HIV-Associated Dementia Case File

HIV-Associated Dementia Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 28

A 52-year-old man is referred for further evaluation of mild forgetfulness, poor concentration, and withdrawal from friends. His wife who has accompanied him feels that he is clumsier, noting that he frequently trips and stumbles. The patient has also noticed that he is clumsier and that he is more forgetful and is having difficulty focusing at work. He reports a recent reduction in libido. His physical examination is notable for an abnormal Montreal Cognitive Assessment (MoCA) score. He had difficulty drawing a clock, following a sequence, and copying a cube. He also had difficulty with delayed recall and attention and was slow in answering questions. Cranial nerves and motor strength are normal. He had difficulty with fine hand movements, and mild ataxia is noted. Deep tendon reflexes are slightly increased. He is concerned because he has been losing weight and is currently awaiting the results of a second human immunodeficiency virus (HIV) test. A previous HIV test 4 weeks ago was positive.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

ANSWERS TO CASE 28:

HIV-Associated Dementia                                                    

Summary: A 52-year-old man with weight loss has been experiencing mild forgetfulness, poor concentration, clumsiness, difficulty focusing at work, reduced libido, and withdrawal from friends. His examination shows abnormal cognitive function by MoCA and mental slowness in answering questions. Mild ataxia and poor coordination of his hands are noted. Additionally, he has mild hyperreflexia. His HIV test 4 weeks ago was positive.

• Most likely diagnosis: Dementia/HIV-associated dementia (HAD).
• Next diagnostic step: Neuropsychological testing; obtain results of his last HIV tests, magnetic resonance imaging (MRI) of the brain, and lumbar puncture for cerebrospinal fluid (CSF) studies.

ANALYSIS

Objectives

1. Be familiar with the diagnosis of HAD.
2. Recognize the treatment strategies for HAD.
3. Describe the differential diagnosis of HAD.

Considerations

This 52-year-old man with a positive HIV test presents with poor concentration, mild forgetfulness, difficulty focusing, withdrawal from friends, clumsiness, and reduced libido. The classic findings of behavioral changes, difficulty with coordination, and mild impaired intellect in the setting of a positive HIV test are likely to be associated with HAD. Depression could also present this way; however, one would not expect there to be problems with coordination. Encephalitis, neurosyphilis, frontal temporal dementia, and HIV-associated opportunistic infections are also in the differential diagnosis. These can be distinguished from HAD by performing an MRI of the brain, lumbar puncture, and neuropsychological testing. Neurologic complications from HIV can be seen from opportunistic infections, drug-related complications, tumors secondary to HIV, and HIV itself. The pathophysiology of HAD is likely multifactorial. First, there is invasion of HIV into the central nervous system (CNS). HIV-infected monocytes are thought to enter the brain and infect microglia, astrocytes, neurons, and oligodendrocytes. Additionally, the virus may replicate in the cells. Viral toxins or HIV proteins may be directly toxic to neurons or may cause damage by activating macrophages, microglia, and astrocytes, which in turn release chemokines, cytokines, or neurotoxic substances. Finally, there is evidence to support oxidative stress and increases in excitatory amino acids and intracellular calcium.

APPROACH TO:

HIV-Associated Dementia                                        

DEFINITIONS

ATAXIA: A neurologic sign demonstrated as incoordination or unsteady motion of the limbs and trunk.

DEMENTIA: A disorder characterized by a general loss of intellectual abilities involving memory, judgment, abstract thinking, and changes in personality.

NEUROPSYCHOLOGICAL TESTING: A battery of tests used to evaluate cognitive impairment more extensively than the Mini-Mental State Examination (MMSE).

HAART: Highly active antiretroviral therapy consisting of multi-agent anti-viral therapy designed to lower viral counts to near undetectable levels.

