HIV Associated Neurocognitive Disorder (HAND)

Original Editor - Blessed Denzel Vhudzijena

Top Contributors - Melissa Coetsee, Blessed Denzel Vhudzijena and Kim Jackson  

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Introduction

People living HIV (PLWH) are at risk of developing a range of cognitive, motor, and/or mood problems collectively known as HIV-Associated Neurocognitive Disorder (HAND). Although severe and progressive neurocognitive impairment has become rare in HIV clinics in the era of potent antiretroviral therapy (ART), most patients with HIV worldwide have poor outcomes on formal neurocognitive tests. Typical symptoms include difficulties with attention, concentration, and memory; loss of motivation; irritability; depression; and slowed movements.

Among HIV infected patients cognitive impairment was and is one of the most feared complications of HIV infection. In addition neurocognitive impairment may affect adherence to treatment and ultimately result in increased morbidity and mortality.

Categories of HAND

Initially known as AIDS Dementia Complex, HAND is categorized into three levels of functional impairment.

1. Asymptomatic Neurocognitive Impairment (ANI) is a mild form of HAND with impaired performance on neuropsychological tests, but affected individuals report independence in performing everyday functions
2. Mild Neurocognitive Disorder (MND) is a common form of HAND that mildly interferes with everyday function.
3. HIV-associated Dementia (HAD) refers to HAND in its most severe form, where there is an inability to complete daily tasks independently. Alternative terms used to describe HAD include HIV Encephalopathy or AIDS-dementia complex.

Epidemiology

The exact prevalence of HAND among PLWH is not well known, as the diagnostic criteria and tools are not very sensitive of specific. There is a wide variation in prevalence between and within countries, but overall studies have shown a reduction in the burden of HAND since the introduction of ART. The mean prevalence of HAND in in the post-ART era in Africa is estimated to be 30.4%.

Aetiology

HAND is a caused by direct effects of the HIV infection, independent of opportunistic infections. HIV crosses the blood-brain barrier and tends to have a regional preferential distribution affecting the basal ganglia and frontal lobe. Encephalitis occurs secondary to the inflammation caused by the HIV infection, and is responsible for the neurological signs associated with HAND. It is however important to note that a poor correlation exists between histopathological changes and clinical severity - this emphasises that factors not relating to structural damage, determine the clinical picture.

Possible risk factors for HAND:

• Advanced age
• Advanced WHO clinical stage
• Low CD4 count
• High viral load
• Anaemia
• Co-morbidities (diabetes and obesity)

Clinical Presentation

The manifestations of HAND include cognitive, behavioural and motor dysfunction which are indicative of frontal lobe and basal ganglia involvement.When clear focal neurological signs are present (eg. hemiplegia, apraxia, aphasia) other pathologies should be considered. The table below summarises the clinical signs associated with HAND:

	Cognitive decline	Behavioural abnormalities	Motor dysfunction
Domains affected and clinical effects	Affects verbal and visual memory, complex sequencing and mental flexibility Poor short-term memory Impaired concentration Executive dysfunction Mental slowing Flawed judgement Forgetfulness	Lack of interest and drive Loss of libido Irritability Emotional blunting Rarely: psychosis, mania, delirium	Difficulties with fine motor movements Balance problems Spasticity and increased reflexes of the lower limbs Ataxia Late stage: seizures, incontinence
Implications	Patients forget appointments and medication adherence may decline. Maintaining conversations become harder. Increasing difficulty in performing more complex ADL's independently.	Social withdrawal and psychiatric presentations that can affect relationships	Deteriorating handwriting and increased clumsiness. Increasing dependence for basic ADLs

The dominant domains affected seems to be influenced by whether HAND developed prior to or after initiating ART:

• Pre-ART HAND: psychomotor slowing - inattention, slow thinking, forgetfulness, unsteady gait, tremor, social withdrawal
• Post-ART HAND: more cortical involvement - impaired learning ability, memory executive function and extrapyramidal motor features

In advanced HAND, patients present develop mutism and incontinence, followed by a vegetative state.

Diagnosis

HAND is a clinical diagnosis based on exclusion. It is however possible for HAND to be present along with other neurological conditions. Diagnosis is based on the following criteria:

• Positive HIV test
• History of progressive changes in cognition and behaviour
• Impairment in at least two domains of neuropsychological performance
• Absence of:
  • Focal neurological signs
  • Intoxication withdrawal
  • Metabolic derangement
  • CNS opportunistic infection
  • CNS neoplastic lesion

Differential Diagnosis

See the page on Neurological Complications Associated with HIV

• CNS Lymphoma
• Progressive multifocal leukoencephalopathy (PML)
• Opportunistic infections, including toxoplasmosis and cryptococcal meningitis.
• Vitamin B-12 and folate deficiency

Investigations

Cerebrospinal fluid (CSF) investigations and neuroimaging (MRI and CT-brain) are useful to exclude other potential causes of cognitive changes in PLWH.Encephalopathies causes by substance abuse or head injury need to be excluded. Blood tests can also be useful to investigate hepatic or renal failure as a possible cause of metabolic encephalopathy.

Useful Investigations to exclude other causes

Blood tests	CSF	Neuroimaging
Full blood count Urea & Creatinine Liver function Vit B12 level Syphilis serology CD4 count and viral load	Usually abnormal in patients with HAND - lymphocytic pleocytosis with mildly elevated protein. These findings are however not specific to HAND. CSF analysis helps to exclude opportunistic infections.	Cerebral atrophy with ventricular enlargement may be present in HAND.

Outcome Measures

Neuropsychological tests that measure psychomotor speed, verbal and non-verbal learning and sustained attention, can be used as a screening and monitoring tool. Normal values for the African regions are however lacking, which questions the validity of many existing tests.

• International HIV Dementia Scale (IHDS): Measures motor speed, psychomotor speed and learning, registration and memory; a score of <10 is regarded to be indicative of HAND, but poor sensitivity and specificity means that this test can not be used in isolation.
• Mini-Mental (MMSE)

Management

The most important strategy is to start ART as early as possible (which also implies early detection of HIV infection). ART can prevent HAND, slow the progression and even lead to some improvements in neurocognitive function.

ART

Early initiation of ART helps to prevent HAND in PLWH. In patients who already present with HAND, some improvement may occur once ART is initiated, but these improvements usually plateau after 9-months on ART. Many patients affected by HAND will experience persistence of symptoms. Combined ART regimes with better central nervous system penetration can help to prevent HAND.

Other Medication

Other strategies aimed at reducing inflammation - such as methotrexate, statins and antiepileptic medication - do not seem to have significant effects.Symptomatic treatment for depression and psychosis in patients with HAND also forms an important part of the management plan.Patients with HAND have an increased sensitivity to neuroleptic drugs, necessitating increased caution and monitoring when these drugs