2 Central nervous system opportunistic infections

Authors


*E-mail: mark.nelson@chelwest.nhs.uk

2.1 Methods

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.

2.2 Introduction

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].

Table 2.1.   Differential diagnosis of HIV-related opportunistic infections and malignancies of the CNS Thumbnail image of
Table 2.2.   Treatment, maintenance and prophylaxis: recommended first-line drugs and alternatives
 RecommendedAlternative
Cerebral toxoplasmosisInduction:
Sulphadiazine Oral therapy (1–2 g qds or15 mg/kg qds) with pyrimethamine (loading dose 200 mg then 50–75 mg daily depending on weight) and folinic acid (10–15 mg daily). Duration 6 weeks.
Maintenance:
Sulphadiazine (500 mg−1 g qds) with pyrimethamine (25 mg daily) and folinic acid (10 mg daily). Sulphadiazine may also be given 1–2 g bd
Primary prophylaxis:
TMP-SMX (480–960 mg daily).
Induction:
Clindamycin (600 mg qds iv/oral) with pyrimethamine (loading dose 200 mg then 50–75 mg daily depending on weight) and folinic acid (10–15 mg daily).
Further alternatives given in text.
Maintenance:
Clindamycin (300 mg qds or 600 mg tds) with pyrimethamine (25 mg daily) and folinic acid (10 mg daily).
Primary prophylaxis:
Dapsone (50 mg daily) with pyrimethamine (50 mg/weekly) and folinic acid (15 mg/weekly).
Progressive multifocal leukoencephalopathyHAART commencement/optimization. 
Cryptococcal meningitisInduction:
Liposomal amphotericin B (4 mg/kg/day) and 5-flucytosine (100 mg/kg/day). Duration 2 weeks.
Maintenance:
Fluconazole (400 mg daily). Duration 8 weeks.
Secondary prophylaxis:
Fluconazole (200 mg daily).
Primary prophylaxis:
Not indicated.
Induction:
Fluconazole (iv/oral 400 mg daily) and flucytosine (iv/oral 100–150 mg/kg/day).
Itraconazole (iv/oral 400 mg daily) – alternative but less effective.
Voriconazole or posaconazole are less studied options.
Maintenance:
Liposomal amphotericin (4 mg/kg/weekly).
Itraconazole(200 mg/od)
Secondary prophylaxis:
Itraconazole (200 mg od) or liposomal amphotericin (4 mg/kg/weekly).
CMV encephalitis and radiculopathyInduction:
IV ganciclovir (5 mg/kg bd). Duration 3 weeks).
Maintenance: IV ganciclovir (5 mg/kg daily) or oral valganciclovir (900 mg daily).
Primary prophylaxis:
Not indicated.
Induction:
Foscarnet (90 mg/kg bd) or cidofovir (5 mg/kg weekly). Duration 2 weeks).
Maintenance:
Foscarnet (90 mg/kg daily) or cidofovir (5 mg/kg fortnightly).
Figure 21.

 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.

2.3 General overview

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.

2.4 Cryptococcus neoformans

2.4.1 Background and epidemiology

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].

2.4.2 Presentation

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.

2.4.3 Diagnosis

  • 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].

2.4.4 Treatment

2.4.4.1 Induction.

  • 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. Flucytosine is associated with haematological toxicity and daily blood counts are required with monitoring of flucytosine levels.

Standard amphotericin B is associated with renal toxicity, and where possible should be replaced by liposomal amphotericin B as the first choice agent (category III recommendation). In one study (including a small number of HIV-seropositive individuals) 30% of those receiving amphotericin B deoxycholate developed acute renal failure with significant associated mortality [41]. Further research has demonstrated that liposomal amphotericin B (4 mg/kg) without concomitant flucytosine therapy sterilized the CSF faster than standard amphotericin B and was associated with lower nephrotoxicity but not with any survival advantage [42]. On the basis of the lower incidence of nephrotoxicity, many pharmacy departments have stopped stocking amphotericin B deoxycholate and, on the basis of at least equivalent efficacy and lower nephrotoxicity, liposomal amphotericin B (4 mg/kg/day intravenously) is the preferred amphotericin B preparation when available for the treatment of cryptococcal meningitis.

