DOI: 10.1212/01.WNL.0000287431.88658.8b 2007;69;1789-1799; originally published online Oct 3, 2007; Neurology

R. Robertson, N. Sacktor, V. Valcour and V. E. Wojna Joseph, K. Marder, C. M. Marra, J. C. McArthur, M. Nunn, R. W. Price, L. Pulliam, K.Clifford, P. Cinque, L. G. Epstein, K. Goodkin, M. Gisslen, I. Grant, R. K. Heaton, J.

A. Antinori, G. Arendt, J. T. Becker, B. J. Brew, D. A. Byrd, M. Cherner, D. B. Updated research nosology for HIV-associated neurocognitive disorders

This information is current as of December 20, 2008

http://www.neurology.org/cgi/content/full/69/18/1789located on the World Wide Web at:

The online version of this article, along with updated information and services, is

All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X. since 1951, it is now a weekly with 48 issues per year. Copyright © 2007 by AAN Enterprises, Inc.

® is the official journal of the American Academy of Neurology. Published continuouslyNeurology

at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

Updated research nosology for HIV-associated neurocognitive disorders

A. Antinori, MDG. Arendt, MDJ.T. Becker, PhDB.J. Brew, MBBS, MD,FRACP

D.A. Byrd, PhDM. Cherner, PhDD.B. Clifford, MDP. Cinque, MD, PhDL.G. Epstein, MDK. Goodkin, MD, PhDM. Gisslen, MD, PhDI. Grant, MDR.K. Heaton, PhDJ. Joseph, PhDK. Marder, MD, MPHC.M. Marra, MDJ.C. McArthur, MBBS,MPH

M. Nunn, PhDR.W. Price, MDL. Pulliam, PhDK.R. Robertson, PhDN. Sacktor, MDV. Valcour, MDV.E. Wojna, MD

ABSTRACT

In 1991, the AIDS Task Force of the American Academy of Neurology published nomenclatureand research case definitions to guide the diagnosis of neurologic manifestations of HIV-1 infec-tion. Now, 16 years later, the National Institute of Mental Health and the National Institute ofNeurological Diseases and Stroke have charged a working group to critically review the adequacyand utility of these definitional criteria and to identify aspects that require updating. This reportrepresents a majority view, and unanimity was not reached on all points. It reviews our collectiveexperience with HIV-associated neurocognitive disorders (HAND), particularly since the advent ofhighly active antiretroviral treatment, and their definitional criteria; discusses the impact of co-morbidities; and suggests inclusion of the term asymptomatic neurocognitive impairment to cate-gorize individuals with subclinical impairment. An algorithm is proposed to assist in standardizeddiagnostic classification of HAND. Neurology® 2007;69:1789–1799

GLOSSARYAAN � American Academy of Neurology; ADLs � activities of daily living; ANI � asymptomatic neurocognitive impairment;HAART � highly active antiretroviral treatment; HAD � HIV-associated dementia; HAND � HIV-associated neurocognitivedisorders; HNRC � HIV Neurobehavioral Research Center; IADLs � instrumental ADLs; MCMD � minor cognitive motordisorder; MND � HIV-associated mild neurocognitive disorder; MSE � mental status examination.

In this report, we describe the existing AmericanAcademy ofNeurology (AAN) criteria,1 anddiscuss suggested areas for revision based on our experience, particularly in the decade sincehighly active antiretroviral treatment (HAART) became widely available in the developedworld. Changes to the diagnostic criteria for HIV-associated myelopathy and sensory neu-ropathies were not discussed. We also present a view of the changing face of HIV-associatedneurocognitive disorders (HAND), specifically how the temporal progressionmay have beenmodified by HAART. An algorithm is presented, which we believe to be a useful operationaltool for diagnosis and identification ofHAND.Although these proposed criteria are based onmore extensive research experience thanwas available when the AAN criteria were originallyproposed, it is recommended that these be regarded as research criteria that will requirefurther study before they are definitively adopted into clinical practice.

