neurological complications of hiv
DESCRIPTION
Complicaciones neurológicas del VIH - Revista Medicine 2014TRANSCRIPT
What’s new?
C The incidence of neurological opportunistic infection and AIDS-
related dementia has fallen since the start of the combination
antiretroviral therapy (cART) era and continues to fall
C Neurocognitive disorders are increasingly recognized in in-
HIV/AIDS BY SYSTEM
Neurological complicationsof HIVAdam Croucher
Alan Winston
dividuals taking long-term cART
C The availability of less neurotoxic cART regimens has reduced
the burden of peripheral neuropathy
C People with HIV are living longer with well-controlled HIV; they
are vulnerable to neurological disease, including age-related
disease, in the same way as the general population
AbstractThe HIV virus is both neurotropic and immunotropic, causing progressive
destruction of both systems. Although their frequency has been markedly
reduced in the combination antiretroviral therapy (cART) era, neurological
presentations and complications of HIV remain common. Neurological
opportunistic infections (OI) and diseases occur in advanced HIV disease
and include cryptococcal meningitis, progressive multifocal encephalopa-
thy, primary cerebral lymphoma and cerebral toxoplasmosis. Neurological
disease directly associated with HIV may occur at any stage in the prog-
ress of HIV disease, from the aseptic meningitis of primary HIV infection
to AIDS-associated dementia observed in subjects with profound immune
deficiency. In the era of effective antiretroviral therapy, where peripheral
HIV viral replication is largely controlled, non-HIV-related neurological dis-
ease such as stroke is of increasing importance as the HIV population
ages.
Keywords cryptococcal meningitis; dementia; highly active antiretroviral
therapy; HIV; lymphoma; neurocognitive impairment; neurology;
peripheral neuropathy; progressive multifocal leukoencephalopathy;
toxoplasmosis
Introduction
Human immunodeficiency virus (HIV) is both a neurotropic and
immunotropic virus causing progressive destruction to the im-
mune system through infection of CD4þ T-lymphocytes. It is
thought that neurological conditions in HIV disease are caused
either directly by HIV itself, or indirectly through immune
depletion and consequent vulnerability to opportunistic infection
(OI). Specific neurological disease in HIV may manifest as
meningitis, encephalitis, dementia, radiculopathy, peripheral
neuropathy or space-occupying lesions. Combination antiretro-
viral therapy (cART), by suppressing HIV replication and
allowing immune recovery, partly protects individuals from the
direct neuropathic effects of HIV infection and from OI. cART is
Adam Croucher MBBChir MRCP is a Specialist Trainee in Genitourinary and
HIV Medicine at St Mary’s Hospital, London, UK. Conflicts of interest:
sponsored to attend EACS 2011 and paid for a presentation on
antiretroviral drug choices in treatment-experienced patients 2012,
both by Janssen.
Alan Winston MBChB MRCP MD is a Consultant in HIV Medicine at St Mary’s
Hospital, London, UK. Research interests include antiretroviral
pharmacokinetics and neurocognitive disease in HIV infection.
Conflicts of interest: none declared.
MEDICINE 41:8 450
crucial in the treatment of all OIs, although it may complicate
disease through potential drug-associated neurological toxicities,
such as peripheral neuropathy, drugedrug interactions and im-
mune reconstitution inflammatory syndrome (IRIS, discussed in
the ‘AIDS-defining diseases’ section).
In the UK in 2009, 30% of adults newly diagnosed with HIV
had CD4þ cell counts below 200 cells/ml.1 Therefore, a large
proportion of individuals with newly diagnosed HIV infection is
vulnerable to AIDS-defining neurological complications. None-
theless, the incidence of all HIV-related neurological disease has
fallen dramatically in the UK since the advent of cART, from 13
to 1 per 1000 person-years.2
The spectrum of neurological disease changes as HIV infection
progresses, with each stage of HIV disease being associated with
differing neurological pathologies (Table 1).