Alternative therapies to an amphotericin-based regimen are listed in Table 2.2. When amphotericin-based therapy is not tolerated, an alternative is fluconazole (400 mg/day) with or without flucytosine (100–150 mg/kg/day) [33,37,43]. Fluconazole alone is associated with a higher early, but not overall, mortality than amphotericin B [33]. In individuals with good prognostic factors (see above) some physicians may choose to use a fluconazole-containing regimen first-line due to its ease of administration and low toxicity (category IV recommendation). The addition of flucytosine to fluconazole may result in higher rates of sterilization of CSF [43]. Higher doses of fluconazole have also been utilized [44].

Itraconazole (400 mg/day) is less active than fluconazole [40,45] and should only be used if other agents are contraindicated. There are few data on the use of newer azoles such as voriconazole and posaconazole in HIV patients with cryptococcal meningitis, although these drugs have in vitro activity [46,47]. There are case reports of refractory cryptococcal meningitis associated with HIV being treated with both voriconazole and posaconazole [47,48]. These agents are expensive and should only be utilized when other agents fail or are not tolerated. Significant drug–drug interactions occur with the azoles and antiretroviral agents and specialist input is required, and often therapeutic drug monitoring of azoles where available, and antiretrovirals may be warranted (see Table 2.3). Caspofungin lacks activity against Cryptococcus species [49].

Table 2.3.   Potential CNS opportunistic infection and antiretroviral drug interactions Thumbnail image of

2.4.4.2 Management of raised intracranial pressure.

  • CSF manometry should be performed on all patients at baseline or if any signs of neurological deterioration occur, and serial lumbar punctures or neurosurgical procedures are indicated for individuals with an opening pressure >250 mmH2O (category III recommendation).

Manometry is essential at diagnostic lumbar puncture as there is a significant incidence of raised intracranial pressure associated with cryptococcal meningitis. If the opening pressure is greater than 250 mmH2O then this should be reduced to below 200 mmH2O or to 50% of the initial pressure. Lumbar punctures should be repeated daily until stable. Repeat lumbar puncture should always be considered in any patient with cryptococcal meningitis who deteriorates or develops new neurological signs. Resistant cases of raised intracranial pressure may require neurosurgical referral for ventriculo-peritoneal shunt.

Corticosteroids and acetazolamide have not been shown to be of benefit [50,51].

2.4.4.3 Maintenance.

  • The preferred maintenance regimen is fluconazole 400 mg once a day orally, started after approximately two weeks of induction therapy (category Ib recommendation).
  • The fluconazole dose is then reduced to 200 mg once a day after 10 weeks (category III recommendation).
  • A lumbar puncture at two weeks and extension of induction therapy until CSF cultures are negative can be considered in select individuals with poor prognosis at baseline or a poor initial clinical response to induction therapy (category IV recommendation).

Maintenance therapy is essential following induction therapy for all individuals developing cryptococcal disease. In one placebo-controlled study of maintenance therapy following successful induction therapy over one-third of patients relapsed whilst receiving placebo [52].

The timing of switching from induction to maintenance therapy is unclear. Some physicians wish to achieve sterilization of CSF, since CSF cryptococcal burden correlates with risk of relapse and mortality [53]. To achieve this, they continue induction therapy until CSF cultures are negative. Others will give a fixed course of therapy, most often two weeks, and switch the patient to a maintenance regimen, if well, without further lumbar puncture. This may be the preferred option for most individuals, bearing in mind that, assuming HAART is started, the risk of relapse and mortality is likely to be lower than that reported in older studies. There should be consideration of a lumbar puncture and extension of therapy in individuals whose initial poor prognostic factors or slow response to therapy raise concerns that they are less likely to be cured by only two weeks' induction (category IV recommendation).

Options for maintenance therapy are daily fluconazole or itraconazole, or weekly liposomal amphotericin B. Fluconazole has been shown to be superior to amphotericin B with less drug-associated toxicity and lower rates of relapse [54], and also to itraconazole which was associated with higher rates of CSF culture-positive relapse [40]. The optimal dose of fluconazole as maintenance therapy remains unclear. Although the standard dose is 200 mg daily, one retrospective study showed a benefit to a higher dose of 400 mg daily with a lower rate of relapse [55]. Serum cryptococcal antigen measurement is not useful in monitoring for relapse of disease [56].