e-Pub ahead of print on October 3, 2007, at www.neurology.org

From the Clinical Department (A.A.), National Institute for Infectious Diseases “Lazzaro Spallanzani,” Instituto di Ricovero e Cura aCarattere Scientifico (IRCCS), Rome, Italy; Department of Neurology (G.A.), Heinrich Heine University, Dusseldorf, Germany; Departmentsof Neurology and Psychiatry (J.T.B.), University of Pittsburgh, PA; Department of Neurology and HIV Medicine (B.J.B.), St. VincentsHospital, University of New South Wales, Sydney, Australia; Department of Psychiatry and Pathology (D.A.B.), The Mount Sinai MedicalCenter, New York, NY; Department of Psychiatry (M.C., I.G., R.K.H., K.R.R.), University of California, San Diego; Department ofNeurology (D.B.C.), Washington University, St. Louis, MO; Clinic of Infectious Diseases (P.C.), San Raffaele Hospital, Milan, Italy;Department of Neurology (L.G.E.), Children’s Memorial Hospital, Chicago, IL; Departments of Psychiatry, Neurology and Psychology(K.G.), University of Miami, FL; Department of Infectious Diseases (M.G.), Sahlgrenska University Hospital, Goteborg, Sweden; Center forMental Health Research on AIDS (J.J.), National Institute of Mental Health, Bethesda, MD; Department of Neurology (K.M.), ColumbiaUniversity, New York, NY; Department of Medicine, Allergy and Infectious Diseases (C.M.M.), Department of Neurology, University ofWashington Seattle; Departments of Neurology, Pathology, and Epidemiology (J.C.M.), and Department of Neurology (N.S.), JohnsHopkins University, Baltimore, MD; National Institute of Neurological Disorders and Stroke (M.N.), NIH, Bethesda, MD; Departments ofNeurology (R.W.P.) and Laboratory Medicine and Medicine (L.P.), University of California, San Francisco; Department of Neurology(K.R.R.), University of North Carolina School of Medicine; Hawaii AIDS Clinical Research Program (V.V.), University of Hawaii, Honolulu;and NeuroAIDS Program and Department of Neurology (V.E.W.), University of Puerto Rico, Medical Sciences Campus.

Disclosure: The authors report no conflicts of interest.

Disclaimer: This work was written as part of Dr. Jeymohan Joseph’s and Dr. Mike Nunn’s official duties as government employees. Theviews expressed in this article do not necessarily represent the views of the NIMH, NINDS, NIH, DHHS, or the United States government.

See also page 1781

Address correspondence andreprint requests to Dr. Justin C.McArthur, Johns HopkinsHospital, Meyer Building,Room 6-109, 600 North WolfeStreet, Baltimore, MD21287-7609jm@jhmi.edu

Supplemental data atwww.neurology.org

ISSUES INNEUROLOGICPRACTICE

Copyright © 2007 by AAN Enterprises, Inc. 1789 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

SECTION 1: REVIEW OF DEFINITIONAL CRI-TERIA A: Current AAN definitional criteria. The1991 AAN criteria defined two levels of neuro-logic manifestations of HIV infection: HIV-associated dementia (HAD) and minor cognitivemotor disorder (MCMD) (table E-1 on the Neu-rology®Web site at www.neurology.org). Briefly,the AAN criteria for HAD were 1) an acquiredabnormality in at least two cognitive (nonmotor)areas causing impairment in work or activities ofdaily living (ADLs), and 2) either an abnormalityof motor function or specified neuropsychiatricor psychosocial functions (e.g., motivation, emo-tional control, social behavior). Moreover, thepatient had to have sufficient consciousness forcognitive abilities to be assessed, and could nothave other etiologies that might explain the disor-der. The AAN diagnostic scheme defined threesubtypes of HAD:

1) HAD with motor symptoms (criterion 1met fully, but only motor symptoms meet-ing criterion 2)

2) HAD with behavioral or psychosocialsymptoms (criterion 1 met fully, but onlybehavioral symptoms meeting criterion 2)

3) HAD with both motor and behavioral/psy-chosocial symptoms (criteria 1 and 2 metfully)

The AAN criteria also defined a less severe con-dition called MCMD. The essential features ofMCMD according to the AAN criteria were a his-tory of impaired cognitive/behavioral function intwo areas (e.g., impaired attention-concentration,mental slowing, abnormal memory or other cogni-tive functions, slowed movements, incoordination,personality change, irritability, lability), and theseabnormalities cause mild impairment in work orADLs, do not meet criteria for HAD or HIV-associated myelopathy, and cannot be attributed toother etiologies.

In our review, we identified issues that mayrestrict the applicability of the 1991 AAN criteria.One issue is that the number of domains of im-pairment that should be examined for diagnosiswas not clearly defined. Moreover, the degree ofneurocognitive impairment was not fully speci-fied, permitting variability in the clinical estima-tion of severity. Third, there appeared to be someoverlap between the criteria for HAD with mildfunctional decline and MCMD. Finally, theschema did not admit mild forms of reliably iden-tified cognitive difficulties which had not devel-oped to the point of interfering substantially witheveryday functioning. There is increasing recogni-tion of the frequency of confounding conditions

that are potentially acting as compounding fac-tors (deficits with mixed etiologies), and thesewere not adequately considered in the 1991schema other than the simple exclusionarystipulation.

B: Proposed research criteria developed by HIVNeurobehavioral Research Center at UCSD. To ad-dress some of these concerns, the HIV Neurobe-havioral Research Center (HNRC) at UCSDestablished working research criteria for HIV-related neurocognitive complications which wereintended to represent a refinement of the AANcriteria. These criteria recognize the followingthree conditions: asymptomatic neurocognitiveimpairment (ANI), HIV-associated mild neuro-cognitive disorder (MND), and HIV-associateddementia (HAD) (table).