Primary infection
Case
A 32-year-old homosexual man presents with rash, fevers and
headaches of 4 days’ duration. On examination, he has a wide-
spread non-blanching maculopapular rash, peripheral lymph-
adenopathy and neck stiffness. He is afebrile. Cerebral imaging is
normal and cerebrospinal fluid examination (CSF) reveals an
elevated lymphocyte count with normal protein and glucose
concentrations.
Differential diagnosis
The differential diagnosis includes secondary syphilis and aseptic
viral meningitides, including primary HIV meningitis.
Primary infection in HIV is frequently symptomatic with a
short-lived rash, fever, malaise and generalized lymphadenopa-
thy. cART is indicated for patients with neurological complica-
tions of primary HIV infection, such as aseptic meningitis,
mononeuritis multiplex, Bell’s palsy and transverse myelitis.3
HIV testing should be undertaken with any of these condi-
tions.4 CSF abnormalities in HIV aseptic meningitis are as for
other viral meningitides (normal/elevated protein, normal
glucose, lymphocytosis), and HIV RNA is often detectable.
Diagnosing primary HIV in patients with such neurological
manifestations is key to preventing HIV disease progression and
onward transmission, while the early institution of cART may
treat these neurological disorders.
� 2013 Published by Elsevier Ltd.
HIV-associated neurological pathologies, by stageof HIV infection
Stage of HIV infection Pathology
Primary infection Aseptic meningitis
GuillaineBarr�e syndrome
Bell’s palsy
Transverse myelitis
AIDS (CD4 count
<200 cells/ml)
Progressive multifocal
leukoencephalopathy
Toxoplasmosis
Cryptococcal meningitis/encephalitis
Cytomegalovirus
Varicella zoster encephalitis
HIV dementia
Lymphoma
Controlled HIV Peripheral neuropathy
Neurocognitive impairment
Starting HIV treatment Immune reconstitution inflammatory
syndrome
All stages of HIV infection Syphilis
GuillaineBarr�e syndrome
Herpes simplex encephalitis
Mycobacterium tuberculosis
Neurocognitive impairment
Table 1
Cerebral toxoplasmosis
Figure 1 MRI showing multiple ring-enhancing lesions typical of cerebral
toxoplasmosis.
HIV/AIDS BY SYSTEM
AIDS-defining diseases
Case
A 45-year-old Eritrean woman presents to the emergency
department having had a witnessed toniceclonic seizure lasting
5 minutes. A family member reports a history of weight loss over
the past 3 months and mild confusion over the past 5 days. On
examination, she is post-ictal and drowsy. She has oral hairy
leucoplakia and a rapid HIV test is positive. A magnetic reso-
nance imaging (MRI) scan of brain reveals multiple bilateral
ring-enhancing lesions (Figure 1).
Differential diagnosis: based on the information we have in this
case, cerebral toxoplasmosis is the most likely diagnosis. How-
ever, careful consideration and monitoring for the other three
main AIDS-defining neurological conditions described below is
paramount.
Toxoplasmosis
Toxoplasmosis is the most frequently observed cerebral space-
occupying lesion in HIV infection worldwide. It results from
reactivation of infection with Toxoplasma gondii, a protozoan
whose definitive host is the cat. Reactivation occurs when the
CD4 count is under 200 cells/ml.
Presentation is usually over days to weeks, with focal symptoms
and signs, and sometimes seizures. There may be features of
raised intracranial pressure. There may be movement disorder,
MEDICINE 41:8 451
as the abscesses commonly appear in the basal ganglia. Confu-
sion may progress to coma and death if untreated.
Diagnosis is by imaging, with characteristic ring-enhancing lesions
of the basal ganglia, thalamus and greyewhite matter interface
considered sufficient for empirical treatment.5 Single lesions are
suggestive of primary central nervous system (CNS) lymphoma
rather than toxoplasmosis.
