Download Article PDF/SlidesDespite the marked benefits of highly active antiretroviral therapy (HAART), up to 70% of patients with HIV develop neurologic complications of the central or peripheral nervous system (Sacktor, 2000). Neurologic consequences of HIV can be divided into primary and secondary disorders. The primary neurologic complications include HIV dementia in adults, encephalopathy in children, HIV-associated (vacuolar) myelopathy, and distal peripheral polyneuropathy. Secondary disorders are due to opportunistic infections resulting from HIV immunosuppression. The focus of the presentation and this article is limited to complications in adults.
Since the late nineties, with the introduction of HAART, incidence rates of opportunistic infections are decreasing (Gona, 2006; Subsai, 2006). There has been a reduction in the number of patients presenting with HIV dementia, cryptococcal meningitis, central nervous system (CNS) toxoplasmosis, progressive multifocal leukoencephalopathy, and primary CNS lymphoma in countries where antiretroviral treatment is readily available. However, as treated patients with HIV live longer, the prevalence of HIV-associated cognitive impairment and distal polyneuropathy has been increasing (Sacktor, 2006). In addition to the neurologic complications attributed to HIV itself, some antiretroviral medications also cause CNS and peripheral nerve adverse effects, and induce the immune restoration inflammatory syndrome(IRIS)
Figure 1. International HIV Dementia Scale (IHDS)
Memory-Registration — Give four words to recall (dog, hat, bean, red) — one second to say each. Then ask the patient all four words after you have said them. Repeat words if the patient does not recall them all immediately. Tell the patient you will ask for recall of the words a bit later.
1. Motor Speed — Have the patient tap the first two fingers of the non-dominant hand as widely and as quickly as possible.
4 = 15 in 5 seconds
3 = 11–14 in 5 seconds
2 = 7–10 in 5 seconds
1 = 3–6 in 5 seconds
0 = 0–2 in 5 seconds
2. Psychomotor Speed — Have the patient perform the following movements with the non-dominant hand as quickly as possible: 1) Clench hand in fist on flat surface. 2) Put hand flat on surface with palm down. 3) Put hand perpendicular to flat surface on the side of the fifth digit. Demonstrate and have patient perform twice for practice.
4 = 4 sequences in 10 seconds
3 = 3 sequences in 10 seconds
2 = 2 sequences in 10 seconds
1 = 1 sequences in 10 seconds
0 = unable to perform
3. Memory-Recall — Ask the patient to recall the four words. For words not recalled, prompt with a semantic clue as follows: animal (dog); piece of clothing (hat); vegetable (bean); color (red);
Give one point for each word spontaneously recalled.
Give 0.5 points for each correct answer after prompting.
Maximum = 4 points
Total International hiv Dementia Scale Score — This is the sum of the scores on items 1–3. The maximum possible score is 12 points. A patient with a score of ≤ 10 should be evaluated further for possible dementia.
Reprinted with permission from: Sacktor NC, Wong M, Nakasujja N, et al. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS. 2005;19:1367-1374.
| HIV Dementia | Top of page |
HIV dementia (HIVD), also known as AIDS dementia-complex (ADC), or HIV-1 associated dementia (HAD), produces a predominantly subcortical memory deficit with variable motor and behavioral symptoms. In patients with HIV, HAART is associated with improvement in neurocognitive and functional performance (Sacktor, 2006), so the severe form of dementia has become much less common. However, the prevalence of HIV-1 minor cognitive-motor disorder (MCMD) appears to be rising (Ghafouri, 2006).