2.4.4.4 Cryptococcal infection without CNS involvement. Pulmonary cryptococcal infection, isolated cryptococcaemia or cryptococcal disease at another site outside the CNS and lungs should be assessed for associated occult CNS infection by performing an LP. If this is present, treatment is as for meningitis. If CSF examination is negative, isolated pulmonary disease can be treated with fluconazole. There are no controlled clinical studies of the treatment of isolated pulmonary cryptococcal disease in either the HIV or the non-HIV setting. All HIV patients with isolated pulmonary disease should be treated due to the almost certain risk of dissemination. In those with moderate symptoms the treatment of choice is fluconazole 400 mg daily followed by secondary prophylaxis [57,58]. In those with more severe disease, liposomal amphotericin B should be used [57,59] until symptoms are controlled; again this should be followed by secondary prophylaxis. Similarly, in patients with isolated cryptococcaemia there are no studies to guide treatment options. Due to the rapid progression to meningitis from this condition [17] patients should be treated with either fluconazole 400 mg daily if mild or moderately symptomatic or liposomal amphotericin B if symptoms are more severe.

2.4.5 Prophylaxis

  • Routine prophylaxis for cryptococcal disease is not recommended (category IV recommendation).

Studies have shown a benefit in reducing the incidence of cryptococcal disease with primary prophylaxis with both itraconazole and fluconazole; however, neither intervention had an effect on survival [60]. There is a risk of the development of resistance and due to this factor and the high cost associated with azole prophylaxis, this approach cannot be recommended.

2.4.6 Impact of HAART

  • All individuals diagnosed with cryptococcal disease should receive HAART (category IIb recommendation), which should be commenced at approximately two weeks, after commencement of cryptococcal treatment, when induction therapy has been completed.

The incidence of cryptococcal disease has decreased post-HAART [61]. All individuals should receive HAART (category IIb recommendation), which should be commenced at approximately two weeks, after commencement of cryptococcal treatment, when induction therapy has been completed (category III recommendation). The optimal time to start HAART in patients with cryptococcal meningitis is not known. Physicians have to balance the risk of HIV progression against the hazards of starting HAART, which include toxicities, side effects, immune reconstitution inflammatory syndrome (IRIS) and drug interactions. An increase in mortality has been observed in patients who were initiated on antiretroviral therapy within 72 h of starting treatment for cryptococcal meningitis. This study was performed in Africa, with a small number of patients and may not be relevant to a resource-rich area [62].

Physicians should be aware of the risk of development of IRIS, which is well described with cryptococcal disease [63,64]. Common manifestations include aseptic meningitis, raised intracranial pressure, space-occupying lesions in the brain, pulmonary infiltrates or cavities, lymphadenopathy and hypercalcaemia. As with other forms of IRIS, treatment is with continued HAART, if at all possible, and if active infection is excluded consideration of steroids or other anti-inflammatory treatment [65].

One prospective multicentre randomized study suggests secondary prophylaxis for cryptococcal meningitis can be discontinued once the CD4 count is >100 cells/μL in the presence of an undetectable viral load for at least 3 months [66] and small prospective nonrandomized series also support this approach [67–69].

2.5 Toxoplasma gondii

2.5.1 Background and epidemiology

Toxoplasma abscesses are the commonest cause of mass lesions in the immunocompromised HIV-seropositive individual world-wide, including sub-Saharan Africa [70]. Toxoplasma gondii is an obligate intracellular protozoan whose definite hosts are members of the cat family, as the parasite can complete its sexual cycle only in the feline intestinal tract. Humans acquire the infection by eating animals with disseminated infection or by ingestion of oocytes shed in cat faeces that have contaminated soil, fruits, vegetables and water [71]. The primary infection, in immunocompetent patients, is often asymptomatic but some individuals may develop a mononucleosis-like syndrome. In immunodeficient patients, toxoplasmosis is usually caused by the reactivation of chronic infection acquired earlier in life [72]. Toxoplasma abscesses are the commonest cause of focal mass lesions in the brains of patients with HIV infection and a CD4 T-cell count <200 cells/μL. Seropositivity for toxoplasma varies world-wide and depends on age, dietary habits and proximity to cats; in the UK and US, seroprevalence rates are10–40%, whereas in France rates of 90% reflect differing dietary habits [71]. The lifetime risk of an untreated HIV-seropositive individual who is IgG seropositive for T. gondii developing toxoplasma encephalitis is around 25% [72]. However, in one study, 16% of patients with toxoplasmosis diagnosed by biopsy or a successful response to treatment were reported to be seronegative either as a result of primary infection or the loss of seropositivity consequent upon impaired humoral immunity [73]. It is useful to document any patient's toxoplasma serology at first diagnosis of HIV.