Treatment: high-dose pyrimethamine, with sulphadiazine or
clindamycin for 6 weeks is first-line therapy.3 Lack of response
clinically or on imaging at 2 weeks of therapy is indicative of an
alternative diagnosis (lymphoma) and brain biopsy should be
considered. cART should be started after 2 weeks of treatment.
Reduced dose pyrimethamine and sulphadiazine as secondary
prophylaxis should be continued until viral suppression and CD4
is over 200 cells/ml for 6 months.
Cryptococcal meningitis
There were an estimated 1 million cases of and 600,000 deaths
from cryptococcal meningitis in 2007, the majority of these in
sub-Saharan Africa.6 Cryptococcus species are ubiquitous envi-
ronmental encapsulated yeasts. Infection is acquired via inhala-
tion, with dissemination via the blood stream, colonizing the
CNS. It may cause pneumonia and molluscum-like umbilicated
papules on the skin.
Presentation: the main features are headache and fever; men-
ingism and features of raised intracranial pressure may also be
present (vomiting, confusion and coma).
Investigation: a positive serum cryptococcal antigen (CRAG)
confirms disseminated infection. Brain imaging is necessary to
� 2013 Published by Elsevier Ltd.
Cryptococcus in CSF
Figure 2 Microscopy India ink stain showing Cryptococcus �400 magni-
fication (courtesy A Abdolrasouli).
HIV/AIDS BY SYSTEM
confirm the safety of lumbar puncture and is often normal. CSF
manometry is of prognostic value and should always be per-
formed. CSF examination should include CRAG, India ink stain
(Figure 2) and fungal culture.
Treatment is in three stages: induction with liposomal ampho-
tericin B and flucytosine for 2 weeks followed by high-dose oral
fluconazole for 8 weeks, and lower-dose fluconazole thereafter
as secondary prophylaxis.3 cART should be started at completion
of the induction phase, and secondary prophylaxis stopped once
serum HIV is lower than 50 copies/ml and CD4 is greater than
100 cells/ml for at least 3 months. Serial lumbar punctures can
relieve symptoms of raised intracranial pressure and will protect
the patient from visual loss.
Features of AIDS-defining neurological complications of HIV (
Cryptococcal
meningitis
Toxoplasmosis PML
CT/MRI Usually normal
Rarely hydrocephalus
or cryptoccomas
Ring-enhancing lesions,
usually multiple, often
in the basal ganglia.
Commonly oedema and
mass effect
MRI: Bilater
white matte
hypointense
hyperintens
surrounding
CSF Raised opening
pressure
India ink positive
CRAG positive
Toxoplasma PCR
positive in 50%
JC virus pos
70e90% on
AIDS, acquired immunodeficiency syndrome; CRAG, cryptococcal antigen; CSF, cereb
associated dementia; HIV, human immunodeficiency virus; MRI, magnetic resonan
PML, progressive multifocal leukoencephalopathy; SOL, space-occupying lesion.a Adapted from Thorpe JW, Deayton JR, Medicine 2009; 37 (7): 352e356.
Table 2
MEDICINE 41:8 452
Progressive multifocal leukoencephalopathy (PML)
PML is caused by reactivation of infection with the polyoma ‘JC’
virus. Around 60% of the UK population are seropositive
following asymptomatic infection.7 The virus remains dormant
in lymphoid tissue. It causes irreversible demyelination of brain
white matter in immunosuppressed individuals.
Presentation is with altered mood, ataxia, speech or cortical
visual symptoms that progress over weeks or months.
Diagnosis is based on imaging with characteristic white matter
changes (Table 2, Figure 3) and CSF examination for the pres-
ence of JC virus.
Treatment is with cART, which may arrest disease progression
with immune restoration. There are no specific PML treatments
that improve prognosis. Survival has improved significantly in
the cART era (50% at 1 year).8
Primary CNS lymphoma
HIV primary CNS lymphoma (PCNSL) (see also AIDS-related
malignant disease on pages 430e434 of this issue) is usually a
large B-cell non-Hodgkin’s lymphoma, with a strong association
with EpsteineBarr virus (EBV) infection.9 Incidence of HIV-
associated PCNSL has fallen markedly in the cART era.10,11
Presentation is usually sub-acute and is often indistinguishable
from cerebral toxoplasmosis.
