This is a seminar presentation on neurocognitive disorders due to HIV, Vascular and other reversible medical conditions!.

1. Neurocognitive disorders due to
-HIV/AIDS
-vascular and
-other medical conditions
By: Shünün G.
AAU, SOM

2. “Dementia is, after all, a symptom of organic
brain damage. It is a condition, a disorder of
the central nervous system, brought about in
my case by a viral assault on brain tissue. When
the assault wiped out certain intellectual
processes, it also affected emotional
processes.”
Floyd Skloot: In the Shadow of Memory

3. Outline
➢Introduction
➢Epidemiology
➢Etiopathology
➢Clinical features
➢Diagnosis
➢Differential diagnosis
➢Management

4. Major or Mild Neurocognitive Disorder Due to HIV
Infection
Introduction
• HIV Emerged as a challenge to the world health in the early 1980s.
• Although a lot has been achieved to decrease its vast and devastating
impact with cART and health education, it still remains challenging
esp in the developing nations (e.g. SSA).
• While recognized for its direct impact on the cellular immune system
through depletion of infected CD4 lymphocytes, it also has had a
broad impact on the nervous system, including evidence for direct
pathology in the brain, spinal cord, and peripheral nerves.

5. Introduction
• It is neurotropic virus, that invades the brain causing wide spectrum of
disorders that vary in severity from very mild to severely disabling.
-Asymptomatic neurocognitive impairment (ANI), Mild
neurocognitive disorder (MND),HIV-associated dementia (HAD).
• These neurocognitive deficits can lead to meaningful changes in
everyday life, compromising occupational function and medication
adherence.

6. Epidemiology
• HAD is one of the end-stage complications of HIV infection, which is
not suppressed completely by HAART, although the incidence rate
of HAD has declined dramatically.
• The prevalence of HAND (ANI, MND,HAD) is estimated in
approximately 40-50% of all cases. (MND) and (ANI) are now more
common than HAD. Sanmarti et al. 2014.
• DSM-5TM- mild NCD-25%, major NCD-<5% in HIV+ patients
• The prevalence of HIV associated major neurocognitive disorder in
cART lowered to 5% in comparison to 20-30% in pre-ART era.

7. Epidemiology
Ethiopia
From ART clinics-based cross-sectional studies around a third of HIV
patients have some kind of neurocognitive deficit.
• The prevalence of HIV dementia at Debre markos hospital was 24.8%. Tilahun
Belete Mossie et al. 2014
• In South Wollo prevalence of HAND was 36.4%. Tsegaw M, Andargie G, Alem G,
Tareke M. 2016
• The prevalence of HIV Associated Neurocognitive Deficit, at Ayder hospital was
33.3% (95% CI; 27.7% -40.6%). Tilahun B. et al. 2017

8. Epidemiology
Risk factors
• Host factors-advanced age, female gender, genetic predisposition?
• More advanced HIV disease (Low CD4 (<200),high viral load, AIDS defining
illnesses, longer duration of illness)
• Use of illicit drugs
• Comorbid conditions (especially anemia and infection with cytomegalovirus,
human herpesvirus 6, and JC virus, Hepatitis C virus infection)
• Cerebrovascular disease risk factors: diabetes, hypertension,
hypercholesterolemia, obesity
• Sleep disorders: insomnia, obstructive sleep apnea, sleep fragmentation
• Psychiatric comorbidity: major depression, anxiety disorders, bipolar disease

9. Etiopathology
• The precise pathogenic mechanisms underlying HAND remain only
partially delineated.
• CNS is one of the target organs where HIV can be detected soon after
primary infection, but neurons are not productively infected
• HIV enters the brain carried within migrating monocytes and
lymphocytes that cross the BBB (Trojan Horse hypothesis).
• monocytes become active mΦs being able to produce HIV within the
CNS, and facilitate infection of microglial cells
• Astrocytes could also be involved with astrogliosis induced by local
chemokines and cytokines leading to increased BBB permeability

10. Etiopathology
Chronic Inflammation-induced neuronal insults
• Release of HIV viral proteins
• inflammation-associated neurodegeneration with macrophage pro-inflammatory
cytokine/chemokine production, excitotoxic neuronal injury, and oxidative stress
• Further disruption of BBB- consequent monocyte and lymphocyte migration
• Synaptic disruption and impairment of neurogenesis
• Autopsy studies- characteristic white matter changes and demyelination,
microglial nodules, multinucleated giant cells and perivascular infiltrates.
• Not all areas of brain are affected similarly- basal ganglia and the hippocampus
most affected, to lesser extent mid-frontal cortex and hence, neuropsychological
impairment of the fronto-subcortical-region.

