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 neurological 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. Between 40 and 70% of people infected with HIV will develop symptomatic neurology.

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 of the nervous system (neurons), but it causes significant inflammation (chemokines and cytokines released by infected microglia and astrocytes) which can cause damage to the central and peripheral nervous system.This cascade of inflammation can lead to encephalitis which is characterised by neuronal loss. Direct HIV infection is typically responsible for HIV-associated neurocognitive disorder (HAND), distal sensory neuropathy (DSN) and vacuolar myelopathy.
2. Opportunistic infections: The nervous system can also be affected by immunosuppression-related infections. These infections are typically responsible for altered level of consciousness, meningitis, stroke, seizures, myelopathy and neuropathy.Most CNS infections occur when CD4 counts are less than 200.
3. Associated diseases: Such as specific cancers that are associated with HIV infection
4. Anti-retroviral medicine: Less common with newer Anti-Retroviral Treatment (ART), but Necleoside (NRTI) class ART is associated with neuropathies, and Zidovudine can cause myopathy. Initiating ART with untreated underlying infection can also lead to immune reconstitution inflammatory syndrome (IRIS).

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 often present with neurological and systemic illness, in which case the conditions are often 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.
• X-rays: A chest x-ray may be indicated when tuberculosis is suspected to be an underlying cause of infective processes. Spinal x-rays can identify TB of the spine and malignant growths in patients that present with myelopathy.
• Neuroimaging: Including CT-brain and MRI - can identify infarction, meningeal enhancement, brain atrophy, lymphomas, tuberculomas and other focal lesions.

• Biopsies: Used to differentiate lymphoma from toxoplasmosis and progressive multifocal leukoencephalopathy (PML).

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 some neurological signs and symptoms often seen in PLWH:

• Seizures - usually related to opportunistic infections that cause meningitis or encephalitis; occasionally seizures may be related to ART medication and hyponatraemia
• Reduced level of consciousness
• Cognitive impairment
• Myelopathy
• Radiculopathy
• Hemiparesis - as a result of cerebral lesions, infarction or haemorrhage
• Nerve palsies - cranial nerve palsies can occur as a result of meningitis
• Headaches, nausea, neck stiffness - typical signs of meningitis
• Confusion and lethargy

Neurological Conditions

Overview

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; Frequency of 6-7%
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 infections can also cause meningitis. 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 with a frequency of 6%; TB is the most common cause of myelopathy in HIV in South Africa
Parasitic infections	Toxoplasmosis encephalitis can develop as a result of a parasitic infection (toxoplasma). The parasite can be dormant and reactivated with immunosuppression, resulting in focal brain lesions.	Most common CNS opportunistic infection in high income countries (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)	Not well documented
Direct HIV infection
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	Accounts for 2% of neurological disease in PLWH in South Africa
Other Causes
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 and may have concurrent psychiatric disorders	See Mental Health and HIV
Autoimmune mediated disorders	PLWH have an increase risk of acute/chronic inflammatory demyelinating polyneuropathy, myasthenia gravis and polymyositis	Uncommon - mostly occurs at seroconversion

Aseptic Meningitis

Meningeal inflammation occurs as a result of HIV crossing the blood-brain barrier (aseptic meningitis), or as a result of an inflammatory response to an opportunistic infection.Typical meningitis symptoms include headache, fever, neck stiffness, nausea. Cranial neuropathies and seizures may also occur.

Aseptic meningitis (AM) refers to meningeal inflammations without a typical bacterial cause. It can be caused by HIV itself (especially during seroconversion and at late stage disease) and can present as an acute symptomatic or chronic asymptomatic condition. Many PLWH (up to two thirds) live with asymptomatic AM. Other infectious causes include other viruses (HSV/ CMV), fungi (cryptococcal) and tuberculosis.

Cryptococcal meningitis

Cryptococcal infection is the leading cause of meningitis in PLWH. It 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 treatment.

TB Meningitis

Signs and symptoms are very similar to viral 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.

Progressive multifocal leukoencephalopathy (PML)

PML is a rare infection of the brain caused by the JC virus and often mimics the CSF findings of aseptic meningitis. The JC virus can remain inactive in a human host, but acquired immunosuppression in HIV can lead to reactivation of the virus. Symptoms include progressive deterioration of speech, cognition and motor function. The prognosis of PML is poor and death often occurs within 1-9 months. It usually only occurs in ART-naïve patients and initiating ART may slow down its progression.

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.

HIV-associated Myelopathies

Myelopathies are not as common as encephalopathies, with a frequency of about 5-10%. Myelopathies are mostly caused by infections or neoplasms, but vacuolar myelopathy and HIV transverse myelitis are manifestations of primary HIV infection. Although there is no existing treatment for vacuolar myelopathy, most of the infectious myelopathies can improve with organism specific treatment.

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 progressive spastic paraparesis and hyperreflexia with bladder involvement. Sensory ataxia and co-existing distal sensory neuropathy is common, and a clear spinal cord sensory level is rare. The use of ART does not seem to decrease established VM and preventions (early ART initiation) is therefore important.

Infectious Myelopathy

Opportunistic infections that can cause myelopathies are listed below.

• Viral: Cytomegalovirus (CMV), Herpes simplex virus (HSV), JC virus, Varicella-zoster virus (VZV),
• Bacterial: Tuberculosis (TB), Pseudomonas, Syphilis, Cryptococcus
  • TB can cause transverse myelitis and spinal meningitis
  • Pott's disease in the spine, caused by TB, can also lead to cord compression
• Fungal/ Parasitic: Aspergillus ,Toxoplasma gondii - not very common

The most common causes of myelopathy in PLWH are TB, Herpes and CMV. Some of these infections can also cause Radiculopathy. 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.

CNS Complications in Children

In children with HIV, neurological conditions are more often causes by HIV itself, and less commonly by opportunistic infections. HIV prevents the development of the blood-brain barrier, rendering an infected child's brain susceptibility to neuro-invasion, with progressive HIV encephalopathy (PHE) as a result. In immature, developing brains, the effects of neurological complications can be devastating and are hard to treat once established. It is therefore critical to focus on preventing HIV transmission to children.

The table below summarises the HIV-related neurological complications in children:

PHE	Static Encephalopathy	CNS infections	Other
Aquired microcephaly - stagnating or decreasing head circumference in children <2 years Progressive motor dysfunction with spasticity - milestones are lost or not achieved Neurodevelopmental decline - cognitive deficit affecting language and concentration Poor prognosis - usually gradual deterioration or rapid decline	Similar presentation to PHE, but non-progressive Spontaneous improvement may occur	Most commonly caused CMV/TB/ Candida leading to encephalitis or meningitis.	Seizures are more common in children with HIV. Uncontrolled seizures can result in neuronal damage. Cerebral infarction and haemorrhage can occur, but less frequent than in adults

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 IRIS.

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

Condition	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 Encephalitis	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.

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 and 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.