Neurological Complications of HIV

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Original Editor - Cindy John-Chu

Top Contributors - Cindy John-Chu, Melissa Coetsee, Kim Jackson and Nupur Smit Shah  

Introduction

The Human Immunodeficiency Virus (HIV) is a virus that attacks cells of the body's immune system, leaving those affected prone to opportunistic infections. HIV infection can also lead to various neurological complications as a result of these infections or the virus itself. HIV belongs to a class of viruses (the lentiviruses) that are known increase the risk of developing chronic neurologic diseases in their human hosts.The video below explains how HIV can cause cell damage, as well as how HIV increases the risk of infections, which can also lead to complications.

Epidemiology

Neurological complications related to HIV can occur throughout the various stages of the infection, but is more common in the advanced stages - i.e when HIV has progressed to AIDS. About 50% of adults who have AIDS suffer from neurological complications.

In the African region, the prevalence and mortality of neurological conditions in people living with HIV (PLWH) is very high, with up to 75% of PLWH presenting with neurological complications and central nervous system (CNS) disorders are responsible for >20% of deaths. Late clinical presentation, advanced immunosuppression and a high burden of infectious diseases make PLWH in Africa particularly vulnerable to developing neurological complications.

Aetiology

HIV can result in neurological complications through various mechanisms, including:

1. Direct HIV infection: HIV does not directly attack the cells in the nervous system, but it causes significant inflammation which can cause damage to the central and peripheral nervous system.Typically responsible for HIV-associated neurocognitive disorder (HAND), distal sensory neuropathy (DSN) and vacuolar myelopathy.
2. Opportunistic infections: typically responsible for altered level of consciousness, meningitis, stroke, seizures, myelopathy and neuropathy.
3. Associated diseases: such as specific cancers that are associated with HIV infection
4. Anti-retroviral medicine: less common with newer ARV medications

PLWH who present with neurological complaints alone, tend to have higher CD4 counts and present with neurological conditions associated with opportunistic infections. On the other hand, PLWH with low CD4 counts and neurological and systemic illness tend to present with conditions caused by HIV itself.

Diagnostic Tools

• Lumbar puncture: Used to withdraw cerebrospinal fluid (CSF). The opening pressure and amount of proteins and lymphocytes present, as well as glucose levels, can help with identifying the underlying cause. CSF may be normal in patients with advanced immunosuppression despite underlying infection, otherwise elevated lymphocytes and proteins usually indicate CNS infection. CSF can also be cultured to identify specific organisms.
• Cultures:
• Neuroimaging: Including CT-brain and MRI. Can identify infarction, meningeal enhancement, brain atrophy, lymphomas, tuberculomas and other focal lesions.

• Biopsies

Neurological Conditions

Underlying Causes

HIV is associated with various CNS and PNS complications. The table below presents some of the main causes and associated conditions.

Common Causes and Conditions

Category	Description & Specific Conditions	Prevalence
Opportunistic infections
Fungal infections	Cryptococcal meningitis, caused by a fungus, can lead to inflammation in the central nervous system	Most common CNS opportunistic infection in HIV in Africa; Affects 4-40% of PLWH
Bacterial infections	TB is the most frequent opportunistic infection in HIV in Africa and can lead to TB meningitis (TBM), myelo-radiculopathy and tuberculomas in the brain. Other bacterial infection can also cause meningitis (eg. pneumococcal). TB can also result in myelopathy if disseminated. Neurosyphilis can also develop in untreated syphilis, causing neurological damage.	TBM is the second leading causes of meningitis in PLWH in Africa
Parasitic infections	Toxoplasmosis encephalitis can develop as a result of a parasitic infection (toxoplasma). The parasite can be dormant and reactivate with immunosuppression, resulting in focal brain lesions.	Most common CNS opportunistic infection in HICs
Viral infections	Common opportunistic viral infections that affect the nervous system include Cytomegalovirus (CMV), Herpes virus and JC Polyomavirus. Each of these can result in unique neurological manifestations (including myelopathy and radiculopathy) with the latter causing Progressive multifocal leukoencephalopathy (PML)
Direct HIV infection	Dependent on the clinical stage and the degree of underlying immunosuppression.
HIV-associated neurocognitive disorder (HAND)	Impaired cognitive function and memory loss as a result of brain atrophy in advanced HIV. Includes mild impairment and HIV-associated dementia.	Frequency varies from 18-80% in Africa
Neuropathies	Damage to peripheral nerves can lead to polyneuropathy, mononeuropathy or inflammatory neuropathy	Frequency of about 36-60%
Vacuolar myelopathy	HIV itself can lead to tiny holes in the nerve fibres of the spinal cord, resulting in myelopathy	Frequency of 1.4-16%
Lymphoma	Lymphomas (tumours) can develop in the brain of people living with HIV (PLWH)	Mostly in advanced HIV, and generally low incidence
Stroke	HIV increases the risk of cerebrovascular incidents, due to increased cardiovascular risk factors, elevated inflammation or often associated meningitis	Affects about 2%of PLWH; more common with low CD4 counts
Psychological conditions	PLWH often suffer from anxiety and/or depression
Autoimmune mediated disorders	PLWH have an increase risk of acute/chronic inflammatory demyelinating polyneuropathy, myasthenia gravis and polymyositis	Uncommon - mostly occurs at seroconversion

Clinical Presentation

Signs and symptoms of neurological compilations vary depending on the specific pathology. We will explore the common neurological complications in more detail, but below is a list of common neurological signs and symptoms in PLWH:

• Seizures - usually related to opportunistic infections that cause meningitis or encephalitis; occasionally seizures may be related to ARV medication and hyponatraemia
• Reduced level of consciousness
• Myelopathy
• Radiculopathy
• Hemiparesis - as a result of cerebral lesions, infarction or haemorrhage
• Nerve palsies
• Headaches
• Confusion and lethargy

Meningitis

Cryptococcal meningitis

Usually presents with a slow onset of symptoms of meningitis, including headache, fever, nausea and seizures. Neck stiffness and cranial nerve fallout may also be present. The case fatality rate (CFR) in Africa is 35-68%.The main risk factors for death include CD4 counts <50, starting ART too early after CMV infection and lack of access to fungicidal treatments.