Diagnosis: characteristic changes on imaging often mimic those
of cerebral toxoplasmosis, with ring-enhancement. The presence
of a non-anti-toxoplasmosis-responsive lesion with detectable
EBV in the CSF is sufficient for a presumptive diagnosis of
PCNSL. However, histology remains the definitive diagnostic
test. Less than 30% of those with PCNSL will have malignant
cells on CSF cytology:12 if CSF is normal, brain biopsy should be
performed. Non-CNS extension of the disease must be sought.
CD4 <200 cells/ml)a
PCNSL HAD
al asymmetric
r lesions, T1
, T2
e, without
oedema
Usually a single SOL, ring-
enhancing in 50%, often
periventricular, with
surrounding oedema
Atrophy
Diffuse white matter
signal changes
itive in
PCR
EBV PCR positive in 90%
Malignant cells on cytology
in <30%
Normal/raised protein
Mild lymphocytosis
Detectable HIV
rospinal fluid; CT, computed tomography; EBV, EpsteineBarr virus; HAD, HIV-
ce imaging; PCNSL, primary CNS lymphoma; PCR, polymerase chain reaction;
� 2013 Published by Elsevier Ltd.
Progressive multifocal leukoencephalopathy
Figure 3 MRI showing changes typical of progressive multifocal leukoencephalopathy (T1 left and T2 right), with multifocal, asymmetric periventricular
and sub-cortical involvement. Lesions typically have little or no mass effect and are hyperintense on T2-weighted images.
HIV/AIDS BY SYSTEM
Management: although PCNSL is responsive to chemotherapy
and radiotherapy, prognosis is poor. Median survival has
increased from 32 to 48 days since the advent of cART.10
Immune reconstitution inflammatory syndrome
Neurological opportunistic infections may worsen or appear
after initiation of cART, due to immune reconstitution inflam-
matory syndrome (IRIS). The recovering immune system pro-
duces an inflammatory response to persistent antigens from
treated infection (‘paradoxical’ IRIS) or unidentified active
infection (‘unmasking’ IRIS). IRIS tends to occur within the
first few months of initiating cART and may be difficult to
differentiate from OI treatment failure. Treating the OI before
initiating cART reduces the risk of IRIS, but the optimal timing
varies between specific OIs,13 and should be considered on a
case-by-case basis. In cases of IRIS, cART should be continued
wherever possible and corticosteroid therapy may be
necessary.
Controlled HIV infection
Neurocognitive impairment
Case: a 62-year-old Caucasian man complains of increasing
forgetfulness and difficulty concentrating over the last 6 months.
He previously worked in a bank and retired 18 months ago. He
has been infected with HIV for 15 years and has been taking
antiretroviral therapy for over 12 years. He is on his fifth antire-
troviral regimen with undetectable plasma HIV RNA. He is hy-
pertensive and hyperlipidaemic and is taking medication for both
these co-morbidities. Neurological examination is normal. An MRI
scan of brain is reported as normal.
Differential diagnoses: the differential diagnosis here includes:
� Anxiety and depression disorders. There may be risk of
depression with recent retirement.
MEDICINE 41:8 453
� Multi-infarct dementia process. He is at risk of cerebro-
vascular disease.
� HIV-associated neurocognitive impairment. With an exten-
sive antiretroviral history, drug-resistant HIV strains may be
present and CSF examination to assess for HIV replication is
justified.
Given the complexity of this case and other potential causes for
this man’s symptoms, a multidisciplinary approach is essential,
involving input from psychiatry and neurology teams.
