2 Central nervous system opportunistic infections

The PubMed database was searched under the following heading: HIV or AIDS and central nervous system infection or space-occupying lesion or meningitis or encephalitis or pneumonitis and/or Cryptococcus neoformans, cryptococcosis, Toxoplasma gondii, toxoplasmosis, progressive multifocal leukoencephalopathy, cytomegalovirus or CMV. Disease of the central nervous system (CNS) is common in HIV. It may be a direct consequence of HIV infection or an indirect result of CD4 cell depletion. Presentation may be predominantly manifested as a space-occupying lesion(s), encephalitis, meningitis, myelitis, spinal root disease or neuropathy (Table 2.1), and may occur in isolation or together with other HIV-related disease. This section deals with cerebral toxoplasmosis, cryptococcal meningitis, progressive multifocal leukoencephalopathy (PML), and cytomegalovirus (CMV) encephalitis and polyradiculitis (Table 2.2 and Fig. 2.1). Mycobacterial disease and primary CNS lymphoma (PCNSL) are not discussed in this section as Mycobacterium tuberculosis is the focus of separate guidelines [1] and PCNSL is discussed within the BHIVA Malignancy Guidelines [2]. Management of HIV patients presenting with focal neurology and CD4 count <200 cells/μL. Notes(1) *MRI preferred as more sensitive(2) If there are signs of raised ICP, treat with dexamethasone 4 mg qds initially. Once the patient is stable, gradually tail off. Improvement on steroids maybe due to reduction of cerebral oedema or partial response of lymphoma to corticosteroids(3) At least 2 weeks maybe necessary to assess for a response to antitoxoplasmal therapy. In some cases, if no urgency, monitor for 4 weeks with repeat MRI. Opportunistic infections of the CNS carry a great risk of morbidity and mortality. Several factors influence the likelihood of a specific aetiology, including CD4 cell count, ethnicity, age, risk group, prophylactic history and geographical location. Clinical evaluation and imaging, often with spinal fluid evaluation, is essential in determining the aetiology and appropriate management. In particular, MR scanning and CSF nucleic acid amplification have refined the approach to diagnostic confirmation so that brain biopsy is less often required (e.g. PML). With the exception of cryptococcal meningitis, therapy is usually commenced without prior confirmation and for toxoplasmosis facilitates distinction of Toxoplasma encephalitis from primary CNS lymphoma with confidence, where imaging is nondiagnostic. Early introduction of HAART is also vital in reducing morbidity and mortality, and indeed for PML is the only form of treatment. Cryptococcosis is the commonest systemic fungal infection associated with immunosuppression secondary to HIV infection [3]. Prior to the availability of highly active antiretroviral therapy (HAART) cryptococcosis occurred in approximately 5–10% of individuals infected with HIV [3], although this was higher in certain areas of the world [4,5]. Since the advent of HAART the incidence of cryptococcal disease has dramatically reduced [6,7]. Cryptococcus is an encapsulated yeast ubiquitous in the environment. Epidemiological studies have confirmed the theory that primary infections occur during childhood and are usually asymptomatic [8]. The organism most commonly associated with HIV-related cryptococcal disease in the UK is C. neoformans var. grubii (serotype A) while C. neoformans var. neoformans (serotype D) is the second major strain in HIV-seropositive individuals [9]. Symptomatic disease with another subtype, Cryptococcus neoformans var. gattii (serotype B/C), is also well described in HIV patients [10]. Other subtypes of Cryptococcus have also been rarely described to cause disease [11]. C. neoformans var. neoformans has been found in association with bird (primarily pigeon) droppings, although nonavian sources are also found [12]. C. neoformans var. gattii has been isolated from eucalyptus trees [13]. Infections caused with C. neoformans var. gattii occur mainly in tropical and subtropical regions. Infection with Cryptococcus spp. is by inhalation of the organism [14] and localized disease in the lung may occur. Without therapy the yeast rapidly spreads to the blood and is neurotropic, leading to the development of cryptococcal meningitis [15,16]. The progression from cryptococcaemia to meningitis is rapid [17]. Other sites of disease after dissemination may include the skin, where appearances resemble molluscum, and the lung. The prostate gland acts as a sanctuary site for Cryptococcus spp. in the immunosuppressed [18]. The presenting symptoms are dependent upon the site of infection. Cryptococcal meningitis is the commonest presentation of cryptococcal disease. The commonest symptoms are headache and fever. The incidence of meningism is variable [17,19]. Raised intracranial pressure may be associated with nausea, vomiting, confusion and coma. Cryptococcal meningitis may also be associated with respiratory symptoms from pulmonary disease or with skin lesions such as papules or umbilicated molluscum-like skin