2.5.2 Presentation

The clinical presentation with cerebral abscesses evolves over a period of days to weeks with the development of focal neurological signs and symptoms and sometimes seizures. As a result of raised intracranial pressure patients may develop headache and vomiting. Focal signs include hemiparesis or hemisensory loss, visual field deficits, dysphasia, a cerebellar syndrome and a variety of movement disorders as toxoplasma abscesses have a predilection for the basal ganglia. Some individuals present with signs of a diffuse encephalitis with confusion, seizures and altered levels of consciousness. This may progress rapidly to coma and death. Rarely, toxoplasma infection may present as toxoplasma myelitis. The spinal cord may be involved with a transverse myelitis, cauda equina syndrome or with contrast-enhancing intramedullary mass lesions. Presentations outside the nervous system include chorioretinitis and pneumonia.

2.5.3 Diagnosis

  • Radiological imaging aids diagnosis. MRI is preferable to CT (category III recommendation).
  • Single photon emission computed tomography (SPECT) may also be helpful in excluding the possibility of PCNSL (category III recommendation).
  • If there is not a contraindication to lumbar puncture a positive CSF PCR for T. gondii helps establish a diagnosis but has only moderate sensitivity (category III recommendation).

The differential diagnosis of toxoplasma abscesses includes PCNSL, tuberculous abscesses and PML. MRI is more sensitive at establishing a diagnosis [74], in particular in detecting lesions in the posterior fossa [75]. If there is a delay in obtaining an MRI, CT should be performed first with MRI later. Typically, the abscesses are multiple ring enhancing lesions at the grey–white interface and in the deep grey matter of the basal ganglia or thalamus [76]. They are associated with cerebral oedema and mass effect. Low CD4 cell counts may be associated with an absence of ring enhancement [75]. Patients with PCNSL cannot be reliably separated from toxoplasma encephalitis by CT/MRI although, when present, lesions that are single, have a periventricular location or demonstrate sub-ependymal spread are suggestive of PCNSL [77]. The lesions found in PML tend to involve mainly white matter, are rarely contrast enhancing and do not exhibit mass effect [75].

SPECT helps to distinguish between infections including abscess and PCNSL, since PCNSL reveal high uptake [78]. Toxoplasma serology is not particularly helpful in the diagnosis [77]. The presence of IgG is only evidence of previous infection. Rising IgG titres would be indicative of reactivation. However, this often does not occur in the immunocompromised patient. Positive serology therefore only indicates that a patient is at risk of developing toxoplasmosis.

In patients presenting with mass lesions, lumbar puncture is often contraindicated due to raised intracranial pressure. If there is no evidence of mass effect, and there is diagnostic uncertainty, CSF examination maybe helpful. Discussion with the neurosurgical team and an experienced neuroradiologist may be necessary. PCR testing for T. gondii on the CSF has a sensitivity of 50% with a specificity of >94% [79–81].

2.5.4 Treatment

  • First line therapy for toxoplasma encephalitis is with pyrimethamine, sulphadiazine, folinic acid for 6 weeks followed by maintenance therapy (category Ib recommendation).
  • For patients allergic to or intolerant of sulphadiazine, clindamycin is the preferred alternative agent (category Ib recommendation).
  • Alternative therapies include trimethoprim-sulphamethoxazole alone (TMP-SMX, co-trimoxazole), atovaquone combined with sulphadiazine or pyrimethamine, but there is limited experience with these (category III recommendations).
  • Lack of response to two weeks of treatment, clinical deterioration or features that are not typical of toxoplasma encephalitis should lead to consideration of a brain biopsy (category IV recommendation).