These modified criteria were developed bystarting with the existing AAN criteria, and intro-duced changes based on research and observa-tions made at HNRC, and other publishedsources. The most notable change is addition ofthe category of ANI based on the observation thatsome individuals have demonstrable (and usuallymild) cognitive impairment demonstrated by for-mal neuropsychological tests without any ob-served abnormality in everyday functioning. Thecaveat to this statement is that the assessment offunctional capacity is difficult and frequently re-quires third-party report, or prolonged observa-tion. Furthermore, the HNRC criteria are morefully specified in terms of types and severities ofcognitive difficulties.

ANI is defined by performance at least 1 SDbelow the mean of demographically adjustednormative scores in at least two cognitive areas(attention-information processing, language,abstraction-executive, complex perceptual motorskills, memory, including learning and recall, sim-ple motor skills or sensory perceptual abilities);these criteria specify that at least five cognitivedomains be examined or observed. Finally, theimpairment does not occur solely as part of a de-lirium (i.e., a confusional state secondary to op-portunistic CNS disease, vascular insult,metabolic derangement, drug effects, or other sys-temic disorders) and, as in all AAN criteria, thediagnosis is possible only if the cognitive impair-ment cannot be explained by other comorbidities.There does appear to be empirical support to add-ing this third category of HIV-related neurocogni-tive disorder, because it appears to have a prioriprognostic value.2

The MND defined by HNRC is similar tothe MCMD previously defined by AAN but, in

1790 Neurology 69 October 30, 2007 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

addition to criteria for asymptomatic neuro-cognitive abnormality, MND requires thatthere also be impairment in everyday function-ing. Specifically, MND is defined by the follow-ing features: 1) an acquired mild-to-moderateimpairment in cognitive function documentedby a score of at least 1 SD below demographi-

cally corrected norms on tests of at least twodifferent cognitive domains, 2) the cognitiveimpairment interferes, at least mildly, with ac-tivities of daily living, 3) the impairment doesnot meet criteria for delirium or dementia, and4) the impairment is not fully explained by co-morbid conditions.

Table Revised research criteria for HIV-associated neurocognitive disorders (HAND) (modified from HIVNeurobehavioral Research Center criteria24)

HIV-associated asymptomatic neurocognitive impairment (ANI)*

1. Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1.0SD below the mean for age-education-appropriate norms on standardized neuropsychological tests. The neuropsychologicalassessment must survey at least the following abilities: verbal/language; attention/working memory; abstraction/executive;memory (learning; recall); speed of information processing; sensory-perceptual, motor skills.

2. The cognitive impairment does not interfere with everyday functioning.

3. The cognitive impairment does not meet criteria for delirium or dementia.

4. There is no evidence of another preexisting cause for the ANI.†

*If there is a prior diagnosis of ANI, but currently the individual does not meet criteria, the diagnosis of ANI in remission can bemade.

†If the individual with suspected ANI also satisfies criteria for a major depressive episode or substance dependence, the diagnosisof ANI should be deferred to a subsequent examination conducted at a time when the major depression has remitted or at least 1month after cessation of substance use.

HIV-1-associated mild neurocognitive disorder (MND)*

1. Acquired impairment in cognitive functioning, involving at least two ability domains, documented by performance of at least 1.0SD below the mean for age-education-appropriate norms on standardized neuropsychological tests. The neuropsychologicalassessment must survey at least the following abilities: verbal/language; attention/working memory; abstraction/executive;memory (learning; recall); speed of information processing; sensory-perceptual, motor skills.

Typically, this would correspond to an MSK scale stage of 0.5 to 1.0.

2. The cognitive impairment produces at least mild interference in daily functioning (at least one of the following):

a) Self-report of reduced mental acuity, inefficiency in work, homemaking, or social functioning.

b) Observation by knowledgeable others that the individual has undergone at least mild decline in mental acuity with resultantinefficiency in work, homemaking, or social functioning.

3. The cognitive impairment does not meet criteria for delirium or dementia.

4. There is no evidence of another preexisting cause for the MND.†

*If there is a prior diagnosis of MND, but currently the individual does not meet criteria, the diagnosis of MND in remission can bemade.

†If the individual with suspected MND also satisfies criteria for a severe episode of major depression with significant functionallimitations or psychotic features, or substance dependence, the diagnosis of MND should be deferred to a subsequentexamination conducted at a time when the major depression has remitted or at least 1 month after cessation of substance use.

