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
White Matter Not Atypical Peri-Vascular T-Lymphocytes T
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 20 50% Antinori et al. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007 Oct 30;69(18):1789-99
s100 IL-1 Blood Brain Barrier Modified from Kaul et al. Nature, 2001
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 frontostriatal 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/MV C
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 HIVassociated neurological syndrome Typically presenting as a steroidresponsive 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
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