lesions. Pulmonary disease may also occur in the absence of neurological disease. However, isolated pulmonary disease due to cryptococcal infection is unusual in HIV disease [20]. Individuals present nonspecifically with fever and cough with or without sputum and shortness of breath. Chest radiograph appearances are variable but include widespread infiltration, nodular disease, isolated abscess formation and pleural effusion [21–23]. Occasional individuals present with haematological spread without meningitis or overt pulmonary disease. Presentation is with fever, night sweats and occasionally rigors. Rare manifestations of cryptococcal disease include ocular palsy, papilloedema, chorioretinitis and osteolytic bone lesions. All individuals with a positive serum cryptococcal antigen should have a lumbar puncture performed (category III recommendation). A positive CSF cryptococcal antigen is the most sensitive diagnostic test for cryptococcal meningitis (category III recommendation). All patients undergoing a CSF examination for suspected cryptococcal meningitis should have manometry performed (category III recommendation). All HIV patients presenting with a CD4 count less than 200 cells/μL and symptoms compatible with cryptococcosis should have this disease excluded. The principle diagnostic test for disseminated cryptococcal disease is serum cryptococcal antigen, which most commonly uses the latex agglutination method. A negative test generally excludes disseminated cryptococcal disease although there are isolated reports of a negative cryptococcal antigen with disseminated disease [24,25]. False positive cryptococcal antigen may occur in the presence of rheumatoid factor, heterophile antibodies, anti-idiotypic antibodies and Trichosporon asahii (beigelii) infection [26–28]. Serum cryptococcal antigen may be negative in isolated pulmonary disease [29] and microscopy and fungal culture of respiratory specimens are required to make the diagnosis. All patients with a positive serum cryptococcal antigen should undergo further evaluation by lumbar puncture after CT or MRI cerebral scanning. Manometry must always be performed to exclude a raised intracranial pressure. A positive CSF cryptococcal antigen, Indian ink stain of CSF, or CSF cryptococcus culture confirms meningitis. CSF should always be sent for fungal culture. Blood culture should always be performed. Where blood cultures or CSF cultures are positive, isolates may be sent for fungal susceptibility testing where facilities exist [30] Strains with increased azole minimum inhibitory concentrations (MICs) have been reported, in particular from sub-Saharan Africa. However, the correlation between clinical response and fluconazole MIC has been variable [31,32]. Although fungal susceptibilities should be requested initially, the decision to switch therapy should not be based on the antifungal MIC alone but requires supportive laboratory or clinical markers of an impaired response to therapy (category IV recommendation). Poor prognostic factors are blood culture positivity, low white blood cell in CSF (<20 cells/mL), high CSF cryptococcal antigen (>1:1024), a confused state and a raised intracranial pressure [33]. Standard induction therapy of cryptococcal meningitis is with amphotericin B, usually combined with flucytosine 100 mg/kg/day (category Ib recommendation). Liposomal amphotericin B 4 mg/kg/day intravenously is the preferred amphotericin B preparation on the basis of lower nephrotoxicity than conventional preparations (category III recommendation). Fluconazole plus flucytosine or the use of voriconazole or posaconazole may be considered where standard regimens fail or are not tolerated (category IV recommendation). Historically, the standard of care for the treatment of cryptococcal meningitis in HIV-seronegative individuals has been amphotericin B deoxycholate (0.7–1 mg/kg/day) combined with flucytosine (100 mg/kg/day) [34,35]. However, the advantages and disadvantages of the addition of flucytosine to amphotericin B deoxycholate in the HIV setting should be carefully weighed for each individual patient [36–39]. The addition of flucytosine speeds the rate of sterilization of the CSF [36,39] and reduces the incidence of relapse [40] in patients not receiving HAART. However, flucytosine has been associated with enhanced toxicity in some (though not other) studies and has not been shown to impact on early or late mortality [14,36]. In addition, most of the benefits of flucytosine have been observed in patients not receiving HAART. When flucytosine is given, it may be prescribed orally or intravenously. is associated with haematological toxicity and blood are required with of flucytosine Standard amphotericin B is associated with and where should be by amphotericin B as the (category III recommendation). In a of HIV-seropositive of receiving amphotericin B deoxycholate with associated mortality has that amphotericin B without flucytosine therapy the CSF than standard amphotericin B and was associated with lower nephrotoxicity but not with the basis of the lower incidence of have amphotericin