TB Meningitis

Signs and symptoms are very similar to CMV meningitis and usually includes headache, fever, nausea and altered level of consciousness. The CFR of TBM in Africa is 59.9%. Multi-drug resistant TB is more common in PLWH and, if present, increases the mortality of TBM. The main risk factors for death include CD4 counts <50, starting ART too early while on TB treatment and advanced immunosuppression.

Myelopathy& Radiculopathy

Vacuolar Myelopathy

Vacuolar Myelopathy (VM) occurs as a direct consequence of HIV infection affecting the spinal cord. VM only occurs in cases of advanced immunosuppression and untreated HIV. It is characterised by by progressive spastic paraparesis with bladder involvement.The use of ART does not seem to decrease established VM and preventions (early ART initiation) is therefore important.

Infectious causes

• Myelopathy can be caused by TB (most common), Herpes zoster and CMV opportunistic infections
• Radiculopathy is usually confined to the lumbosacral nerve roots and results in flaccid paraplegia with areflexia and urinary incontinence. The main causes are usually TB (through granulomas or Pott's disease) or CMV (usually only in advanced stages)

HIV-related Neuropathy

Neuropathies can occur during all stages of HIV infection and occur as a result of the virus itself, and occasionally because of ARV toxicity (although this has become less common with newer ARVs). Common neuropathies include:

• Distal Sensory Neuropathy: Most common type of neuropathy, affecting the distal extremities in a symmetrical pattern. Paraesthesia and neuropathic pain are the main symptoms.
• Polyneuropathy: Affects multiple sensory and motor nerves in the distal limbs, with similar symptoms DSN, but with associated weakness
• Mononeuropathy: The most common is Bell's Palsy
• Inflammatory neuropathy: Results in condition similar to Guillain-Barre Syndrome, or isolated nerve pain if only certain nerves are affected

It is important to note that vitamin B6 and B12 deficiency (often associated with HIV) can also contribute to neuropathic symptoms. For more detail see the page on HIV-related Neuropathy.

HIV Associated Neurocognitive Disorder (HAND)

HAND is caused by the direct effect of the HIV virus, and not as a result of opportunistic infections. HAND includes a spectrum of neurocognitive impairment, ranging from asymptomatic and mild impairment to HIV-associated dementia (the most severe form of HAND).

PLWH who have HAND often present with reduced motor speed, declining cognitive function, behavioural changes and memory loss.Although ART can decrease the burden of HAND, milder symptoms my persist.

Management

Although each neurological condition will have unique treatment strategies, an important first step is to ensure that a person living with HIV is virally suppressed - i.e. receiving and adhering to ART medication. A study conducted in South Africa indicated a 40% decrease in TB Meningitis following expanded ART programs.

In patients who need to be initiated on ART, with a concurrent opportunistic infection, extreme care needs to be taken to prevent immune reconstitution inflammatory syndrome (IRIS).

The table below summarises the additional treatment strategies for the more common neurological complications of HIV:

Important Management Strategies

Cryptococcal Meningitis	Targeted Cryptococcus screening during HIV screening and pre-emptive therapy (Flucanozole) if positive and CD4<100; Amphotericin-based treatment regimens Defer starting ART for 4-6 weeks after CM treatment
TB Meningitis	Intermittent (6 month) isoniazid chemoprophylaxis Improved TBM case finding and diagnosis Defer starting ART for 4-6 weeks after starting TBM treatment
Toxoplasmosis Encaphilitis	Screening for toxoplasmosis Chemoprophylaxis with trimethoprim-sulphamethoxazole until CD4 is >200 ART initiation 2 weeks after the start of treatment
Neuropathies	Neuropathic pain medication can help to relieve pain related to neuropathies.

PML and CNS Lymphoma are not curable

Role of the Multi-disciplinary Team (MDT)

Team member	Possible role
Medical Doctor	Investigations, including blood and CSF tests and neuroimaging Altering ARV regime as needed in some cases of neuropathy Accurate diagnosis and treatment of any opportunistic infections Additional prescriptions for concomitant symptoms/conditions such as pain, depression an seizures, with ARV drug interactions in mind Management of increased CSF pressure Ensuring delayed ART (4-6 weeks) when infections are present, to prevent IRIS
Psychologist/ Counsellor	Counselling of family members when a patient presents with advanced neurological condition Counselling and CBT in cases of non-adherence to ARVs Psychotherapeutic interventions for anxiety and depression
Occupational Therapist
Physiotherapist

Implications for Physiotherapy

The similarities between the nervous system complications of HIV and other neurological conditions call for thorough assessment of patients with neurological disorders to ascertain the underlying cause of their conditions. This would be resourceful to guide future research in these areas.

Conclusion

Although the introduction of ARVs has resulted improved outcomes, neurological complications associated with HIV is still very common, especially in Africa. Early diagnosis and ART initiation, ART-adherence support, early detection of opportunistic infections and provision of adequate rehabilitation support is imperative to reduce the negative impact that these complications can have on the overall wellbeing of PLWH.