11. Etiopathology
Saylor et al. Nat Rev Neurol. 2016

12. Clinical features
• Subcortical pattern NCD with prominently impaired executive function,
slowing of processing speed, problems with more demanding attentional
tasks, and difficulty in learning new information, but fewer problems with
recall of learned information.
• Aphasia, agnosia and apraxia, that are more typical of cortical dementias
are less common, but can be seen in advanced HAD.
• After cART: Mixed ‘cortical and subcortical’
• Neuromotor features such as severe incoordination, ataxia, and motor
slowing.
• There may be loss of emotional control, including aggressive or
inappropriate affect or apathy.
• Other manifestations of advanced HIV disease.

13. Diagnosis
• DX of HAND like other NCD remains clinical.
• HAND is diagnosis of exclusion- exclude all possible medical and psychiatric
illnesses.
• Clinical- HX, PE, neuropsychological tests
Screening tools
• MMSE
• the Montreal cognitive assessment (MoCA)
• Brief Neurocognitive Screen (BNCS)
• Memorial Sloan-Kettering (MSK) dementia severity scale
• HIV dementia scale
• International HIV dementia scale

14. Diagnosis
HDS
It is Score of 4 items
with max- possible score 16.
Score of <10 indicates
Possible HAD.
C. Power et al.
J Acquir Immune Defc Syndr
Hum Retrovirol. 1995;8(3):275

15. Diagnosis
IHDS
sum of the scores of 3 items.
maximum possible score is 12 .
score of ≤ 10 possible dementia.
Sacktor et.al.
AIDS. 2005;19(13):1369.

16. Diagnosis
Work up
• Serum HIV testing, CD4, viral load (serum & CSF).
• Laboratory tests: CBC, electrolytes, RFT, LFT, TFT, RBS, vit. B12, RPR /
VDRL, HCV.
• Neuroimaging (CT/MRI)- r/o SOL and other lesions; cortical atrophy
may be seen in advanced HAD; this finding is not specific.
• CSF analysis- if CNS infections are likely
• Toxi. screen- if substance abuse is suspected

17. Diagnosis
Post contrast CT scan
Harrison's Principles of Internal Medicine, 19th ed. Lancet Infect Dis 2013; 13: 976–86

18. Diagnosis
DSM-5TM Major or Mild Neurocognitive Disorder Due to HIV Infection

19. Diagnosis
AAN Frascati criteria, 2007
Saylor et al. Nat Rev Neurol. 2016

20. Differential diagnosis
• OIs and neoplasia- e.g. syphilis, crypto, toxo, TB, PML, CMV, PCNSL
• NCD due to cerebrovascular disease/neurodegeretion-AD, FTD, PD,TBI-in general,
stable, fluctuating (no progress) or improving NC status favor HAND.
• Delirium
• Substance/medication-induced NCD
• metabolic states (e.g. vitamin B-12 deficiency, thyroid disorders, liver disease,
renal disease)
• Pseudo-dementia due to other psychiatric illnesses- e.g. depression, anxiety
disorder, psychosis etc.
• ADHD/ADD, neurodevelopmental disorders

21. Management
• No specific Rx. For HAND, cART remains main option
• ART reverses the features of dementia, but not fully effective.
• Other pharmacologic interventions- in trial include Minocycline,
Memantine
• Non pharmacologic interventions- Neuropsychological intervention

22. Vascular Neurocognitive Disorder
Introduction
• Vascular dementia is a common form of dementia
• It is recognized as a cognitive disorder explained by vascular causes in
the absence of other pathologies.
• It is a group of syndromes with d/t subtypes relating to different
vascular mechanisms.
• CVD and AD are common and age related pathologies – hence mixed
dementia is the norm not the exception.