CLINICAL APPROACH

HAD has an incidence of 10.5 cases per 1000 person-years in the United States. This incidence has decreased since HAART was introduced, as before HAART (before 1992) the incidence was 21 cases per 1000 person-years. Nevertheless, there remains a population of patients presenting with this complication, as well as other HIV-associated diseases, who are unaware of their HIV status at the time of diagnosis. In fact, in a retrospective study of a population over 20 years, most patients who developed a neurologic complication during the HAART era were untreated or not known to be HIV-infected. Older patients with HIV have a higher likelihood of having HAD. A poor prognosis has been associated with low CD4 counts, high HIV RNA levels, low body mass index, lower educational levels, and anemia. Most patients with HAD have developed an AIDS-defining systemic illness. A few patients, however, present only with immunosuppression by laboratory criteria. In fact, a recent study of cognitive disorders in newly diagnosed HIV patients found a high prevalence of HIV-associated neurocognitive disorders (47.1%): particularly, asymptomatic neurocognitive impairment in 30.6%, mild neurocognitive disorder in 15%, and HAD in 1.5%. Male gender, low degree of education, AIDS diagnosis, and hepatitis B virus (HBV) coinfection were factors independently associated with these disorders.

The earliest symptoms of HAD include difficulty with concentration, attention, and mentation. Forgetfulness is present early on, and patients have increasing difficulty performing complex tasks. Personality changes begin to appear such as apathy, social withdrawal, and quietness. Dysphoria and psychosis are rare. Psychomotor dysfunction, manifested by poor balance and lack of coordination, follows cognitive dysfunction, although rarely it can be the initial symptom of HAD. Tripping or falling, along with poor handwriting, are the more common motor symptoms due to involvement of the basal ganglia and cerebellum. As the disease progresses, the ataxia worsens and can become disabling. Myoclonic jerks, postural tremor, and bowel and bladder dysfunction can be present in the later stages of the disease. Patients at the end stage of the disease are unable to ambulate, are incontinent, and are almost in a vegetative state. Importantly, focal neurologic deficits tend to be absent.

Early in the disease course, neuropsychological testing may be normal; however, as time progresses, there is evidence of subcortical dementia. Typical abnormalities include difficulty in concentration, motor manipulation, and motor speed. Mild problems with word finding and impaired retrieval can be present. Eventually, severe psychomotor slowing and language impairment occur. Initially, the neurologic examination is normal, and at this time, subtle impairment in rapid limb and eye movements can be found. As the disease progresses, hyperreflexia, spasticity, and frontal release signs can be found. Additionally, apraxia (inability to perform previously learned tasks) and akinetic mutism (severely decreased motor-verbal output) can develop.

Neuroimaging (MRI brain) studies are essential in evaluating patients with AIDS and cognitive impairment. Diffuse cerebral atrophy is typical in HAD. Some patients have white matter changes and abnormalities in the thalamus and basal ganglia (Figure 28–1). Other conditions that can mimic or cause dementia can be excluded by MRI. CSF studies are nonspecific and are performed primarily to exclude other diagnoses. These nonspecific findings include a mildly elevated CSF protein (60% of cases) and mild mononuclear pleocytosis (25%). Quantitative HIV polymerase chain reaction (PCR) that evaluates CSF in viral load is the best parameter that relates to HAD. Improvement in CSF viral load leads to improvement in the clinical status of HAD.

Differential Diagnosis

1. CNS lymphoma
2. Progressive multifocal leukoencephalopathy
3. CNS infections such as cryptococcal meningitis, toxoplasmosis, cytomegalovirus encephalitis, neurosyphilis, histoplasmosis, and Coccidioides
4. Toxic metabolic states such as vitamin B12 deficiency, thyroid disease, alcoholism, medication effect, and illicit drug abuse

Figure 28–1. T2-weighted MRI in AIDS dementia complex. Arrows show diffuse symmetric hyperintensities in the hemispheric white matter. (Reproduced, with permission, from Aminoff MJ, Simon RR, Greenberg D. Clinical Neurology. 6th ed. New York, NY: McGraw-Hill; 2005:58.)

