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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