B deoxycholate on the basis of least and lower amphotericin B mg/kg/day is the preferred amphotericin B preparation for the treatment of cryptococcal meningitis. to an are in When therapy is not an is fluconazole with or without flucytosine mg/kg/day) Fluconazole alone is associated with a higher but not mortality than amphotericin B [33]. In individuals with prognostic factors some may to use a due to of and low toxicity (category IV recommendation). The addition of flucytosine to fluconazole may result in higher of sterilization of CSF of fluconazole have also been is less active than fluconazole and should only be if other are are on the use of such as voriconazole and posaconazole in HIV patients with cryptococcal meningitis, although have in are reports of cryptococcal meningitis associated with HIV with voriconazole and posaconazole are and should only be other fail or are not occur with the and antiretroviral and is and often of where and may be Cryptococcus CSF manometry should be performed on patients or if signs of neurological and lumbar or are for individuals with an pressure (category III recommendation). Manometry is essential diagnostic lumbar puncture as there is a incidence of raised intracranial pressure associated with cryptococcal meningitis. If the pressure is than this should be reduced to 200 or to of the pressure. should be lumbar puncture should always be considered in patient with cryptococcal meningitis or neurological of raised intracranial pressure may for and have not been shown to be of The preferred is fluconazole mg a after approximately weeks of induction therapy (category Ib recommendation). The fluconazole is reduced to 200 mg a after weeks (category III recommendation). A lumbar puncture weeks and of induction therapy CSF cultures are negative be considered in individuals with or a clinical response to induction therapy (category IV recommendation). therapy is essential following induction therapy for individuals cryptococcal disease. In of therapy following induction therapy of patients receiving The of from induction to therapy is to sterilization of CSF, CSF cryptococcal with risk of relapse and mortality induction therapy CSF cultures are a of most often and switch the patient to a if without further lumbar This may be the preferred for most in HAART is the risk of relapse and mortality is to be lower than that in should be of a lumbar puncture and of therapy in individuals prognostic factors or response to therapy that are less to be by only induction (category IV recommendation). for therapy are fluconazole or or amphotericin Fluconazole has been shown to be to amphotericin B with less toxicity and lower of relapse and also to which was associated with higher of CSF relapse The of fluconazole as therapy Although the standard is 200 mg a to a higher of mg with a lower rate of relapse Serum cryptococcal antigen is not in for relapse of disease Cryptococcal infection without CNS Pulmonary cryptococcal isolated cryptococcaemia or cryptococcal disease another site the CNS and should be for associated CNS infection by an If this is treatment is as for meningitis. If CSF examination is isolated pulmonary disease be with are no clinical studies of the treatment of isolated pulmonary cryptococcal disease in the HIV or the All HIV patients with isolated pulmonary disease should be due to the certain risk of In with symptoms the treatment of is fluconazole mg by secondary In with more disease, amphotericin B should be symptoms are this should be by secondary in patients with isolated cryptococcaemia there are no studies to treatment to the rapid progression to meningitis from this patients should be with fluconazole mg if or or amphotericin B if symptoms are more for cryptococcal disease is not (category IV recommendation). have shown a in reducing the incidence of cryptococcal disease with primary with and an on is a risk of the development of and due to this and the high associated with azole this approach be All individuals with cryptococcal disease should HAART (category which should be commenced approximately after of cryptococcal induction therapy has been The incidence of cryptococcal disease has All individuals should HAART (category which should be commenced approximately after of cryptococcal induction therapy has been (category III recommendation). The to HAART in patients with cryptococcal meningitis is not have to the risk of HIV progression the of which include and in mortality has been observed in patients on antiretroviral therapy within of treatment for cryptococcal meningitis. This was performed in with a of patients and may not be to a should be of the risk of development of which is well described with cryptococcal disease manifestations include meningitis, raised intracranial space-occupying lesions in the pulmonary or and with other of treatment is with if and if active infection is of steroids or other treatment secondary for cryptococcal meningitis be the CD4 count is cells/μL in the presence of an for least and also this approach Toxoplasma are the commonest cause of lesions in the