Treatment

The management of HAD depends on viral suppression by means of HAART. HAART not only protects against but also leads to remission of HAD. Selective retroviral drugs that enter the CSF can be helpful and include zidovudine, indinavir, and lamivudine.

CASE CORRELATION

• See also Case 20 (Alzheimer Dementia) and Case 21 (Lewy Body Dementia)

COMPREHENSION QUESTIONS

28.1 A 29-year-old man with a history of illicit drug abuse in the past presents with complaints of mild forgetfulness, social withdrawal, and difficulty concentrating. He has a good appetite and has not experienced alteration in his sleep cycle. His neurologic examination is nonfocal; however, his MoCA is abnormal, 23/30. His girlfriend has commented that she has seen him stumble more frequently. What is the next step in evaluating this individual?

A. Obtain neuropsychological testing to evaluate for personality disorder.

B. Obtain an MRI of the brain.

C. Obtain a STAT lumbar puncture for CSF studies to exclude meningitis/encephalitis.

D. Clinically observe and follow the patient.

28.2 Which of the following has not been associated with a poor prognosis in HAD?

A. A history of multiple AIDS-defining illnesses

B. Low CD4 counts and low body mass index

C. Head trauma with loss of consciousness prior to becoming HIV positive

D. Low CD4 counts, anemia, and low HIV RNA

28.3 A 32-year-old HIV-positive man is noted to have forgetfulness, gait disturbance, and confusion. A lumbar puncture is performed, and the India ink preparation is positive. Which of the following is the most likely diagnosis?

A. HAD

B. Cryptococcal meningitis

C. Toxoplasmosis

D. CNS lymphoma

ANSWERS

28.1 B. The first test to request in evaluating this patient is an imaging study. This will determine whether there is increased intracranial pressure so that a lumbar puncture can be safely performed. Although neuropsychological testing should be performed, it is appropriate to perform neuroimaging to evaluate for a structural or vascular lesion.

28.2 B. A history of multiple AIDS-defining illnesses would be a poor prognostic factor for HAD. Prior head trauma, anemia, and low HIV RNA are not poor prognostic factors.

28.3 B. India ink–positive stain is highly suggestive of cryptococcal meningitis. Cryptococcosis, a round or oval yeast, is the most common fungal infection of the CNS in HIV-infected individuals. Cryptococcus neoformans is spread hematogenously from the lungs, typically when the CD4 count falls below 100 cells/mm3. Its thick capsule is very distinctive when stained with India ink.

    CLINICAL PEARLS    

▶ HIV-associated dementia (HAD) typically presents with forgetfulness, difficulty concentrating, slowness in thinking, and loss of coordination. ▶ HAD is more commonly seen in individuals with low CD4 counts, high HIV RNA, low body mass index, anemia, and low levels of education. ▶ The best way to prevent and reduce the severity of HAD is by using HAART.

REFERENCES

Dorland’s Illustrated Medical Dictionary. 27th ed. Philadelphia, PA: WB Saunders; 1988. 

Focà E, Magro P, Motta D, et al. Screening for neurocognitive impairment in HIV-infected individuals at first contact after HIV diagnosis: the experience of a large clinical center in Northern Italy. Int J Mol Sci. 2016;17(4):434. 

Gibbie T, Mijch A, Ellen S, et al. Depression and neurocognitive performance in individuals with HIV/AIDS: 2-year follow-up. HIV Med. 2006;7(2):112-121. 

Kaul M, Lipton SA. Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res. 2006;4(3):307-318. 

Matinella A, Lanzafame M, Bonometti MA, et al. Neurological complications of HIV infection in pre-HAART and HAART era: a retrospective study. J Neurol. 2015;262(5):1317-1327. 

McArthur JC. HIV dementia: an evolving disease. J Neuroimmunol. 2004;157(1-2):3-10.

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