Neurological Complications of HIV

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.

Although the incidence and survival related to neurological disease in PLWH has improved significantly since the introduction of ART, mortality remains high and morbidity is of increasing concern.CNS conditions can result in long hospital stays, reduced quality of life and significant disability.

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, or stroke as a result of increased cardiovascular risk factors.
4. Anti-retroviral medicine: Less common with newer Anti-Retroviral Treatment (ART), but Nucleoside (NRTI) class ART is associated with neuropathies, and Zidovudine can cause myopathy. Efavirenz is associated with poor neurocognitive performance and neuropsychological dysfunction. Initiating ART with untreated underlying infection can also lead to immune reconstitution inflammatory syndrome (IRIS).
5. Nutrient Deficiencies: PLWH often present with vit B12 deficiency, which may contribute to neurological disease.

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

Diagnosis is often challenging as presentation tends to be atypical and multiple causes may co-exist. Furthermore, investigations often yield confusing results and ART may also alter the way CNS conditions manifest.

• 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.CSF and clinical findings can often be non-specific, in which case neuroimaging can be very useful in differential diagnosis.

• Biopsies: Used to differentiate lymphoma from toxoplasmosis and progressive multifocal leukoencephalopathy (PML).
• CD4 count: Knowing the CD4 count of a patient can help to narrow down the differential diagnosis. Patients with CD4 counts >200 are more less likely to have neurological conditions caused by HIV itself.

Differential Diagnosis based on CD4 count

Seroconversion and/or CD4 >500	CD4 >200-<500	CD4 <200
Aseptic meningitis Guillain-Barré Transverse myelitis Meningoencephalitis	TB Meningitis Guillain-Barré Distal sensory poly-neuropathy (DSPN) Mild neurocognitive disorder	HIV-dementia TB Meningitis Cryptococcal Meningitis Toxoplasmosis PML CNS Lymphoma Vacuolar Myelopathy DSPN Ischaemic CVA Viral Encaphilitis (Herpes or CMV) Viral radiculopathy
DSPN = Distal Sensory Polyneuropathy HAND = HIV-associated Neurocognitive Disorder PML = Progressive Multifocal Leukoencephalopathy CMV = Cytomegalovirus CVA = Cerebrovascular Accident (stroke)

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 - spastic paraparesis
• Radiculopathy - flaccid paraparesis
• 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

The following pathologies are the most common underlying causes of neurological disorders in PLWH.

• Meningitis (inflammation of the meninges) - can be caused by HIV itself or by opportunistic infections
• Encephalitis (inflammation of the brain) - can be caused by HIV itself or by opportunistic infections
• Space occupying lesions - usually caused by CNS lymphoma, PML, TB or Toxoplasmosis
• Myelopathy - caused by viral/bacterial infections or HIV itself
• Radiculopathy
• Peripheral Neuropathy - related to HIV itself or certain ART

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; 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 (JCV). Each of these can result in unique neurological manifestations (including encephalitis, transverse myelitis and radiculopathy) with JCV causing Progressive multifocal leukoencephalopathy (PML)	Not well documented
Direct HIV infection
Aseptic Meningitis	Although this can be caused by other viral infection, HIV can also be the primary cause. May be asymptomatic in early HIV.
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
Peripheral Neuropathies	Damage to peripheral nerves can lead to polyneuropathy, mononeuropathy or inflammatory neuropathy. Certain ART can also cause 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). CNS lymphoma seems to be associated with the Ebstein-Barr virus	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 increased risk of acute/chronic inflammatory demyelinating polyneuropathy (such as Guillain-Barre), 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 progressive, demyelinating disease of the CNS caused by the JC virus and it often mimics the CSF findings of aseptic meningitis. The JC virus can remain latent 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 exact presentation differs depending on which area of white matter is affected, but ataxia and aphasia are common. The prognosis of PML is poor and death often occurs within 1-9 months. It usually only occurs in ART-naïve patients and although initiating ART will not cure PML, it may prolong survival. It is also possible for PML to be cause by IRIS in patients already on ART.

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). It is also sometimes referred to as HIV Encephalopathy.

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. For more detail see this PP page on HAND.

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.

Infection-related Myelopathy

Opportunistic infections that can cause myelopathies are listed below.

• Viral: Cytomegalovirus (CMV), Herpes simplex virus (HSV), JC virus, Varicella-zoster virus (VZV) - can cause transverse myelitis
• 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

Medical 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 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.

Rehabilitation

Rehabilitation strategies are essential to improve quality of life, function and to prevent further cognitive impairment.Neurological rehabilitation strategies harness the concept of neuroplasticity to restore/retrain function and cognition. Rehabilitation should always be based on a thorough assessment and should be personalised and patient specific - this is especially important considering the wide range of neurological presentations associated with HIV.

See also Exercise for People Living with HIV; Physiotherapy Interventions in HIV

Role of the Multi-disciplinary Team (MDT)

Team member	Possible role
Medical Doctor	Investigations, including blood and CSF tests and neuroimaging Altering ART 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	Assessment and monitoring of cognitive function Neurcognitive training Home adaptations to improve safety Caregiver education and support Neurological rehabilitation on non-progressive conditions Wheelchair seating for patients who are non-ambulatory
Physiotherapist	Pain management strategies for neuropathic pain Exercise to improve function Neurological rehabilitation in non-progressive conditions Assistive devices to assist with mobilisation Care-giver and patient education Rehabilitation to assist with recovery from episodic disability

Conclusion

HIV infection can result in a myriad of CNS and PNS disorders, and it is important to differentiate whether these are caused by primary HIV infection, opportunistic infections or related to ART. Accurate diagnosis can improve management and understanding of prognosis.

Although the introduction of ART 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.