With increasing experience it is now standard practice to treat any HIV patient with a CD4 count of <200 cells/μL and a brain mass lesion with anti-toxoplasma therapy. Patients should be screened for G6PDH deficiency as this is highly prevalent in individuals originating from Africa, Asia, Oceania and Southern Europe. However, sulphadiazine has been found not to be haemolytic in many G6PDH-deficient individuals although any drop in haemoglobin during therapy should prompt testing. Antimicrobial therapy is effective in toxoplasmosis with 90% of patients showing a response clinically and radiologically within 2 weeks [82]. A response to treatment is good evidence of diagnosis without having to resort to more invasive procedures. Regimens that include sulphadiazine or clindamycin combined with pyrimethamine and folinic acid show efficacy in the treatment of toxoplasma encephalitis [82–84]. In a randomized clinical trial, both showed comparable efficacy in the acute phase of treatment, although there was a trend towards less response clinically in the group receiving the clindamycin-containing regimen and significantly more side effects in the sulphadiazine-containing regimen [84]. In the maintenance phase of treatment there was an approximately two-fold increase in the risk of progression in the group who received the clindamycin-containing regimen. On this basis the sulphadiazine-containing regimen is the preferred regimen with the clindamycin-containing regimen reserved for those who are intolerant of sulphadiazine.

For acute therapy, because of poor absorption, a loading dose of 200 mg of pyrimethamine followed by 50 mg/day (<60 kg) to 75 mg/day (>60 kg) should be given together with folinic acid 15 mg/day (to counteract the myelosuppressive effects of pyrimethamine) and either sulphadiazine 1–2 g qds, although consideration should be given to weight based dosing with 15 mg/kg qds or clindamycin 600 mg qds. Sulphadiazine and clindamycin have good bioavailability so the oral route is preferred. Some studies show that sulphadiazine can be given. The intravenous form of sulphadiazine is not currently available within the United Kingdom. In the unconscious patient, a nasogastric tube may be necessary to give pyrimethamine as it is also not available as an intravenous preparation. Clindamycin can also be given intravenously. If a patient develops a rash, usually generalized and maculopapular, this is most likely to be the sulphadiazine or clindamycin component. The offending drug should be stopped and switched if possible to the other. Sulpha desensitization can be undertaken but this is a complicated and lengthy process.

After initial acute therapy for 6 weeks, patients require switching to maintenance therapy (secondary prophylaxis). This involves using the same drugs but in lower doses: pyrimethamine 25 mg/day plus sulphadiazine 500 mg−1 g qds or 1–2 g bd or clindamycin 300 mg qds or 600 mg tid with supplemental folinic acid 15 mg/day. Although sulphadiazine has traditionally been administered four times a day more recent pharmacokinetic data suggests bd dosing may be as effective and could be used for maintenance therapy [85]. There is, however, to our knowledge no direct comparison of bd and qid dosing although the bd regimen has been compared to a thrice-weekly maintenance regimen of sulphadiazine and pyrimethamine [86]. There is limited experience to guide therapy if sulphadiazine or clindamycin-containing regimens cannot be tolerated. Possible alternatives include: pyrimethamine and folinic acid (doses as above for acute therapy) with atovaquone (1500 mg bd) [87]; sulphadiazine (doses as above for acute therapy) plus atovaquone (1500 mg bd) [87]; pyrimethamine and folinic acid (doses as above for acute therapy) with either azithromycin, clarithromycin, doxycycline or dapsone; and trimethoprim 10 mg/kg/day and sulphamethoxazole 50 mg/kg/day tds or qds orally or IV [88,89]. To date, these alternative regimens have not been shown to be as effective as the first-line options but intravenously administered trimethoprim-sulphamethoxazole is a useful option when an oral formulation cannot be used in an unconscious patient.

Corticosteroids should not be used routinely as they cloud the diagnostic therapeutic trial. They are indicated in patients with symptoms and signs of raised intracranial pressure such as headache, vomiting, drowsiness and papilloedema. When indicated dexamethasone 4 mg qds, gradually reducing, is the treatment of choice. However, any response clinically and radiologically may be due to a reduction in cerebral oedema rather than a response to the anti-toxoplasma therapy. Clinical deterioration after tapering the steroids merits consideration of a diagnostic brain biopsy. Brain biopsy should be considered when there is (1) failure of response to at least two weeks of anti-toxoplasma therapy; (2) clinical deterioration while on therapy; (3) a single, especially periventricular, lesion on MRI; or (4) a mass lesion(s) if the CD4 count is above 200 cells/μL. If a patient presents with or develops seizures (25–30%), antiepileptic medication is necessary. However, there is no evidence to support the routine prescribing of antiepileptic drugs in patients with toxoplasmosis.