23. Introduction
Subtypes of vascular dementia
O’Brien and Thomas. Lancet 2015; 386: 1699

24. Epidemiology
• Second most common cause of NCD following AD.
• Prevalence rises with age (e.g. US- 0.2% in 65-70 yrs. age group to
16% in those ≥ 80 yrs.) DSM-5TM
• Risk (attack rate) of vascular dementia roughly doubles every 5·3
years, an exponential rise slightly less pronounced than that of
Alzheimer’s disease, which doubles every 4·5 years.
• Dementia develops in around 15–30% of subjects 3 months after a
stroke, 9x ↑ at 5 yrs.

25. Epidemiology
Risk factors
• Generally are the same as those for stroke, and include advanced age, male
sex, smoking, hypertension, DM, dyslipidemia, homocysteinemia , and
cardiac diseases.
• Other important risk factors are Cerebral amyloid angiopathy and cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy(CADASIL).
• Environmental- education, diet, physical exercise, and mental activity
could affect neurocognitive outcome of stroke.
• Late life depression, which is risk factor for AD and associated with many
vascular abnormalities also is risk factor for vascular NCD.

26. Etiopathology
• The pathogenesis of VNCD is complex and incompletely understood.
• Heterogeneous nature of vascular pathology- large vessel and small
vessel arteriosclerosis (and other vascular diseases—e.g. cerebral
amyloid angiopathy) can lead to cortical and subcortical infarcts, sub-
infarct ischemic lesions (micro-infarcts in grey matter and white
matter lesions), and large and small cerebral haemorrhages
(microbleeds).
• Site, size, and numbers of affected brain area matters.

27. Interplay of pathogenic factors causing VNCD
Jellinger KA. Front Aging Neurosci. 2013;5(17):10.

28. Clinical features
• Course: variable, classically abrupt onset of CI, stepwise deterioration but
commonly gradual.
• Symptoms and signs- focal signs, motor/sensory deficits, bulbar, gait;
depression, anxiety
• Depression relatively common; emotional lability common
• Neuropsychometric findings- Executive dysfunction (vs memory and
language function); attentional deficits.
• Hx. and findings of CVD and risks-high BP, stroke, cardiac disease

29. Diagnosis
• Clinical- HX, PE, neuropsychological tests
• Neuroimaging (CT/MRI), functional and metabolic in difficult cases.
• Lab tests-CBC, RBS, electrolytes, RFT, LFT, TFT, vit. B12, sero-status for
RVI, syphilis.
• EEG
Clinical dxic. Criteria
• DSM-5, NINDS-AIREN, ADDTC, Hachinski Ischemic Score.

30. Diagnosis
A) Extensive(>25%)
white matter lesions (FLAIR)
B) large cortical infarction (FLAIR)
C) Microbleed (T2W)
D) multiple lacunar infarcts (T1W).
O’Brien and Thomas.
Lancet 2015; 386: 1700

31. Diagnosis
DSM-5 key domains of cognitive function
Identifying the domains and
subdomains affected in a particular
patient can help establish the
etiology and severity of
the neurocognitive disorder.
Sachdev, P. S. et al.Nat. Rev. Neurol. 2014.

32. Diagnosis
DSM-5TM Major or Mild Vascular Neurocognitive Disorder

33. Diagnosis
DSM-5TM Major or Mild Vascular Neurocognitive Disorder

34. NINDS-AIREN Criteria for the Diagnosis of Vascular Dementia
• Dementia (memory and 2 or more domains)
• Cerebrovascular disease (focal neurology and CVD on brain imaging)
• Link between the 2 (3 months or abrupt/fluctuating clinical course)
• Possible VaD if brain imaging negative or relationship (3/12) not clear
Roman et al. Neurology 1993;43:250-260

35. Differential diagnosis
• Other NCD- AD, PD, FTNCD, NCD with Lewy bodies
• Other medical condition- brain tumor, multiple sclerosis, encephalitis,
toxic or metabolic disorders
• Other mental disorder- e.g. delirium, depression