HIVD is characterized by impaired short term-memory coupled with reduced ability in mental concentration (see Table 1). Lack of visuospatial memory may be manifested in the misplacing of objects, and a lack of visuomotor coordination reflects eye movement abnormalities. For example, the patient might be unable to follow instructions regarding where to direct his stare. There is usually difficulty in performing previously learned complex tasks, such as cutting up food or unbuttoning a shirt. There is also a marked difficulty in word-finding ability. In general, mental slowness seems to be the rule. While these changes may be subtle, they can be assessed early with the HIV dementia scale (NYCDH, 2006) (see Figure 1). Affective and behavioral symptoms often precede or simultaneously occur with memory loss. The affective symptoms are characterized by apathy, severe irritability, bouts of manic episodes or new onset psychosis, slowed speech or response time, personality changes, and social withdrawal. Motor changes are characterized by parkinsonian-like rigidity and slowness affecting movement and gait. Unsteady walk, loss of balance, dropping things, tremors, poor handwriting, and a decline in fine motor skills are usually present in late stages. In MCMD, the clinical manifestations are similar to those seen in HIVD, but the cognitive deficit and motor dysfunction are much less pronounced.
The differential diagnosis of HIVD should include infectious diseases and tumors within the CNS, systemic metabolic and endocrine illness, psychiatric conditions and substance withdrawal or intoxication (see Table 2). Because there are as yet no pathognomonic diagnostic tests, HIVD remains a diagnosis of exclusion.
The pathogenesis of HIVD is not fully understood, but HIV-1 is known to cross the blood-brain barrier in monocytes at an early stage of the infection and can persist without symptoms in the CNS for decades. Once in the CNS, HIV can infect microglia and macrophages, as well as replicate within these cells. Astrocytes and oligodendrocytes can be infected by HIV, but there is no viral replication (restricted infection). Neurons are not directly infected by HIV; however, secondary neuronal damage caused by other infected cells and activated cell lines is probably required to cause HIVD or MCMD.
| Table 1. Clinical Manifestations of HIV-Associated Dementia | |
| Type of Impairment | Manifestations |
| Affective | • Apathy
(depression-like features) • Irritability • Mania, new-onset psychosis |
| Behavioral | • Psychomotor retardation (slowed
speech orresponse time) • Personality changes • Social withdrawal |
| Cognitive | • Lack of
visuospatial memory (misplacing things) • Lack of visuomotor coordination (eye movement abnormalities) • Difficulty with complex sequencing (difficultyin performing previously learned complex tasks) • Impaired concentration and attention • Impaired verbal memory (word-finding ability) • Mental slowing |
| Motor | • Unsteady gait, loss of balance • Dropping things • Tremors, poor handwriting • Decline in fine motor skills |
| Reprinted with permission from: New York City Department of Health aids institute in collaboration with the (ohm Hopkins University Division of Infectious Diseases. Neurologic Complications of hi* Infection. Available here. Accessed October 12. 2006. | |
In the brain, HIV may cause direct and indirect effects. Direct mechanisms correlate with the presence in the CNS of activated, although not necessarily HIV-1–infected, microglia and CNS macrophages (Ghafouri, 2006). Indirect mechanisms consist of neuronal injury and death as a consequence of this activation, related tothe release of cytokines (TNF-a), and dysfunction of various cellular channels (ie, calcium, NMDA). Since neurons are not directly infected by HIV-1, the secondary mechanisms are thought to be responsible, at least in part, for their deterioration seen in HIVD. Cerebrospinal fluid (CSF) HIV RNA and beta2-microglobulin are being used in the research setting as surrogate markers for brain infection and associated neurologic disease (McArthur, 1997), but are complicated tests not recommended for clinical use. They may also fail to discriminate among milder degrees of HIVD and MCMD (McArthur, 2004).
The CNS is an important potential reservoir of HIV due to the unique features of the blood-brain barrier and its selective permeability. There are three different compartments within the CNS in which HIV may be sequestered: the brain, the extracellular space, and the CSF. The CSF is the only compartment that is routinely accessible for measurement and provides an adequate reflection of viral activity within the other compartments.