2.5.5 Prophylaxis

  • HIV patients with a CD4 count of <200 cells/μL and positive toxoplasma serology require prophylaxis against toxoplasma encephalitis (category IIb recommendation).

Although there are no randomized clinical trials of toxoplasma prophylaxis per se, trials of PCP prophylaxis have demonstrated efficacy of TMP-SMX and dapsone plus pyrimethamine against toxoplasma encephalitis [90,91]. Various doses can be used but TMP-SMX 480–960 mg/day is the preferred regimen. Dapsone 50 mg/day and weekly pyrimethamine 50 mg is reserved for individuals who are allergic to TMP-SMX. Atovaquone may also be considered. In addition, all HIV-seropositive individuals should be advised to avoid the ingestion of undercooked red meat, to wash their hands after any contact with soil, and to avoid emptying cat litter trays. If this is not feasible, emptying cat litter trays daily and ensuring that hands are washed after all disposal of cat excreta must be advised.

2.5.6 Impact of HAART

  • Primary and secondary prophylaxis can be discontinued when the CD4 count is repeatedly above 200 cells/μL (level Ib recommendation).

HAART has lessened the incidence of toxoplasma encephalitis. HAART has been associated with a decline in toxoplasma encephalitis and should be initiated as soon as the patient is clinically stable (usually approximately 2 weeks after commencing acute treatment of toxoplasma encephalitis to lessen the likelihood of IRIS). There have been a number of reports of IRIS associated with toxoplasma encephalitis [92]. After the initiation of HAART, primary prophylaxis maybe discontinued after successful suppression of HIV viral replication and restoration of the CD4 counts to >200 cells/μL for 3 months [93]. After HAART, maintenance therapy may be discontinued after 6 months of successful suppression of HIV viral replication and elevation of CD4 count to >200 cells/μL [69,94,95].

2.6 Progressive multifocal leukoencephalopathy (PML)

2.6.1 Background and epidemiology

First identified as a clinical entity in 1958, progressive multifocal leukoencephalopathy (PML) was subsequently characterised to be an opportunistic infection (OI) in 1971 when virus particles were identified from a patient with underlying Hodgkin disease (named JC virus after the patient initials). This was later further identified as being a double-stranded DNA 40-nm icosahedron virus belonging to the subfamily of Polyoma viruses.

Asymptomatic seroconversion occurs predominantly in childhood although seroprevalence continues to increase until old age and over 70% of the population are seropositive [96]. The exact mechanism of transmission is ill-understood but is probably by respiratory secretions and via the tonsillar tissues. Following primary infection, the virus disseminates and sets up latent infection in several organs (spleen, bone marrow, kidneys and B-lymphocytes). With subsequent immune suppression, JC virus productively replicates and is transported to the brain by B-lymphocytes where it infects permissive oligodendrocytes via the serotonin receptor [97].

The advent of HIV radically changed the epidemiology from what was an exceptionally rare complication of patients with reticuloendothelial disease or immunosuppressed following organ transplantation, to an OI identified in up to 5% of patients with AIDS with limited reduction after introduction of HAART and no change in the high mortality rate [98,99]. PML caused approximately 20% of focal brain lesions pre-HAART [100].

2.6.2 Presentation

The cardinal pathological feature and underlying process determining the clinical presentation is demyelination of white matter, which is irreversible. Classic PML presents as a subacute illness without constitutional symptoms in patients with severe immunodeficiency. Progressive focal neurology, mainly motor deficit, altered mental or mood status, ataxia or cortical visual symptoms, develop over weeks to months. The presence of the focal features helps distinguish the cognitive syndrome associated with PML from HIV encephalopathy. Seizures may rarely occur. Rare but increasingly recognized PML may present after the introduction of ARV treatment and reflects an immune reconstitution phenomenon [101].

2.6.3 Diagnosis

  • MRI appearances and JC virus detection by PCR in a CSF sample are sufficient to make a diagnosis in most cases and avoid the need for a brain biopsy (level III recommendation).