HIV-associated neurocognitive impairment (NCI) is reported
to remain prevalent in HIV-infected individuals despite effective
cART (up to 52%).14 NCI is characterized by progressive
deterioration in learning and executive function. For research
purposes, NCI has been categorized according to severity:
asymptomatic neurocognitive impairment (ANI); mild neuro-
cognitive disorder (MND) and HIV-associated dementia (HAD).
Progression is associated with the degree of immune suppres-
sion, although all stages of NCI can occur at all stages of HIV
infection, even when well-controlled.15
Diagnosis: the clinical relevance of ANI, which is identified on
neuropsychometric testing alone, is unknown and screening is not
recommended.16 Those with symptomatic disease (MND, HAD)
should undergo neurocognitive testing, brain MRI and CSF ex-
amination to rule out other HIV-associated neurological disease
and non-HIV-associated co-morbidities such as vascular disease,
depression etc. MRI changes are often not present but cerebral
atrophy and diffuse white matter changes may be detected.17
Management: in patients not taking antiretroviral therapy,
symptomatic NCI is an indication to initiate cART,18 which may
arrest or reverse disease progression. The presence of NCI in
well-controlled HIV is often multifactorial. Emphasis should
be on optimizing management of age-related or psychiatric
co-morbidities thatmay be present. Finally, examination of CSF for
� 2013 Published by Elsevier Ltd.
HIV/AIDS BY SYSTEM
evidence of HIV replication or HIV-resistant strains should be
undertaken, with antiretroviral therapy modified accordingly.19
Peripheral neuropathy
Peripheral neuropathy may be caused directly by HIV, or by
toxicity from antiretroviral drugs, in particular didanosine and
stavudine, although these drugs are now little used in the UK.
Other causes of neuropathy (e.g. vitamin deficiency, diabetes,
alcohol toxicity) are common in the HIV population and must be
considered. Diagnosis is clinical; nerve conduction studies may
aid diagnosis. Management is by correcting the potential causes
(e.g. optimizing cART to minimize neurotoxicity; optimizing
blood glucose control in those with diabetes). Neuropathic pain
is managed symptomatically, although treatment options are
limited.20
Incidental neurological disease in controlled HIV
Any of the likely immune-based neurological syndromes such as
GuillaineBarr�e syndrome can occur, presumably as part of the
immune dysregulation that characterizes HIV infection. Rela-
tively high-grade pathogens may also cause infection at any
stage of HIV infection; herpes simplex encephalitis, syphilis and
Mycobacterium tuberculosis meningitis/tuberculoma are all more
common in individuals with HIV infection. HIV testing is indi-
cated with all these diagnoses.4
Cerebrovascular disease may be more common in the HIV-
positive population, possibly linked to a chronic inflammatory
response in HIV disease despite cART.21 Optimizing ‘traditional’
cardiovascular risk factors is of increased importance as the HIV
population ages.
Ophthalmic manifestations of HIV infection
Ocular disease is commonly reported in HIV infection. It may
result from direct eye disease (uveitis, retinitis, keratitis, vas-
culopathy) or from cerebral lesions (cranial nerve palsies, pap-
illoedema, visual field defects). Those with a CD4 lower than 200
cells/ml are at greatest risk and should be carefully assessed for
asymptomatic ocular disease. Cytomegalovirus (CMV) retinitis is
the commonest ocular OI (see Figure in Natural history of HIV
and AIDS on pages 411e416 of this issue), and while incidence
has fallen dramatically in the HAART era, it remains common in
those with a CD4 count lower than 50 cells/ml. Non-CMV OIs,
such as syphilis, toxoplasma and varicella-zoster rarely manifest
as direct ocular disease (less than 1% of cases for each path-
ogen).22 Nonetheless, if they occur, all have the potential to
result in blindness. OI treatments may themselves cause eye
disease (e.g. anterior uveitis with rifabutin). New ocular or visual
symptoms should be promptly assessed and referred to an
ophthalmologist, whilst central causes (such as space-occupying
lesions or encephalitis) should also be considered. A
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