36. Management
• General management principles of dementia- ensuring a timely
diagnosis, assessing and treating comorbidities, providing information
and support for the patient with dementia and their care givers, and
maximizing independence.
• 2 ° prevention - optimally manage vascular risk factors (statins, anti-
HTNives, aspirin), smoking cessation, wt. reduction, diet, exercise, ↓
alcohol.
• Progress towards finding effective treatments for vascular dementia
has proved even more elusive than for AD

37. Management
• The best studied treatments are cholinesterase inhibitors and
memantine, both of which are licensed and established drugs for AD
• Cholinesterase inhibitors do not seem to confer benefit in pure
vascular dementia, but they are beneficial in cases of mixed
Alzheimer’s disease and vascular dementia
• Trials- Calcium channel blockers (nimodipine)

38. Neurocognitive Disorder Due to Another Medical
Condition ( previously under the category of Amnestic disorders)
A number of medical conditions can cause NCDs and include
• Structural lesions
• Hypoxia related to hypoperfusion
• Endocrine conditions
• Nutritional conditions
• Other Infections
• Immune disorders
• Hepatic or Renal failure
• Metabolic conditions
• Other neurological conditions
• Unusual causes – electrical shock, radiation

39. Neurocognitive Disorder Due to Another
Medical Condition
Causes of reversible dementia
• Drugs
• Endocrine
• Metabolic
• Emotional
• Nutritional
• Tumor/ trauma
• Infections
• Atherosclerosis

40. Diagnosis
DSM-5TM Major or Mild Neurocognitive Disorder Due to Another
Medical Condition

41. References
• American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders
5th ed. American Psychiatric Association; 2013.
• Sadock BJ, Sadock VA, Ruiz P. Kaplan and Sadock’s Synopsis of Psychiatry: Behavioral
Sciences/Clinical Psychiatry, 11th ed. Wolters Kluwer; 2015.
• Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L. 1., Jameson, J. L., & Loscalzo, J.
Harrison's principles of internal medicine (19th edition.). New York: McGraw Hill
Education; 2015.
• Sanmarti et al. HIV-associated neurocognitive disorders. Journal of Molecular Psychiatry
2014, 2:2
• Tilahun Belete Mossie et al. HIV Dementia among HIV Positive People at Debre Markos
Hospital, Northwest Ethiopia. American Journal of Psychiatry and Neuroscience. Vol. 2,
No. 2, 2014, pp. 18-24.
• Tsegaw M, Andargie G, Alem G, and Tareke M. Screening HIV-associated neurocognitive
disorders (HAND) among HIV positive patients attending antiretroviral therapy in South
Wollo, Ethiopia. J Psychiatr Res. 2017;85:37-41.
• Tilahun B. et al. Prevalence of HIV Associated Neurocognitive Deficit among HIV Positive
People in Ethiopia: A Cross Sectional Study at Ayder Referral Hospital. Ethiop J Health Sci
2017;27(1):67-76.

42. References
• Saylor D et al. HIV associated neurocognitive disorder pathogenesis and prospects for
treatment. Nature Reviews Neurology. 2016; 12: 234-48.
• Clifford DB, and Ances BM. HIV-associated neurocognitive disorder Lancet Infect Dis
2013;13: 976–86.
• Sacktor et.al. The International HIV Dementia Scale: a new rapid screening test for HIV
dementia. AIDS. 2005;19(13): 1367–1374.
• C. Power et al. HIV Dementia Scale: a rapid screening test. J Acquir Immune Defc Syndr
Hum Retrovirol. 1995;8(3): 273-8.
• O’Brien JT, and Thomas A. Non-Alzheimer’s dementia 3: Vascular dementia. Lancet 2015;
386: 1698-1706.
• Jellinger KA. Pathology and pathogenesis of vascular cognitive impairment-a critical
update. Front Aging Neurosci. 2013;5(17):1-19.
• Sachdev, P. S. et al. Classifying neurocognitive disorders: the DSM-5 approach. Nat. Rev.
Neurol. 2014: 1-9.
• Roman et al. Vascular dementia: diagnostic criteria for research studies. Report of the
NINDS-AIREN International Workshop. Neurology. 1993; 43(2):250-260.