PO q4h or 1 g PO tid for lifeFoscarnet 90-120 mg/kg IV daily for life

In cryptococcal meningitis, maintenance therapy should be continued with fluconazole 200mg/day. Lifelong secondary prevention may be required. Consideration might be given to

discontinuing secondary antifungal prophylaxis in selected patients who have responded well tohighly active antiretroviral therapy (HAART), with 12-18 months of successful suppression of

HIV viral replication.

Symptomatic increased intracranial pressure should be treated with repeated lumbar punctures. Patients with mild disease, pancytopenia, renal insufficiency, or abnormalities in electrolytes

(potassium, magnesium) may be treated with fluconazole 200 mg twice daily for 8-10 weeks.

Untreated, cryptococcal meningitis is fatal. Management of HAND

The mainstay of management of HAND is antiretroviral therapy, and this is especiallyimportant

Unfortunately, there are no currently approved adjunctive therapies for HAND. Therehave been

multiple treatment trials that have been unsuccessful, but research is still ongoing. Typically, we recommend nonpharmacologic therapies that are helpful for other forms of

cognitive impairment. These include things like cognitive behavioral therapy, aerobicexercise, a Mediterranean diet, increased activity levels, and were always careful to

point out that the management of HAND involves a multidisciplinary team. We work not

only with the patient, but also the patients family social workers and psychiatry for amultidisciplinary approach.
http://reference.medscape.com/drug/fungizone-amphotericin-b-conventional-amphotericin-b-deoxycholate-342582http://reference.medscape.com/drug/flucytosine-342589http://reference.medscape.com/drug/diflucan-fluconazole-342587http://reference.medscape.com/drug/cytovene-ganciclovir-342619http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614http://reference.medscape.com/drug/foscavir-phosphonoformic-acid-foscarnet-342614http://reference.medscape.com/drug/cytovene-ganciclovir-342619http://reference.medscape.com/drug/diflucan-fluconazole-342587http://reference.medscape.com/drug/flucytosine-342589http://reference.medscape.com/drug/fungizone-amphotericin-b-conventional-amphotericin-b-deoxycholate-342582


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COMPLICATIONS Immediate: septic shock, including disseminated intravascular coagulation, coma with loss of

protective airway reflexes, seizures (30-40% of children, 20-30% of adults), cerebral oedema and

raised intracranial pressure, septic arthritis, pericardial effusion, andhaemolytic anaemia (H.

influenzae). Subdural effusions: reported in 40% of children aged 1-18 months with bacterial meningitis.

Risk factors include young age, rapid onset of illness, low peripheral white cell count and high

CSF protein.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH). Seizures: occur more commonly during the acute stage of the disease. Delayed: decreased hearing or deafness, other cranial nerve dysfunction, multiple seizures, focal

paralysis, subdural effusions, hydrocephalus, intellectual deficits, ataxia, blindness, Waterhouse-Friderichsen syndrome, and peripheral gangrene.

Dementia HIV-associated neurocognitive disorders (HAND) place a significant burden on the lives of

people living with HIV/AIDS (PLWH), substantially affecting quality of life and increasingmortality risk by over three-fold compared with those without a neurological disorder. HAND

can have several consequences:

decreased adherence to medication impaired driving difficulty with activities of daily living, such as finances and meal preparation employment challenges five times more likely to complain of problems at work twice as likely to be unemployed shorter survival

Prognosis

Prognosis depends on the pathogen, the patient's age and condition, and the severity of acute illness. Patients with severe neurological impairment on presentation or with extremely rapid onset of illness,

even if treated immediately, have a 50-90% mortality rate and an even higher rate of morbidity.

Pneumococcal meningitis has the highest rates of mortality (21%) and morbidity (15%). Meningococcal disease has a better prognosis when meningitis accompanies the septicaemia than when

it does not.