HIV-1-associated dementia (HAD)*

1. Marked acquired impairment in cognitive functioning, involving at least two ability domains; typically the impairment is inmultiple domains, especially in learning of new information, slowed information processing, and defectiveattention/concentration. The cognitive impairment must be ascertained by neuropsychological testing with at least two domains2 SD or greater than demographically corrected means. (Note that where neuropsychological testing is not available, standardneurological evaluation and simple bedside testing may be used, but this should be done as indicated in algorithm; see below).

Typically, this would correspond to an MSK scale stage of 2.0 or greater.

2. The cognitive impairment produces marked interference with day-to-day functioning (work, home life, social activities).

3. The pattern of cognitive impairment does not meet criteria for delirium (e.g., clouding of consciousness is not a prominentfeature); or, if delirium is present, criteria for dementia need to have been met on a prior examination when delirium was notpresent.

4. There is no evidence of another, preexisting cause for the dementia (e.g., other CNS infection, CNS neoplasm, cerebrovasculardisease, preexisting neurologic disease, or severe substance abuse compatible with CNS disorder).†

*If there is a prior diagnosis of HAD, but currently the individual does not meet criteria, the diagnosis of HAD in remission can bemade.

†If the individual with suspected HAD also satisfies criteria for a severe episode of major depression with significant functionallimitations or psychotic features, or substance dependence, the diagnosis of HAD should be deferred to a subsequentexamination conducted at a time when the major depression has remitted or at least 1 month has elapsed following cessation ofsubstance use. Note that the consensus was that even when major depression and HAD occurred together, there is little evidencethat pseudodementia exists and the cognitive deficits do not generally improve with treatment of depression.

Neurology 69 October 30, 2007 1791 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

Finally, diagnosis of HAD according to thesesuggested criteria requires 1) acquired moderate-to-severe cognitive impairment, documented by ascore at least 2 SD below demographically cor-rected normative means in at least two differentcognitive areas, 2) marked difficulty in ADLs dueto the cognitive impairment, 3) the impairmentdoes not meet criteria for delirium, and 4) the im-pairment is not adequately explained by comor-bid conditions. (Note that there is an expandeddiscussion of comorbid conditions, and how tointerpret their possible impact in the context ofHAND, on theNeurology® Web site.)

C: Comparison of updated and existing definitional cri-teria. A fundamental aspect of the updated defini-tional criteria for HIV-associated neurocognitivecomplications is the greater priority given to thecognitive aspects of impairment compared to mo-tor, social/personality, or emotional difficulties.

To determine if giving more weight to the cog-nitive area had validity, Cherner et al.2,3 examinedthe correspondence of AAN and HNRC diag-noses to neuropathologic outcome, i.e., presenceof HIV encephalitis at autopsy. When the two setsof definitional criteria were compared regardingthe classification of patients as either neurocogni-tively normal or impaired before death, the agree-ment was 79% (31 of 39 patients). However,when specific diagnoses were compared, the twosets of criteria gave consistent diagnoses only for21 patients (54%). When pathologic evidence ofHIV encephalitis was considered as the gold stan-dard, 25 patients were correctly classified byAAN criteria as having neurocognitive involve-ment, compared to 28 patients correctly classifiedby HNRC criteria. In particular, 4 patients withHIV encephalitis were considered neurocogni-tively normal by AAN criteria, while 1 patientwith encephalitis was considered normal byHNRC criteria; 8 patients with HIV encephalitiswere classified as neurocognitively normal byboth sets of criteria. Thus, both sets of defini-tional criteria were reasonably accurate in pre-dicting autopsy diagnoses of HIV encephalitis.However, the HNRC criteria were slightly betterin terms of positive predictive power (95% vs88%), sensitivity (67% vs 56%), and specificity(92% vs 83%), possibly due to the inclusion of athird, asymptomatic neurocognitive condition.

Another study, carried out by Wojna and col-leagues in San Juan, Puerto Rico, compared thediagnoses of cognitive impairment in HIV-infected women using several sets of criteria, in-cluding the standard AAN criteria as well as AANcriteria modified to include a class of impairment

without functional decline in ADLs (similar to theHNRC asymptomatic category).4 By standardAAN criteria, 53.6% of subjects were consideredneurocognitively normal, 18.8% had a diagnosisof MCMD, and 23.2% had HAD. Modificationof the AAN criteria to include asymptomatic neu-rocognitive abnormality had a notable effect:31.1% of cases were cognitively normal, 20.3%had ANI, 18.8% had MCMD, and 23.2% werediagnosed with HAD. Thus, the modified criteriahelped investigators distinguish a subgroup ofHIV-infected patients with asymptomatic neuro-cognitive impairment (more than one-third ofthose initially considered normal). The NationalNeuroAIDS Tissue Consortium has utilized asubsyndromic category in their neuropsychologicassessments since 1999; as of August 2006, 14% of1,328 advanced-stage HIV-infected individualshad diagnoses of subsyndromic impairment attheir baseline evaluation (Dr. Susan Morgello,personal communication, 2007).