HIV-seropositive individual including sub-Saharan Toxoplasma is an are of the as the only in the the infection by with disseminated infection or by of in that have and The primary in is often asymptomatic but some individuals may a In toxoplasmosis is usually caused by the of infection in Toxoplasma are the commonest cause of focal lesions in the of patients with HIV infection and a CD4 count <200 cells/μL. for and on age, and to in the UK and in of The risk of an HIV-seropositive individual is for encephalitis is However, in of patients with toxoplasmosis by biopsy or a response to treatment to be as a result of primary infection or the of upon impaired It is to of HIV. The clinical presentation with cerebral a of to weeks with the development of focal neurological signs and symptoms and a result of raised intracranial pressure patients may headache and signs include or a and a of as have a for the individuals present with signs of a encephalitis with and of This may rapidly to and infection may present as The spinal may be with a myelitis, or with lesions. the nervous system include chorioretinitis and imaging diagnosis. MRI is to CT (category III recommendation). may also be in the of PCNSL (category III recommendation). If there is not a to lumbar puncture a positive CSF for a but has only (category III recommendation). The of and MRI is more sensitive a in particular in lesions in the If there is a in an CT should be performed with MRI the are lesions the and in the of the or are associated with cerebral oedema and CD4 cell may be associated with an absence of with PCNSL be from encephalitis by lesions that are have a or spread are of PCNSL The lesions found in PML to mainly white are rarely and not to between infections including abscess and PCNSL high Toxoplasma is not in the The presence of is only of infection. be of However, this often not occur in the only that a patient is risk of In patients presenting with lumbar puncture is often due to raised intracranial pressure. If there is no of and there is diagnostic CSF examination maybe with the and an may be testing for on the CSF has a of with a of therapy for encephalitis is with acid for weeks by therapy (category Ib recommendation). patients to or of is the preferred (category Ib recommendation). include alone combined with or but there is with (category III of response to weeks of clinical or that are not of encephalitis should to of a brain biopsy (category IV recommendation). With it is standard to treat HIV patient with a CD4 count of <200 cells/μL and a brain lesion with therapy. should be for as this is highly in individuals from and However, has been found not to be in individuals although in during therapy should therapy is in toxoplasmosis with of patients a response and within 2 weeks A response to treatment is of without to to more that include or combined with and acid in the treatment of encephalitis In a clinical in the of although there was a less response in the receiving the and more in the In the of treatment there was an approximately in the risk of progression in the the this basis the is the preferred with the for are of of a of 200 mg of by to should be together with acid the of and although should be to based with qds or mg and have so the is studies that be The form of is not within the In the a may be necessary to as it is also not as an also be intravenously. If a patient a usually and this is most to be the or The should be and if to the be but this is a and therapy for patients to therapy This the but in lower plus qds or or mg qds or mg with acid Although has been a more may be as and be for therapy to no direct of and although the has been to a of and is to therapy if or regimens be and acid as for with mg as for plus mg and acid as for with or and mg/kg/day and mg/kg/day or qds orally or IV regimens have not been shown to be as as the but intravenously is a an be in an should not be as the diagnostic are in patients with symptoms and signs of raised intracranial pressure such as vomiting, and When dexamethasone 4 mg gradually is the treatment of However, response and may be due to a reduction in cerebral oedema than a response to the therapy. Clinical after the steroids of a diagnostic brain biopsy should be considered there is of response to least weeks of clinical while on a lesion on or a if the CD4 count is 200 cells/μL. If a patient with or is However, there is no to the of in patients with HIV patients with a CD4 count of <200 cells/μL and positive encephalitis (category recommendation). Although there are no clinical of of have of and plus encephalitis be but is the preferred and mg is for individuals are to may also be In addition, HIV-seropositive individuals should be to the of to after with and to If this is not and that are after of must be and secondary be the CD4 count is 200 cells/μL Ib recommendation). HAART has the incidence of HAART has been associated with a in encephalitis and should be as as the patient is approximately 2 weeks after treatment of encephalitis to the likelihood of have been a of reports of associated with encephalitis