The prognosis for viral meningitis is usually excellent, with complete resolution usually within 10 days.Prevention

Vaccination againstH. influenzae type b, meningococcus group C and S. pneumoniae. Appropriate prophylaxis of people in close contact with those diagnosed.
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Serial No 2 :Skills to be learnt : Diagnosis and management of encephalitis presenting as global cerebralsyndromes in HIV infected patientsHands on Training :.Assist in the management of 3 patients with encephalitis and write downthe subjective objective assessment and planning till discharge

Tasks : How will you differentiate CMV encephalitis, Herpes simplex encephalitis andVaricella zoster encephalitis radiologically and by CSF analysis? How will you manage these

conditions? What are the complications you look for?

Ans :

Diagnosis and management of encephalitis presenting as global cerebral syndromes in

HIV infected patients

HIV-meningoencephalitis is infection of the brain and the lining of the brain (called the meninges) by the HIV

(human immunodeficiency virus). It occurs shortly after the person is first infected with HIV and may cause

headache, neck stiffness, drowsiness, confusion and/or seizures.

Usually HIV-meningoencephalitis occurs a few weeks or months after the person first contracts HIV infection.This is the time when the body first starts to recognise the HIV virus and the immune system tries to attack it, a

process known as seroconversion.

Most people with HIV develop some symptoms at seroconversion. These tend to be mild and non-specific suchas fever, tiredness, sore throat, headache, rash and muscle aches. These are often mistaken for a common cold

or flu and most people do not go to the doctor with this illness.

In some people, the lining of the brain (meninges) may become affected around the time of seroconversion, andthis is called HIV-meningitis. Symptoms of headache and neck stiffness develop over hours or days. People feel

generally unwell and often find light hurts their eyes. Although HIV-meningitis may be unpleasant, it is not

dangerous and tends to improve on its own.

Rarely the virus may affect the brain itself and this is called HIV-meningoencephalitis or just HIV-encephalitis

if the lining of the brain (meninges) are not involved. People start to become drowsy or confused, and maydevelop seizures. Symptoms develop over hours or a few days. Although HIV-meningoencephalitis may remain

mild and resolve on its own, it can sometimes be severe and occasionally it may lead to uncontrollable seizures,coma and even death.

DIAGNOSIS :

Although HIV levels may be raised in the spinal fluid, there is no specific test for HIV-meningoencephalitis.

The diagnosis relies on excluding other possible explanations.Encephalitis is defined by the presence of an inflammatory process of the brain in association with clinical

evidence of neurologic dysfunction. Of the pathogens reported to cause encephalitis, the majority are viruses.

However, despite extensive testing, the etiology of encephalitis remains unknown in most patients. Another

major challenge for patients with encephalitis is to determine the relevance of an infectious agent identified

outside of the CNS; these agents may play a role in the neurologic manifestations of illness but not necessarilyby directly invading the CNS. In addition, it is important to distinguish between infectious encephalitis and

postinfectious or postimmunization encephalitis or en-cephalomyelitis (e.g., acute disseminatedencephalomyelitis [ADEM]), which may be mediated by an immunologic response to an antecedent antigenic

stimulus from an infecting microorganism or immunization. Noninfectious CNS diseases (e.g., vasculitis,

collagen vascular disorders, and paraneoplastic syndromes) can have clinical presentations similar to thoseof infectious causes of encephalitis and should also be considered in the differential diagnosis.

In the approach to the patient with encephalitis, an attempt should be made to establish an etiologic diagnosis.

Although there are no definitive effective treatments in many cases of encephalitis, identification ofa specific agent may be important for prognosis, potential prophylaxis, counseling of patients and family

members, and public health interventions. Epidemiologic clues that may help in directing the investigation


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for an etiologic diagnosis include season of the year, geographic locale, prevalence of disease in the local

community, travel history, recreational activities, occupational exposure, insect contact, animal contact,vaccination history, and immune status of the patient. Various clinical clues may also be helpful to physicians

in considering specific etiologies.