The ability of different antiretrovirals (ARV) to cross the blood brain barrier and thus enter the CNS varies. Therefore, an undetectable serum HIV viral load and a high CD4+ count do not necessarily reflect concomitant good virologic control within the CNS. Likewise, ARV concentrations in the cerebrospinal fluid (CSF) cannot be accurately predicted by plasma concentrations. Levels of ARV, simultaneously obtained in the CSF and the blood permit the calculation of a CNS-plasma ARV ratio. The lower this ratio, the less ARV penetrates from the plasma to CNS compartments. However, there is a wide variation in ratios of the ability of ARV to cross the blood brain barrier. Factors governing CNS penetration include the degree of ARV protein binding (ie, only free drug crosses the blood brain barrier), molecular weight (larger molecules penetrate poorly), lipophilicity, pH, ionization, and the variable action of molecular pumps. The most effective CNS penetrators are AZT, d4T, abacavir, nevirapine, indinavir and combined lopinavir/ritonavir (Kaletra®) (see Tables 3 and 4).
An alternative complex system has been established to assign penetration scores to groups of ARV, graded from 0.5 to 1 (Antinori, 2005). Based on these penetration scores, it is possible to predict the ability of the various drugs to reduce CSF viral load, as well as provide information regarding the resistance of the virus. Some studies have shown that cognitive performance improves when the CSF viral load is suppressed with regimens containing greater numbers of CSF-penetrating drugs (Letendre, 2004). While the correlation between neuropsychological functioning and the extent of a drug’s CSF penetration and the subsequent CSF viral load reduction remains to be fully elucidated, this subject is of particular clinical relevance and interest, since HAART is currently the only treatment that has proved to be of some benefit for HIVD.
The standard of care for HIVD remains HAART, preferably with agents with optimal CNS penetration. Once the patient has advanced HIVD, some CNS damage may be irreversible. However, the aim of therapy is to at least prevent further progression if not to reverse deficits. Zidovudine (AZT) is the only agent proven to be effective in improving cognitive performance as shown in a placebo-controlled study of HIVD (Sidtis, 1993). It should be noted however, that the doses of AZT used in this early monotherapy study were 1000 to 2000 mg, much higher than those in use today. Although abacavir was studied in a placebo-controlled study for HIVD, it did not meet the primary endpoint of neuropsychologic improvement (Cysique, 2005). This study points out the methodologic challenges in performing a clinical trial of ARVs in HIVD, including the addition of a single agent versus placebo to optimized background HAART for a relatively brief study duration.
Since there are likely secondary nonviral mechanisms contributing to the pathogenesis of HIVD, other non-ARV drugs have been employed in clinical trials. These drugs include calcium channel blockers (nimodipine), N-methyl-D-aspartate (NMDA) antagonists (eg, memantine), monoamine oxidase (MAO)-B antagonists (eg, selegiline), and antioxidants or free radical scavengers (vitamin E). None have been proven to be effective.
| Table 2. Differential Diagnosis of Symptoms Presenting as Possible HIV-Associated Dementia | |
| Central
nervous system disease |
Infectious • CMV encephalitis • Neurosyphilis • Cryptococcal meningitis • Tuberculous meningitis • CNS toxoplasmosis • Progressive multifocal leukoencephalopathy* • HIV minor cognitive motor disorder Tumors • CNS lymphoma • Metastatic disease Vasculitis |
| Systemic/metabolic/ endocrine disease |
B12 deficiency Anemia Thyroid disease Addison's disease |
| Psychiatric illness | Mood disorders (major depression,* dysthymia) Delirium |
| Substance
withdrawal or intoxication |
Alcohol Opioids Chronic cannabis |
| Reprinted with permission from: New York City Department of Health aids Institute in collaboration with
the Johns Hopkins University Division of Infectious Diseases. Neurologic Complications of hiv Infection. Available here. Accessed October 12, 2006. | |
| Drug Related Toxicity | Top of page |
Despite the benefits achieved with ARV regimens, certain drugs contribute to neurologic and psychiatric adverse effects. Prominent among these are the neuropsychiatric adverse effects of efavirenz (EFV), a novel nonnucleoside inhibitor of HIV-1 reverse transcriptase. A controlled trial (ACTG 5097S) demonstrated that symptoms attributable to efavirenz include vivid dreams, dizziness, balance problems, unsteadiness and light-headedness (Adkins, 1998; Clifford, 2005). Suicidal ideation has been reported. Neuropsychiatric adverse reactions occur mainly during the first month of EFV therapy, usually by day seven of treatment. Fortunately, most of these symptoms resolve by day thirty with continued treatment. However, some patients are unable to tolerate the adverse effects and the medication has to be withdrawn. Of these patients, most have complete resolution of the symptoms. However some may experience continued neuropsychologic effects (Clifford, 2006). It is important that patients be queried about psychiatric comorbidity prior to starting EFV.
