HIV and Dementia

London Dementia Clinical Network

14 June 2018

Dr Patricia McNamara MB BCh BAO MRCP PhD Locum Consultant Neurologist, NHNN

Patricia.mcnamara2@nhs.net

History of HIV Infection

HIV

• 36 million people were living with HIV in 2016

• 1.8 million people were newly infected with HIV in 2016

• 1 million people died from AIDS related illnesses in 2016

• Approximately just over 50% of people had access to treatment

• UK – 89,400 people living with HIV in 2016 (1.6/1000) – 54% of new infections were in MSMs – 96% on HAART and 94% virally suppressed

Historical Nomenclature

• The term “sub-acute encephalitis” was first used in 1983 (Snider et al)

• In 1986 the term “AIDS dementia complex” was introduced (Navia et al)

• “HIV encephalopathy” was introduced in 1988 by Levy and Bredesen

• Criteria were developed by the AAN AIDS Task Force for AIDS dementia in 1991 and the term HIV-1 associated cognitive/motor complex was introduced

• The most recent term, HIV Associated Neurocognitive Disorders, was introduced by the AAN in 2007

• "HIV encephalitis" should only be used to refer to the pathological features of HIV in the brain with the typical multinucleated giant cell encephalitis.

Prevalence of HAND • Prior to the introduction of HAART up to 20% of patients with AIDS

developed HIV dementia – It was associated with a high mortality rate with a mean survival of six months

to one year after the development of dementia.

• Prior to HAART mild neurocognitive impairment was described in 30% of

patients with asymptomatic HIV disease and in up to 50% of patients with AIDS defining illnesses.

• The incidence of HIV associated dementia has declined in the post-HAART era to approximately 2%

• Cognitive impairment continues to be an ongoing clinical issue despite good virological control of HIV

• Prevalence rates of 20% to 50% of HAND have been demonstrated in large prospective studies.

Neuropathology • HIV is neuroinvasive, neurotropic and neurovirulent.

• “Trojan horse” mechanism • Neurons are not infected directly by HIV. Microglial cells and macrophages are the

primary targets for productive HIV infection within the CNS as they both possess receptors for CD4 and CCR5.

• Astrocytes are also infected by HIV despite their lack of receptors for viral attachment but in a more restricted fashion.

• The chemokine receptor CCR5 is the dominant receptor used within the brain.

• HIVE - presence of multinucleated giant cells; predilection for the basal ganglia and

white matter

• Other pathological features of HIV include myelin pallor, axonal loss, microglial nodules and gliosis.

• There is also disruption of the blood brain barrier and apoptosis of astrocytes. This leads to dendritic and neuronal loss.

Case 1

• 40 yo R handed man • June 2010

– weight loss, night sweats, fatigue

– 3 episodes of oral candidiasis

• Dx HIV positive • Commenced ART July 2010 • Aug – Sept 2010

– Urinary and faecal incontinence

– Nocturnal confusion – Withdrawn – Low mood, tearful and weepy

• Examination: – Orientated with good

knowledge of recent events – Motor impersistence – Apraxia – Luria sequences – poor – Positive grasp reflex – Cranial nerves – normal – Tone, power, reflexes, co-ord,

sensation normal – Plantars upgoing bilaterally

– MoCA 16/30

Investigations

CD4 VL

• June 2010 44 > 6 million • August 2010 247 2291 • Sept 2010 196 247

• CSF

– WCC 1 – Protein 0.52 – Gluc 2.8 – Viral PCR negative for JC, BK, HSV I & II, VZV, CMV,

Enterovirus

21/9/10

Cortex – NORMAL

Peri-Vascular T-Lymphocytes

White Matter

T

Not Atypical

Deep White Matter

Vacuolar Change

Vacuolar Change

Axonal Injury

Diagnosis

• HIV Dementia

• ART continued

• Required supervision

• Unable to return to work

HAND

• Asymptomatic neurocognitive impairment

• Mild neurocognitive disorder

• HIV associated dementia

Antinori et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007 Oct 30;69(18):1789-99

20 – 50%

Blood Brain Barrier

Modified from Kaul et al. Nature, 2001

s100

IL-1

Risk Factors for HAND

• Low nadir CD4

• Older age

• Substance abuse

• Lower educational level

• Co-infection with hepatitis C

• CCR2 polymorphisms

Functional Consequences

• Increased mortality

• Poor medication adherence

– Older HIV positive patients with CI were more likely to be less adherent to HAART

• Unemployment

– Memory – most important predictor of return to employment

• Functional impairment – cooking, shopping, finances

Clinical Features of Impairment

Cognition Memory loss

Concentration Mental slowing Comprehension

Behavior Apathy

Depression Agitation, Mania

Motor Unsteady gait

Poor coordination Tremor

From Valcour at Atlanta IAS 2013

Neuropsychology of HAND

• Classical triad of cognitive, behaviour and motor disturbance

• Subcortical pattern - attention, speed of information processing and learning efficiency

• Post HAART era more cortical features - impairment in learning and memory and executive function were more predominant

• Episodic memory impairment is a sensitive indicator of HAND. Deficits are most consistent with a mixed encoding and retrieval profile.

MRI in HAND • Early MR-based studies reported volumetric changes of the whole brain,

basal ganglia and white matter in patients with HIV

• Atrophy has been demonstrated affecting both nigro-striatal and fronto-striatal circuits and frontal, parietal, temporal and occipital cortices.

• Hippocampal atrophy has also been demonstrated.

• Nadir CD4 count and duration of infection have been shown to correlate with atrophy of the parietal, temporal and frontal lobes and the hippocampus whilst plasma HIV RNA levels correlated with atrophy of basal ganglia.