The diagnostic evaluation of a patient who presents with encephalitis needs to be individualized and shouldbe

guided by epidemiologic and clinical clues and lab-oratory data; these generally include cultures and analysis(i.e., antigen detection and nucleic acid amplification tests, such as PCR) of body fluid specimens, biopsy of

specific tissues (with culture, antigen detection, PCR, and histopathologic evaluation) outside the CNS, and

serologic testing (for specific IgM and acute- and convalescent-phase IgG antibody titers). MRI of the brainshould be performed in all patients, with CT used only if MRI is unavailable, unreliable, or cannot be

performed; neuroimaging findings may also suggest disease caused by specific etiologic agents.

CSF analysis is critical, unless contraindicated, and may be quite helpful in establishing an etiology. Detectionof specific viral IgM antibodies in CSF specimens obtained from patients with encephalitis caused by numerous

viruses is considered to be diagnostic of neuroinvasive disease. CSF cultures are generally of limited value in

the determination of the viral causes of encephalitis but are very important in the diagnosis of bacterial and

fungal infections. The utility of nucleic acid amplification testing (e.g., PCR) of CSF specimens has greatlyincreased the ability to diagnose infections of the CNS, especially viral infections caused by the herpesviruses.

At present, brain biopsy is rarely performed to establish the etiology of encephalitis, but it may play a role in

some patients with encephalitis of unknown etiology whose conditions deteriorate despite treatment with

acyclovir.Despite the wide range of viruses that have been reported to cause encephalitis, specific antiviraltherapy is generally limited to infections caused by the herpesvirusesspecifically, herpes

simplex virusand HIV. Acyclovir treatment should be initiated in all patients with suspected encephalitis,

pending results of diagnostic studies. During the appropriate season, patients who present with clinical cluessuggestive of rickettsial or ehrlichial infection should be treated empirically with doxycycline. Empirical

therapy for acute bacterial meningitis should also be initiated if clinically indicated. In patients with

acute disseminated encephalomyelitis, corticosteroids are recommended; plasma exchange should be consideredin patients who do not respond to this treatment.

Etiological consideration

.Epidemiologic clues and assessment of risk factors to identify potential etiologic agents should besought in all patients with encephalitis

Clinical clues (general and specific neurologic findings) may be helpful in suggesting certain causativeagents in patients with encephalitis

In patients with encephalitis and a history of recent infectious illness or vaccination, the diagnosis ofADEM (e.g., acute disseminated encephalomyelitis ) should be considered

Diagnostic work up

Specific diagnostic studies should be performed for the majority of patients who present withencephalitis

Additional diagnostic studies should be performed for patients with encephalitis on the basis of specificepidemiologicand clinical clues

Diagnostic Studies outside the CNS

Cultures of body fluid specimens (e.g., from blood, stool, nasopharynx, or sputum), if clinical andepidemiologic clues are suggestive, should be performed in an attempt to identify various viral,bacterial, and fungal etiologies of encephalitis positive results do not necessarily indicate that the

isolated microorganism is the etiology of encephalitis and must be interpreted in the context of theappropriate epidemiologic findings, clinical findings, and other diagnostic study results.

Biopsy of specific tissues for culture, antigen detection, nucleic acid amplification tests (such as PCR),and histopathologic examination should be performed in an attempt to establish an etiologic diagnosis of

encephalitis

Certain causes of encephalitis may be diagnosed by detection of IgM antibodies in serum


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Although acute- and convalescent-phase serum samples are generally not useful in establishing theetiology during the acute presentation in a patient with encephalitis, they may be useful for the

retrospective diagnosis of an infectious agent

Nucleic acid amplification tests (such as PCR) of body fluids outside of the CNS may be helpful inestablishing the etiology in some patients with encephalitis

Neurodiagnostic Studies MRI is the most sensitive neuroimaging test to evaluate patients with encephalitis (A-I). CT, with and without contrast enhancement, should be used to evaluate patients with encephalitis if

MRI is unavailable, impractical, or cannot be performed .

Fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning is not routinelyrecommended for patients with encephalitis.