the of primary maybe after of HIV and of the CD4 to cells/μL for therapy may be after of of HIV and of CD4 count to cells/μL as a clinical in progressive multifocal leukoencephalopathy was to be an infection in from a patient with disease after the patient This was further as a to the of predominantly in childhood although to and of the are The of is but is by respiratory and the primary the and infection in bone and With and is to the brain by where it the The advent of HIV the from was an of patients with disease or immunosuppressed following to an in to of patients with AIDS with reduction after introduction of HAART and no in the high mortality rate PML caused approximately of focal brain lesions The and determining the clinical presentation is of white which is PML as a without symptoms in patients with focal mainly or or weeks to The presence of the focal the associated with PML from HIV may rarely occur. Rare but PML may present after the introduction of treatment and an MRI appearances and by in a CSF are to make a in most and the for a brain biopsy III recommendation). Early is biopsy has been as the standard with a of and a of With imaging MRI combined with CSF amplification has of are usually to white and with no The and from HIV In the of antiretroviral may be in the CSF by of and a of However, the introduction of HAART has to approximately reduced and increased of from the CSF associated with a include clinical age, of CSF with with and count of higher CD4 cell on imaging, and are associated with HAART is the only that has clinical with PML (category III recommendation). Although and are active and in with reduction in CSF in has been shown to the disease and there no specific treatment for PML other than or treatment. was shown in a to no to HAART alone and have been confirmed in of from prior or studies intravenously or to to this was HAART the only The of HAART should CNS as has shown a with based on CNS is no therapy that has been as in a of of patients receiving HAART for this of and some patients of disease with of neurological morbidity and the development of and on MRI. the impact of HAART on PML may be less than for other focal neurological the of PML to the incidence of focal lesions in the brain may have increased (CMV) is a of the other it has the to and infection after primary In the of this may result in primary or clinical disease. have with are in and the rate is With clinical progression of leading to in a disease. Prior to the advent of studies that of patients with AIDS disease, with more patients of disease disease incidence higher the CD4 count to cells/μL. The major sites of disease are the which for approximately of cases, the the the and the and the nervous system and The widespread of HAART has the with most patients treatment risk for disease. system infection for of clinical disease Clinical signs and symptoms are and to from A history with progressive and is symptoms of and are more in the form is often or to more encephalitis is more than HIV brain disease. Clinical of or is present in of polyradiculitis and to may Presentation of polyradiculitis is usually as a rapidly with and MRI scanning and CSF are the preferred diagnostic (category III recommendation). of neurological in a patient with HIV with a low CD4 cell count with if not lumbar CT white with and focal or nodular lesions are However, MRI is more sensitive are on enhanced with commonly However, imaging and patients have or CSF examination is rarely although a raised and are not In patients with isolated or of and is on MR and a cell is studies neuropathy and polyradiculitis from an of is based nucleic acid amplification of A positive CSF has a of and a of with negative and positive of and However, may rarely be negative in patients found to have active disease of the biopsy is rarely in of with or without is the treatment of (category III recommendation). HAART should also be after therapy (category III recommendation). have been no for neurological disease although well on the of and exist for the of be to encephalitis or polyradiculitis In a in the treatment with and or in of HIV-seropositive patients with neurological was only clinical in polyradiculitis have been found with or together in have also been shown to CSF the by or HAART is in although no specific exist for disease of the nervous of treatment for is not required but HAART is to the incidence of (category IV recommendation). have been no for neurological disease although on the prophylactic of and exist for the of be to encephalitis that HAART has been to the risk of disease and that this is a rarely where the CD4 is the to encephalitis is of to and treatment guidelines Although is to therapy be for with and a in CD4 no such for neurological disease and a more approach is This decision should be based upon CSF and blood and imaging HAART the incidence of and disease in but specific for encephalitis not Although is in other there are on presentation as a neurological disease this progressive multifocal primary central nervous system cryptococcal ICP, intracranial pressure.