• The pattern of HIV-associated brain loss may be changing from a predominantly subcortical disease to a more cortical disease in the post-HAART era.

Kuper et al. Structural gray and white matter changes in patients with HIV. J Neurol (2011) 258:1066–1075

Other causes of CI in HIV

• Opportunistic infections – toxoplasmosis, tuberculosis, PML, cryptococcal meningitis, CMV encephalitis

• CNS Viral escape

• Depression

• Psychoactive drugs

• Neurodegeneration – Alzheimers, FTD

Case 2

• 49yo right handed man – Dx HIV positive 2007

– Commenced ART August 2007 with ABC/SAQ/RIT

– Did not respond so switched to TFV/FTC/RTV/DRV in early 2008

• Sept 2014

– 6/52 hx

– Tremor in upper limbs – right initially then left also – Difficulty walking - off balance and slow – Cognitive impairment – forgetful and distracted – Recently lost job and mood lower

Exam

• MMSE 22/30 (attention, orientation and recall deficits)

• Asterixis • Tremor – postural and action > rest and mild RUL rest tremor • Slow fine finger movements bilaterally • Left palmomental present and pout reflex present

• Increased tone in limbs with clonus bilaterally • Power normal • Brisk reflexes • Plantars R ↓ L equivocal

• Gait – wide based, unable to perform tandem gait

Investigations

• CD4 308

• LP – OP 7 – WCC 20 (99% mononuclear) – Protein 0.82 – Glucose 3.7 (4.4) – CRAG negative – CSF VL 5980 (plasma VL 122)

• EEG – moderately severe encephalopathy

• HTLV negative

• CSF Resistance testing

– M184V – D67N – K70E – K219Q

MRI Brain Oct 2014

MRI Brain Feb 2015

Clinical Progress

• Returned to work

• Repeat CSF April 2015 normal

• Neuropsychology testing – Deficits in memory and information processing – Good visuospatial and language skills

• Follow up Neuropsychology in August 2016

– Good expressive verbal skills – Improvements and recovery in domains of verbal memory, verbal

fluency and executive function – Relative impairment in concentration and processing speed and

some aspects of visuospatial skills and non-verbal memory (some improved from impaired to low average from previous)

MRI Brain Sept 2016

Nov 2016

• Presented late with an inferior MI - Emergency CABG

• TIA – Mini sternotomy to remove flail segment of papillary muscle

• Missed some doses of ARVs

• April 2017 – Difficulty with short term memory – Slowed down – Slurred speech – Difficulty formulating words

May 2017 June 2017

• CSF (31.05.2017)

– WCC 1

– Glucose 2.9 (5.2)

– Protein 0.68

• HIV CSF VL 400 (plasma VL < 20)

• CSF genotypic resistance test did not amplify

• CSF integrase resistance test showed N155H and A128T

• Tremor in hand

• Memory worse

• Deterioration in handwriting

• Clumsy

• MoCA 24/30 (executive, attention, fluency, recall)

• Mild postural tremor and impaired fine finger movements

• Switched to TAF/FTC/RTV/DAR/DTG/MVC

July 2017

CNS Viral Escape

• Neurological presentations may include focal or non-focal neurological symptoms and signs.

• Onset is most often subacute

• Impairment varies in severity

• Neurocognitive impairment, behavioural changes, fatigue, headache, cerebellar dysfunction and focal sensory or motor signs.

• MRI findings – Diffuse white matter hyperintensities on T2-weighted and FLAIR

sequences – There may be subtle contrast enhancement – Predilection for periventricular areas, basal ganglia, cerebellum, and white

matter

CNS Viral Escape

• CSF pleocytosis

• Dissociation between CSF and plasma virus concentrations – In those with undetectable plasma VLs, detectable CSF levels may be

present – In those with low but measureable plasma VLs, levels at least twice as high

are usually present in the CSF

• Patients usually have high current CD4 cell counts and low nadir CD4

counts

• Aetiology – development of resistance within CNS (compartmentalization) – CNS penetration of ART – Compliance

• Rx – ART optimization

CD8 Encephalitis

• CD8+ encephalitis is an emerging and incompletely understood HIV-associated neurological syndrome

• Typically presenting as a steroid-responsive subacute encephalopathy with prominent white matter changes in patients with apparently well-controlled HIV infection.

• Multiple linear GAD enhancing perivascular lesions

• CSF pleocytosis

• Pathophysiology is thought to involve an attack on HIV-infected CD4+ lymphocytes by autoreactive CD8+ cells

CD8 Encephalitis

• Potential triggers – Minor infection – CNS IRIS – Viral escape – HAART interruption

• The presence of numerous CD8 lymphocytes

in association with reactive astrocytosis and microglial activation suggests that the immune activation of the brain is triggered by HIV alone

• Treatment with steroids but mixed outcome in studies (recovery, cognitive impairment, death)

• Postmortem findings - perivascular cuffing with lymphocytes positive for CD8 and negative for CD4 and CD20 markers on immunohistochemistry

UCSF HIV Over 60 Cohort Predictors of Cognitive Impairment

Correlated to CI

• CD4 T-lymphocyte nadir*

• Diabetes *

• Apo E4 genotype

• Monocyte effectiveness (ME) score

NOT Correlated to CI

• Age and duration of HIV

• Current CD4 T-lymphocyte count

• Plasma Viral load

• Non-diabetes CVD risk factors

• CNS penetration effectiveness score (CPE)

From Valcour at Atlanta IAS 2013

From Valcour at Atlanta IAS 2013

Summary

• HAND 20% - 50%

• Dementia rates have declined but rates of ANI and MND remain high

• Increasing numbers of patients over the age of 50

• Chronic condition

• Exclude viral escape

• Aetiology remains to be fully elucidated

Questions ?