Electroencephalography (EEG) is rarely helpful in establishing an etiology in patients with encephalitis,but it has a role in identifying patients with nonconvulsive seizure activity who are confused, obtunded,or comatose and should be performed in all patients with encephalitis

CSF analysis is essential (unless contraindicated) in all patients with encephalitisDiagnostic Studies in the CNS

For certain viral agents, the presence of virus-specific IgM in CSF specimens may be indicative of CNSdisease caused by that pathogen

Nucleic acid amplification tests (such as PCR) should be performed on CSF specimens to identifycertain etiologic agents in patients with encephalitis Although a positive test result is helpful in

diagnosing infection caused by a specific pathogen, a negative result cannot be used as definitive

evidence against the diagnosis.

Herpes simplex PCR should be performed on all CSF specimens in patients with encephalitis (A-III). Inpatients with encephalitis who have a negative herpes simplex PCR result, consideration should be given

to repeating the test 37 days later in those with a compatible clinical syndrome or temporal lobe

localization on neuroimaging

Viral cultures of CSF specimens are of limited value in patients with encephalitis and are not routinelyrecommended.

Brain biopsy should not be routinely used in patients with encephalitis but should be considered inpatients with encephalitis of unknown etiology whose condition deteriorates despite treatment withacyclovir

MANAGEMENT

Treatment

Empirical Therapy

. Acyclovir should be initiated in all patients with suspected encephalitis, pending results of diagnosticstudies

. Other empirical antimicrobial agents should be initiated on the basis of specific epidemiologic orclinical factors including appropriate therapy for presumed bacterial meningitis, if clinically indicated

In patients with clinical clues suggestive of rickettsial or ehrlichial infection during the appropriateseason, doxycycline should be added to empirical treatment regimensSpecific Therapy

Viruses

Herpes simplex virus: acyclovir is recommended Varicella-zoster virus: acyclovir is recommended ganciclovir can be considered an alternative (C-III);

adjunctive corticosteroids can be considered

Cytomegalovirus: the combination of ganciclovir plus foscarnet is recommended ; cidofovir is notrecommended, because its ability to penetrate the blood-brain barrier has been poorly studied.


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Epstein-Barr virus: acyclovir is not recommended; the use of corticosteroids may be beneficial but thepotential risks must be weighed against the benefits.

Human herpesvirus 6: ganciclovir or foscarnet should be used in immunocompromised patients use ofthese agents in immunocompetent patients can be considered , but there are not good data on theireffectiveness.

B virus: valacyclovir is recommended ; alternative agents are ganciclovir and acyclovirInfluenza virus: oseltamivir can be considered

Measles virus: ribavirin can be considered intrathecal ribavirin can be considered in patients withsubacute sclerosing panencephalitis

HIV: HAART is recommended JC virus: reversal of immunosuppression or HAART in HIV-infected patientsis recommended.

Bacteria

Bartonella bacilliformis: chloramphenicol, ciprofloxacin, doxycycline, ampicillin, or trimethoprim-sulfamethoxazole is recommended

Bartonella henselae: doxycycline or azithromycin, with or without rifampin, can be considered Listeria monocytogenes: ampicillin plus gentamicin is recommended trimethoprim-sulfamethoxazole is

an alternative in the penicillin-allergic patient

Mycoplasma pneumoniae: antimicrobial therapy (azithromycin, doxycycline, or a fluoroquinolone) canbe considered

Tropheryma whipplei: ceftriaxone, followed by either trimethoprim-sulfamethoxazole or cefixime, isrecommended

Mycobacteria

Mycobacterium tuberculosis: 4-drug antituberculous therapy should be initiated adjunctivedexamethasone should be added in patients with meningitis