CONCLUSIONS: SECTION 1 The existing AANcriteria have served researchers and clinicians wellfor 15 years. They offer reasonable sensitivity andspecificity for predicting future neuropathologic di-agnoses of HIV encephalitis, although the positivepredictive power can be enhanced by consideringasymptomatic neurocognitive abnormality. A limi-tation of the existing AAN criteria is that they donot recognize a subgroup of HIV-infected patients(�15%) who actually have neurocognitive impair-ment despite the absence of overt functional declinein ADLs. We recognize that further work needs tobe conducted on the real-life impact of ANI, but atthis stage recommend adding this condition to thecriteria for HAND. We recommend that the pres-ence and degree of neurocognitive impairment con-stitute the fundamental criteria for establishing adiagnosis, while other criteria, e.g., motor disor-ders and emotional or personality changes, beconsidered ancillary or corroborative informa-tion, possibly for defining disorder subtypes.Finally, determination of neurocognitive impair-ment should be based on appropriately normedtests (see the Neurology® Web site), and shouldconsider the presence of confounding factors. It istimely to work toward a revision of the diagnosticcriteria along the lines displayed in the table, andwe strongly recommend that revised criteria befield tested and further refined through research.

The area of quantitative testing of motor func-tion needs further exploration, but data fromArendt et al.5 seem promising in that relativelysimple quantitative measures seem to track with

1792 Neurology 69 October 30, 2007 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

cognitive improvements associated with HAART.The predictive value of quantitative motor test ab-normalities for evolving cognitive impairment needsfurther delineation and field testing.

SECTION 2: CHANGES IN THE SYNDROMICNATURE OF HIV-ASSOCIATED NEUROCOG-NITIVE DISBURBANCES There have beensubstantial changes to HIV disease with the intro-duction of HAARTwhich have affected cognitiveimpairment in a number of areas.6 Such changesimpact on the recognition of the disorder andraise questions relating to its fundamental nature.These encompass the areas of epidemiology, nat-ural history, clinical phenotype, and confoundingconditions. We have also observed that a substan-tial proportion of HIV-infected persons (�20%)have bidirectional changes in neurocognitivesymptomatology, fluctuating from normal to ab-normal and vice versa, at different levels of sever-ity. Any revised nosology should recognize thisfluctuating category, while research should try tounderstand the causes of this fluctuation and theeffects on treatment outcomes, everyday func-tioning, and patient survival. The inherent vari-ability of neuropsychological testing needs to betaken into account in the interpretation of thesefluctuations.

A: Time course and stability of neurocognitive im-pairment. The time course and stability of neuro-cognitive impairment in HIV/AIDS over time

have been explored using data from several co-horts. For example, an HNRC cohort that in-cluded 534 HIV-seropositive and 141 seronegativepersons showed that at baseline, 14% of HIV-negative persons were cognitively impaired (atany level), as were 27%, 44%, and 52% of sub-jects with CDC stages A, B, and C disease (figure1). Over time, considering only HIV-infected per-sons, 47% remained cognitively normal and 11%remained impaired; furthermore, 18% improvedand stayed improved (stably improved), 4%worsened and remained so (stably declined), and19% fluctuated between impaired and normal atthe different examinations. Data from demo-graphically matched seronegative controls testedrepeatedly (n � 30) showed that 80% remainedcognitively normal, 3% were stably impaired, 7%improved, 3% worsened, and 7% fluctuated. Toaddress the possibility that changes in neurocog-nitive classification might reflect error variance,the rates of changed vs unchanged classificationswere compared between groups. The proportionof HIV� who changed (42%) was greater thanthat for HIV� (17%) (�2 � 7.629; df � 1; p �

0.01), suggesting that the frequency of neurocog-nitive change in HIV� was unlikely to be due tochance. These data are summarized in figure 2.

Diagnostic transitions over 1 year were alsostudied by Valcour and colleagues in the HawaiiAging with HIV cohort, with similar findings (V.Valcour, personal communication, 2005). Of 37patients who at baseline were neurocognitivelynormal, at 1 year 30% had progressed to somestage of impairment. Of 53 patients initially diag-nosed with asymptomatic neurocognitive abnor-mality (neurocognitively abnormal withoutfunctional decline), 17.7% were classified as nor-mal 1 year later, while 44.1% had progressed tomore severe categories of impairment. This pat-tern was repeated for other patients with baselinediagnoses of MCMD and HAD, although theproportions of patients improving 1 year later (re-ceiving less severe diagnoses or considered cogni-tively normal) reduced as the initial severity of thedisease increased (figure 3).