Early diagnosis is paramount. Brain biopsy has long been regarded as the gold standard with a sensitivity of 64–96% and a specificity of 100%. With imaging refinements, MRI combined with CSF DNA amplification has allowed avoidance of biopsy. Lesions are usually bilateral, asymmetric, non-enhancing T2 hyperintense T1 hypointense, restricted to white matter and with no oedema. The asymmetric nature and sharp demarcation helps differentiate from HIV encephalopathy. In the context of antiretroviral treatment, features may be atypical. Pre-HAART, JC DNA in the CSF detected by PCR had sensitivity of 72–92% and a specificity of 92–100%. However, since the introduction of HAART sensitivity has fallen to approximately 50% reflecting reduced viral replication and increased clearance of virus from the CSF [102,103].

Factors associated with a poor prognosis include clinical (older age, brainstem involvement, lowered level of consciousness), viral (high CSF JC viral load with delayed clearance with HAART), radiological (early brainstem involvement), and immunological (CD4 count <100 cells/μL) [104]. Evidence of immunological responsiveness, higher CD4 cell counts, contrast enhancement on imaging, perivascular mononuclear infiltrates and JC-specific cytotoxic T lymphocytes are associated with improved prognosis.

2.6.4 Treatment

  • HAART is the only intervention that has improved clinical outcomes with PML (category III recommendation).

Although cidofovir and cytarabine (ARA-C) are active against non-human Polyoma virus and JC virus in vitro, respectively, with identifiable reduction in CSF JC viral load in vivo, neither drug has been shown to arrest the disease process and there remains no specific treatment for PML other than commencing or optimizing ARV treatment. Cidofovir was shown in a large multicentre study to provide no additional benefit to HAART alone [105] and these results have been confirmed in retrospective analyses of pooled data from prior cohort or observational studies [106,107]. Similarly, cytarabine, either intravenously or intrathecally, failed to demonstrate additional benefit to ARV treatment, albeit this study was conducted pre-HAART [108]. Hence, HAART remains the only therapeutic option. The choice of HAART should consider probable CNS penetration as one study has shown a better outcome with drugs based on their CNS penetration score [110].

2.6.5 Prophylaxis

There is no therapy that has been identified as effective in preventing PML.

2.6.6 Impact of HAART

From a predicted survival of 10% at one year, 50% of patients receiving HAART now survive for this length of time [110] and some patients enter true remission of disease with stabilization of neurological morbidity and the development of atrophy and gliosis on MRI. Also, since the impact of HAART on PML may be less than for other focal neurological lesions, the relative contribution of PML to the incidence of focal lesions in the brain may have increased [100].

2.7 Cytomegalovirus (CMV)

2.7.1 Background and epidemiology

Cytomegalovirus (CMV) is a member of the human β-herpesviruses. Like other members, it has the ability to establish lifelong persistent and latent infection after primary exposure. In the context of immunodeficiency, particularly cell-mediated, this may result in severe primary or reactivated clinical disease.

Nearly all men who have sex with men (MSM) are seropositive whereas in heterosexuals and injection drug users, the rate is 50–75% [111]. With clinical progression of HIV, latent CMV reactivates, leading to viraemia and, in a proportion, end-organ disease. Prior to the advent of HAART, observational studies demonstrated that 20–40% of patients with AIDS developed CMV disease, with many more patients having evidence of disease at post mortem. End-organ disease incidence becomes substantially higher when the CD4 count falls to <50 cells/μL. The major sites of CMV disease are the retina, which accounts for approximately three-quarters of cases, the GI tract, the lung, the liver and biliary tract, the heart, adrenal glands and the nervous system (encephalitis and polyradiculitis). The widespread uptake of HAART has radically altered the epidemiology with most patients starting treatment before they become at risk for CMV disease. Nervous system infection accounts for <1% of clinical CMV disease [112,113].

2.7.2 Presentation

Clinical signs and symptoms are insensitive and difficult to distinguish from AIDS-dementia complex. A subacute history with progressive disorientation, withdrawal, apathy, cranial nerve palsies, and nystagmus is typical whereas symptoms of depression and mental slowing are more evident in AIDS-dementia complex: the micronodular form is often subclinical or gives rise to more subtle cognitive impairment. CMV encephalitis is typically more aggressive than HIV brain disease. Clinical evidence of cerebellar or brainstem involvement is present in 30%: features of polyradiculitis and retinitis (up to 75%) may coexist [114]. Presentation of lumbosacral polyradiculitis is usually as a rapidly progressive, painful, bilateral ascending flaccid paralysis with saddle anaesthesia, areflexia, sphincter dysfunction and urinary retention.