Rickettsioses and ehrlichioses

Anaplasma phagocytophilum: doxycycline is recommended Ehrlichia chaffeensis: doxycycline is recommended Rickettsia rickettsii: doxycycline is recommended chloramphenicol can be considered an alternative in

selected clinical scenarios, such as pregnancy

Coxiella burnetii: doxycycline plus a fluoroquinolone plus rifampin is recommendedSpirochetes Borrelia burgdorferi: ceftriaxone, cefotaxime, or penicillin G is recommended Treponema pallidum: penicillin G is recommended ceftriaxone is an alternative

Fungi

Coccidioides species: fluconazole is recommended alternatives are itraconazole voriconazole and amphotericin B (intravenous and intrathecal) Cryptococcus neoformans: initial treatment with amphotericin B deoxycholate plus flucytosine or a

lipid formulation of amphotericin B plus flucytosine is recommended.

Histoplasma capsulatum: liposomal amphotericin B followed by itraconazole is recommendedProtozoa

Acanthamoeba: trimethoprim-sulfamethoxazole plus rifampin plus ketoconazole or fluconazole plussulfadiazine plus pyrimethamine) can be considered.

Balamuthia mandrillaris: pentamidine, combined with a macrolide (azithromycin or clarithromycin),fluconazole, sulfadiazine, flucytosine, and a phenothiazine can be considered .

Naegleria fowleri: amphotericin B (intravenous and intrathecal) and rifampin, combined with otheragents, can be considered .

Plasmodium falciparum: quinine, quinidine, or artemether is recommended atovaquone-proguanil is analternative ; exchange transfusion is recommended for patients with >10% parasitemia or cerebral

malaria corticosteroids are not recommended.


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Toxoplasma gondii: pyrimethamine plus either sulfadiazine or clindamycin is recommendedtrimethoprim-sulfamethoxazole alone ) and pyrimethamine plus either atovaquone, clarithromycin,

azithromycin, or dapsone are alternatives.

Trypanosoma brucei gambiense: eflornithine is recommended melarsoprol is an alternative Trypanosoma brucei rhodesiense: melarsoprol is recommended

Helminths

Baylisascaris procyonis: albendazole plus diethycarbamazine can be considered adjunctivecorticosteroids should also be considered

Gnathostoma species: albendazole ) or ivermectin is recommended. Taenia solium: need for treatment should be individualized; albendazole and corticosteroids are

recommended praziquantel can be considered as an alternative

Postinfectious/postvaccination status

Acute disseminated encephalomyelitis: high-dose corticosteroids are recommended alternatives includeplasma exchange and intravenous immunoglobulin

How will you differentiate CMV encephalitis, Herpes simplex encephalitis and Varicella

zoster encephalitis radiologically and by CSF analysis? How will you manage theseconditions? What are the complications you look for?

Ans :HIV-associated cytomegalovirus (CMV) encephalitisIt is one of several central and peripheral nervous system infections seen in late-stage disease. Neurologic

manifestations of CMV infection include encephalitis, ventriculitis, myelitis, retinitis, radiculoganglionitis, andperipheral neuropathies. These infections usually occur in patients with severe immunodeficiency:

CD4+

lymphocyte counts typically are lower than 50/L.

Prior to the development of highly active antiretroviral therapy (HAART), 2% of HIV-infected patients with

CD4+

counts less than 50/L developed CMV neurologic disease. The incidence has decreased since HAARTbecame available. CMV infection of the CNS is recognized at autopsy in 18-28% of patients with AIDS.

Histologic findings include ventriculoencephalitis, microglial nodules, focal parenchymal necrosis, isolatedcytomegalic cells, and nuclear inclusions.Cerebrospinal fluid (CSF) analysis not only can point to the correct diagnosis but also permits exclusion of

other diagnostic considerations. Prompt initiation of antiviral drugs is essential. If left untreated, HIV-associated

CMV encephalitis typically progresses to death in days to weeks. Death may result from other complications ofadvanced AIDS rather than the neurologic condition.