Mitochondrial toxicity related to d-drug ARV peripheral neuropathy has been discussed above. Other neuromuscular adverse events potentially related to ARV-induced mitochondrial dysfunction are myopathy and ascending neuromuscular weakness syndrome. There are several mechanisms by which ARV may interfere with mitochondrial DNA (mtDNA). The inhibition of DNA polymerase-gamma and other mitochondrial enzymes can gradually lead to mitochondrial dysfunction and cellular toxicity. However, the data indicate that inhibition of isolated DNA polymerases may not be predictive of in vitro or in vivo toxicity (Martin, 1994).
HIV-associated neuromuscular weakness syndrome (HANWS) is a severe neurologic disorder that occurs in HIV-infected individuals. It is associated with hyperlactemia and ARV exposure, especially stavudine (d4T)–containing regimens (Shah, 2003). Mitochondrial mechanisms have been suggested; however, some patients have neurologic symptoms beginning or worsening after discontinuation of ARVs, suggesting other etiologic mechanisms, such as immune-mediated processes.
Zidovudine (AZT) has been associated with the development of myopathy, although the extent of this relationship has been the subject of controversy. The incidence of HIV and ARV-related myopathy is unknown. Myopathy associated with HIV is characterized by predominant involvement of proximal lower limb muscles, with difficulty in climbing stairs and rising from chairs. Myalgia may be exacerbated by exertion. The primary laboratory abnormality is variable elevation of serum creatinine phosphokinase (CPK). Ragged red fibers, a hallmark of mitochondrial dysfunction, have been reported on muscle biopsy in AZT myopathy (Dalakas, 1990; Peters, 1993). Other features include myofibrillar alterations, degeneration and necrotic fibers, and an inflammatory infiltrate. The correlation of these findings to AZT exposure remains unclear (Morgello, 1995).
Electromyography reveals abnormal spontaneous activity and myopathic features in most patients. The clinical and pathologic features of ARV-associated myopathy are indistinguishable from the myopathy associated with primary HIV infection or polymyositis in HIV-seronegative patients. Myopathy associated with AZT may respond to the discontinuation of the drug. Prednisone or intravenous immunoglobulin may be used in severe cases, although they have not been systematically studied.
| Immune Restoration Inflammatory Syndrome | Top of page |
The advent of potent ARV regimens has led to the development of an increasingly recognized condition, termed immune restoration inflammatory syndrome (IRIS). Following initiation of a HAART regimen, IRIS causes exacerbation of neurologic features in some patients (Venkataramana, 2006). Manifestations are related to a paradoxical clinical deterioration typically occurring within eight weeks of treatment onset. Immune restoration inflammatory syndrome is characterized by worsening clinical, laboratory, or radiologic findings despite improvement in HIV RNA level and CD4+ count. It is due to rapid improvement in the immune system that triggers an exuberant inflammatory response against previously unrecognized occult infection, autoimmune, or malignancy-related conditions. Risk factors for IRIS include low CD4+ count, the presence of latent infection, and a robust virologic and immunologic response to HAART (Crum-Cianflone, 2006). Factors that may reduce the risk of IRIS include initiation of HAART before the CD4+ cell count reaches very low levels (less than 100/µL), screening for hepatitis coinfection (since hepatitis B and C may be first recognized, or may flare, after the start of antiretroviral therapy), and performance of a chest radiograph and routine laboratory tests before initiating ARV. If an opportunistic infection is identified, many experts suggest delaying HAART for four weeks to reduce the potential for IRIS. Improvement of IRIS-related symptoms has been reported with the use of NSAIDs or corticosteroids.
| References | Top of page |