2.7.3 Diagnosis

  • MRI scanning and CSF PCR are the preferred diagnostic tests (category III recommendation).

Development of any neurological feature in a patient with HIV with a low CD4 cell count warrants urgent investigation, initially with neuroimaging and, if not contraindicated, lumbar puncture. On CT scan, diffuse white matter hypodensities with ependymal enhancement, ventricular enlargement, meningeal enhancement and focal or nodular ring-enhancing lesions are seen. However, MRI is far more sensitive when these features are best revealed on gadolinium enhanced T1 weighted scans with periventricular enhancement commonly seen. However, imaging lacks sensitivity and many patients have normal or nonspecific changes [115]. CSF examination is rarely grossly abnormal although a slightly raised protein and mild lymphocytosis are not infrequent. In patients with isolated or concomitant polyradiculitis, diffuse enhancement of cord parenchyma, nerve roots and meninges is seen on contrast-enhanced MR and a characteristically pronounced polymorphonuclear cell pleocytosis is usual. Electromyogram studies demonstrate axonal neuropathy and can help distinguish CMV polyradiculitis from an acute inflammatory demyelinating polyneuropathy. Diagnosis of both conditions is based around nucleic acid amplification of CMV DNA. A positive CSF PCR has a sensitivity of >80% and a specificity of >90% with negative and positive predictive values of 86–92% and 95–98%, respectively [116–119]. However, PCR may rarely be negative in patients subsequently found to have active CMV disease of the brain. Brain biopsy is rarely indicated in view of localization.

2.7.4 Treatment

  • Ganciclovir with or without foscarnet is the treatment of choice (category III recommendation).
  • HAART should also be instituted after initial anti-CMV therapy (category III recommendation).

There have been no prospective controlled trials for CMV neurological disease and, although well designed randomized controlled trials on the therapeutic efficacy of ganciclovir, foscarnet, valganciclovir and cidofovir (all effective) exist for CMV retinitis, the results of these cannot be extrapolated to encephalitis or polyradiculitis [119–121]. In a small open noncomparative study in the pre-HAART era, combination treatment with ganciclovir and foscarnet did improve or stabilize encephalitis/polyradiculitis in 74% of 31 HIV-seropositive patients with neurological disease; however, overall mean survival was only 3 months [122]. Similar clinical improvements in CMV polyradiculitis have been found with both drugs individually or together in retrospective cohort analyses [123,124]. Both drugs have also been shown to reduce CSF CMV-DNA load. Correcting the profound immunodeficiency by commencing or optimizing HAART is critical in management although no specific data exist for CMV disease of the nervous system. Optimal duration of treatment for both conditions remains uncertain.

2.7.5 Prophylaxis

  • Prophylaxis against CMV encephalitis/polyradiculitis is not required but HAART is likely to decrease the incidence of these conditions (category IV recommendation).

There have been no prospective controlled trials for CMV neurological disease and, although well-designed randomized controlled trials on the prophylactic efficacy of aciclovir (not effective), valaciclovir, ganciclovir, and valganciclovir (all effective) exist for CMV retinitis, the results of these cannot be extrapolated to encephalitis [125–127]. Given that HAART has been demonstrated to reduce the risk of CMV end-organ disease and that this is a complication rarely seen where the CD4 is >50 cells/μL, the key to preventing encephalitis is initiation of ARV drugs according to national and international treatment guidelines [128]. Although good information is available to suggest maintenance therapy can be discontinued for CMV retinitis with immune recovery and a sustained rise in CD4 >100 cells/μL, no such evidence exists for neurological disease and a more cautious approach is advised. This decision should be based upon clinical, CSF and blood CMV-DNA levels, and imaging improvement.

2.7.6 Impact of HAART

HAART decreases the incidence of CMV retinitis and CMV disease in general but specific data for encephalitis do not exist. Although CMV IRIS is reported in other settings, there are limited data on its presentation as a neurological disease at this time.

Abbreviations: PML, progressive multifocal leukoencephalopathy; PCNSL, primary central nervous system lymphoma; NHL, non-Hodgkin's lymphoma; KS, Kaposi's sarcoma; CT, computed tomography; MRI, magnetic resonance imaging; CRAG, cryptococcal antigen; TB, tuberculosis; ICP, intracranial pressure.

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