Finally, similar observations were made by theNortheast AIDS Dementia Consortium. In partic-ular, 21% of subjects initially diagnosed withMCMD became neurocognitively normal atfollow-up, while 23% of those considered normalat study entry were diagnosed with MCMD atfollow-up. The degree of fluctuation observed inthese cases of changed diagnostic category wasrelatively small; i.e., gross changes in levels offunctioning were not seen.

Figure 1 Prevalence of neurocognitive disordersby stage of HIV disease

Figure 2 Neuropsychological course forneurocognitive states of HIV�

(n � 534) vs HIV� subjects (n � 30)

Neurology 69 October 30, 2007 1793 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

Thus, observations from at least three separatecohorts suggest that a sizable proportion of pa-tients have a fluctuating course of neurocognitiveimpairment over time, and that normalization ofsymptoms is possible. For this reason, the quali-fier “in remission” is proposed for the three re-search criterion sets displayed in the table. Itremains to be determined whether these transi-tions reflect biologic changes induced by re-sponses (or failures) of antiretroviral therapy.Similar observations have been noted in other co-horts, and appear to be independent of plasmaviral load and switches in HAART7 (J.C.McArthur, personal observation, 2006). Thesefluctuations in the cognitive state have parallelswith mild cognitive impairment, a disorder com-monly observed in the elderly, and the cognitivefluctuations that are also observed in relapsing-remitting multiple sclerosis.

B: Changes in the temporal progression of HIV-associated neurocognitive disorders with HAART.HAND remains frequent even in the era ofHAART. Epidemiologically there has been a sig-nificant decrease in the incidence of the most se-vere manifestation of HAND (i.e., HAD) but inmost studies this has been counterbalanced by anincrease in the prevalence.7,8 However, the epide-miologic aspects of less severe forms of HANDare much less well defined, although informallymost investigators consider both incidence andprevalence to be increasing. Recognition of HADalso requires understanding that it is somewhatdifferent to its counterpart in the pre-HAARTera, and is perhaps evolving. For example, in thepre-HAART era HAD almost exclusively oc-curred in those with CD4 cell counts below 200.Now patients who develop the disorder onHAART may have normal or near-normal CD4cell counts.9 The plasma HIV viral load, which

was always elevated and often markedly so inthose with HAD, is usually now less elevated andvery occasionally may be below the detectionlimit. HIV neurocognitive disorders are nowmilder and survival is considerably longer. None-theless, they can still impact upon quality of lifeand optimal medical management. HIV neuro-cognitive disorders in the HAART era may occureven in those patients who do not have other evi-dence of active HIV disease. The latter is impor-tant to recognize as no current therapies would beexpected to produce neurologic improvementwhen there is no active viral replication.10

HIV neurocognitive disorders may be evolvingin terms of their associated features. In the preHAART era, the confounding conditions werelargely related to opportunistic complications.Now with the higher CD4 cell counts there arenew factors such as the effects of hepatitis C, in-creased age and associated conditions such asHAART-related hyperlipidemia, hypertension,and possibly Alzheimer disease. These confoundsmay also interact with HIV’s effect on the brain,leading to a compounding of the deficit.

To assist clinicians in diagnosing the disorderand provide a framework that allows these issuesto be addressed, we propose changes to the defini-tion of the disorder and introduce criteria that al-low qualification of the progression of HANDaccording to its activity.

C: Importance of other confounding conditions inassociation with HAND. It is clear that HIV-infected patients are potentially vulnerable tocognitive effects from other conditions. Whilethese can be confounds to the accurate diagnosisof HAND, they can also have a compounding ef-fect if HAND is already present. The word “con-found” has the connotation of an alternatediagnosis, not necessarily an additional diagnosis.It is important for clinicians to realize that con-founding conditions may also be acting as com-pounding conditions (table E-4). As such,treatment for HAND needs to be considered inaddition to treatment of the confounding condi-tion. There are, of course, numerous conditionswhich might confound the accurate diagnosis ofANI, MND, or HAD. Rather than listing all, wewill focus on those that the group believed weremost relevant.

D: Importance of demographic adjustments in inter-preting neurocognitive test results. An importantissue regarding the use of neurocognitive tests isthat they be appropriately normed for the studypopulation. In particular, performance on these

Figure 3 Hawaii Aging with HIV cohort:Diagnostic transitions from baselineto year 1

1794 Neurology 69 October 30, 2007 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

tests is subject to influence by age, educationlevel, ethnic or racial background, and gender.