CSF Analysis : Cerebrospinal fluid (CSF) analysis not only can point to the correct diagnosis but also permits

exclusion of other diagnostic considerations. Typical CSF findings are an elevated protein level and

mononuclear leukocytosis. Cytomegalovirus (CMV) can be detected by means of culture, polymerase chainreaction (PCR), CMV antigen testing, or cytology. In patients without CMV infection, CMV is rarely detected

by PCR in the CSF. PCR of the CSF may help confirm the diagnosis

Radiological examination Computed tomography (CT) and magnetic resonance imaging (MRI) can aid in thediagnosis and can exclude other diagnostic considerations (eg, absence of parenchymal enhancement, evidenceof increased intracranial pressure [ICP]). Head CT and MRI findings include encephalitis involving the cerebral

hemispheres and brainstem, ventriculitis, meningitis, and infarcts. Hydrocephalus and cerebral atrophy have

been reported. Periventricular calcification, a marker of congenital CMV infection, is not seen.Mass lesions due to CMV have been reported but are rare. T2-weighted MRI may show diffuse white matter

hyperintensity similar to that seen in HIV encephalopathy and other HIV-associated central nervous system

(CNS) disorders. Gadolinium contrast MRI may reveal meningeal and ependymal enhancement, as well as ringenhancing lesions.


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Management ;Prompt initiation of antiviral drugs is essential for treatment of cytomegalovirus (CMV) encephalitis.

[3]These

agents inhibit viral replication by competing with deoxyguanosine triphosphate for viral DNA polymerase,

inhibiting DNA synthesis. Medical support is required in cooperation with the primary care physician and aninfectious diseases specialist.

Because the clinical presentation, cerebrospinal fluid (CSF) studies, and imaging studies may not provide a

definitive diagnosis, a high level of suspicion is necessary to avoid a delay in proper therapy. Delayed diagnosisand treatment can lead to death.

Ganciclovir and foscarnet

Ganciclovirand foscarnet are indicated for CMV infections in the induction phase. The 2 agents may be used incombination, although this combination results in substantial rates of adverse effects.

[4, 3]Long-term intravenous

(IV) maintenance therapy may be indicated for patients who have a clinical response.

Valganciclovir

Oral valganciclovirhas very good bioavailability and can be used for long-term prophylaxis. Patients notresponding to ganciclovir should be evaluated for ganciclovir resistance, a common cause of treatment failure.

Most of these patients remain sensitive to foscarnet.

The goal of pharmacotherapy is to shorten the clinical course and prevent or decrease complications, latency,

recurrences, transmission, and established latency. Highly active antiretroviral therapy (HAART) is effective inreconstituting the immune system and preventing CMV reactivation.

[5]Current guidelines recommend

discontinuation of secondary prophylaxis in HAART recipients with a sustained (>6 mo) increase in CD4+

T

cells to greater than 100-150 cells/L

HIV Associated Herpes Simplex Encephalitis

DiagnosisThere are no pathognomonic clinical findings associated with HSE. Focal neurologic deficits, CSF pleocytosis,

and abnormalities on CT scanning may be absent initially. Therefore, a high index of suspicion is required to

make the diagnosis, particularly in immunocompromised patients with febrile encephalopathy. Expeditious

evaluation is indicated after the diagnosis of HSE is considered.

HSE occurs as 2 distinct entities:In children older than 3 months and in adults, HSE is usually localized to the temporal and frontal lobes and is

caused by HSV-1In neonates, however, brain involvement is generalized, and the usual cause is HSV-2, which is acquired at the

time of delivery

CSF Findings :

CSF PCR for HSV (gold standard)

Test Sensitivity: 95%

False negatives occur in first 12 hours and after 10 days

CSF Cell Count

Test Sensitivity: 95% for Pleocytosis at 10-200 cellsPredominantly Lymphocytosis or monocytosis

CSF ProteinIncreased to 100 mg/dl in 80% of cases

CSF Glucose

Normal to low

Radiographic featuresIn the adult immunocompetent patient, the pattern is quite characteristic, involving the medial temporal lobes,

insular cortex and inferolateral frontal lobes. The basal ganglia are typically spared, helping to

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