Byrd and colleagues (New York, NY) studiedthe effect of ethnic background on the apparentprevalence of HIV-associated neurocognitive dis-orders in an urban cohort of advanced HIV-infected adults using the standard AAN criteria.Results indicate that using standard AAN crite-ria, which are primarily based upon data fromwhite normal subjects, over 90% of HIV-infectedminorities were diagnosed with HAD/MCMD. Incontrast, only about 78% of the white populationwas considered impaired. Heaton and colleaguesmade similar observations at the HNRC: usingstandard test norms to rate a group of healthyuninfected subjects, 33% of African Americansand 15% of white subjects were considered cogni-tively impaired. When African Americans werescored using norms derived from a large group ofhealthy African Americans, the percentage of im-paired subjects was reduced to 19%, indistin-guishable from that for white subjects. RegardingHIV-seropositive subjects, cognitive impairmentamong white subjects was 38%, while that for Af-rican Americans was 71% using standard norms,but 44% using culturally adapted norms (figure4). Finally, Cherner and colleagues at HNRC ad-ministered the figure learning test to healthySpanish-speaking persons: using standard norms31% were considered to be cognitively impaired,but with norms designed for Spanish-speakingpersons only 15% were classified as impaired(similar to the rate in a majority population ofHIV- native English speakers). Cherner and col-leagues also demonstrated the effects of educationon neuropsychological test results: 40% of per-sons with 1 to 5 years of education were classifiedas impaired on the figure learning test, but wheneducation-adjusted norms were applied, the rateof impaired persons dropped to under 20%.

SUMMARY: SECTION 2 The concept of HIV-associated neurocognitive disorders has evolvedsince the original descriptions of HAD in the earlyyears of the epidemic. Antiretroviral therapy hasimproved longevity substantially, and also mayreverse neurocognitive deficits in many cases.One obvious impact of recognizing the term ofANI and incorporating it into clinical practiceand research usage would be to encourage morefrequent neurologic follow-up for individualswith ANI, to detect early functional impairmentsand potential transition to MND or HAD. In ad-dition, the recognition of ANI might promote theinitiation of antiretroviral therapy, independentof CD4 count or plasma HIV RNA levels. Theseissues/questions are unresolved and require futurestudy.

SECTION 3: PROPOSED ALGORITHM FORCLASSIFYING HAND The three conditions com-prising HAND—ANI, MND, and HAD—may beclassified using a variety of specific clinical andlaboratory-based methods, depending upon theresources available in the setting where the pa-tients are being evaluated. Nevertheless, stan-dardized procedures should be followedwhenever possible, both to collect the needed in-formation and to interpret that information tomake three types of determination: 1) the pres-ence and severity of neurocognitive impairment,2) the presence and severity of functional decline,and 3) the degree to which cognitive impairmentor functional decline are likely to have been influ-enced by comorbid conditions or confounds (in-cluding HIV-related opportunistic CNSconditions, or unrelated developmental, psychiat-ric, or neuromedical confounds).

Table E-2 provides an algorithm, or an outlineof basic criteria, for classifying the three neuro-cognitive disorders. Separate columns specifysimilar criteria (levels of impairment) that can bemet using formal neuropsychological testing vsclinical mental status testing. In order to reliablyuse the algorithm in table E-2, additional opera-tional definitions and guidelines are needed re-garding establishing neurocognitive impairment,functional decline, and confounds. This addi-tional guidance about methods of assessment andinterpretation is provided in tables E-2 and E-4,and related text below.

To facilitate reliable use of this algorithm, wesuggest specific examples of standardized assess-ments that can be used to establish the variouscriteria in table E-2. It is recognized, however,that in many resource-limited settings, standard-

Figure 4 Results of using different normativedata sets to identifyneuropsychological impairment inAfrican American subjects

0

10

20

30

40

50

60

70

80

African Americans

Using published norms based on Caucasians

African Americans

Using published norms based on African Americans

Caucasians

Using published norms based on Caucasians

Normal ControlsHIV+

% Im

paire

d

Neurology 69 October 30, 2007 1795 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

ized neurobehavioral examination proceduresand other diagnostic technologies (e.g., MRIscanning) are not yet available. In particular, theneuropsychological tests and functional assess-ments listed in table E-3 may not have been vali-dated in the languages of many countries, orappropriate normative standards may be lacking.In such cases the algorithm may still be followedin principle, using clinical assessments and clini-cal judgment aimed at establishing the same crite-ria. Ideally, these clinical methods themselves willbecome increasingly standardized, so that resultscan be compared across patients and across clini-cians. Table E-4 provides descriptions of comor-bid conditions and their grading, but is notdesigned to be exhaustive. Rather it is intended toassist clinicians in grading these particular condi-tions in patients who otherwise meet criteria forHAND. They also provide conceptual guidelinesthat should be more broadly applicable to a rangeof comorbid conditions, and hopefully will pro-mote more reliable classification of confounds ingeneral.

Neurocognitive impairment. If neuropsychological(NP) testing is available, this testing should covermultiple ability domains (see below). Test resultson at least two of these domains must be abnor-mal in order for the patient to be classified overallas having NP impairment. Impairment on indi-vidual tests would require a performance that ismore than one SD below the mean of a demo-graphically comparable HIV seronegative group,or greater than one SD below the normative meanusing published norms that are demographicallyadjusted (for age, education, gender, and/or eth-nicity, as appropriate for the test). The impor-tance of addressing appropriate norms wasdescribed above. Ideally, the examination wouldinclude tests of the following ability domains (ifpossible, with at least two test measures per do-main): verbal/language; attention/working mem-ory; abstraction/executive; memory (learning;recall); speed of information processing; sensory-perceptual; motor skills. Neurocognitive impair-ment requires that at least one of the tested abilitydeficits be primarily cognitive in nature (i.e., im-pairment that is limited solely to motor andsensory-perceptual functions would not qualify).Classification of moderate or greater overall NPimpairment (a criterion for HAD) requires per-formances on two ability domains that are greaterthan 2 SD below the normative mean; alterna-tively, the patient could score greater than 2.5 SDbelow normative expectations (an operationaldefinition for moderate to severe impairment) for

one domain and greater than one SD below ex-pectations for another. Further details regardingprocedures for reliably classifying NP impairmentin HIV-infected adults, involving multiple abilitydomains and multiple test measures within eachdomain, can be found in Woods et al.11

Examples of published NP tests within theabove-mentioned ability domains along with se-lected references are provided in table E-3. Thislist is not intended to be exhaustive, and primarilyincludes tests that have been standardized inWestern countries (particularly the United States)and used with HIV-infected populations there.Many of these tests are being adapted for use inother regions (e.g., in Asia, Africa, and SouthAmerica). However, population-specific norma-tive standards and evidence of cross-cultural va-lidity are needed before such tests can be used toconfidently diagnose individual patients whohave substantially different linguistic, cultural,and/or educational backgrounds than people inthe original test standardization samples.

If NP testing is not available, presence of cog-nitive impairment involving two or more abilitydomains may be detected by standardized mentalstatus examinations (MSEs), using demographi-cally appropriate normative cutoffs if available.For example, in the United States and other West-ern countries, mild cognitive impairment mightbe inferred if a young or middle aged adult (�60years old) with at least 12 years of educationachieves scores of 25 to 26 on the Folstein et al.12

Mini-Mental State Examination; a score less than25 would signify moderate (or worse) impairment(cutoffs estimated from data provided in Crum etal.13). Other MSEs that might be used include theHIV Dementia Scale,14 the International HIV De-mentia Scale,15 and the Mattis Dementia RatingScale.16 Ideally, in considering impairment, thepatient should also give evidence of involvementof at least two different aspects of cognition. Thisis consistent with the requirements for when neu-ropsychological testing is available.

It is not possible to provide a complete listinghere of items on MSEs that may demonstrate im-pairments of the cognitive domains mentionedabove. However, some examples from theMini-Mental State Examination are as follows:Registration � verbal learning, Attention andConcentration (both serial 7s and spelling“world” backwards) � attention/workingmemory, Recall � verbal memory, Language �

language skills, and Copy Design � spatialskills. For the HIV Dementia Scale, Anti-saccadic Errors � Attention, Psychomotor

1796 Neurology 69 October 30, 2007 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

Speed � speed of information processing,Memory Recall � verbal memory, and Con-struction � perceptual-spatial skills. Similarly,for the International HIV Dementia Scale, Psy-chomotor Speed (rapid motor sequencing) � ei-ther executive functions or speed of informationprocessing, Memory-Recall � verbal memory,and Motor Speed � motor.

The working group recognized that extrapyra-midal abnormalities (such as rigidity, bradykine-sia, or hypomimia) and psychiatric features (suchas apathy, personality change, irritability, or dis-inhibition) occur commonly in this context. Wedecided not to include these in the proposed clas-sification criteria because such symptoms oftenare difficult to establish as a result of HIV infec-tion (as opposed to representing pre-existing orcomorbid phenomena). Furthermore, there is in-sufficient evidence that these symptoms are reli-ably associated with neurocognitive impairmentsor (nonbehavioral) indications of CNS involve-ment of HIV-1 (e.g., neuropathology, neuroimag-ing abnormalities, CSF viral load, biomarkers ofinflammatory processes).

Future research should assess reliability of diag-nostic classifications based upon clinical methods vsmore formal testing methods. Validity of the diag-noses may be studied by examining relationshipswith disease history and outcomes, imaging and bi-omarker evidence of CNS involvement, and neuro-pathologic criteria.

Functional decline. Acquired impairment of every-day functioning can be assessed by self report orreport of a knowledgeable informant (familymember, close friend, caregiver), or by objectiveassessment of the patient’s ability to perform cog-nitively related instrumental ADLs (IADLs) suchas financial management and medication man-agement. Both the report-based information andobjective functional assessments should be ob-tained using standardized instruments, and ide-ally these instruments would have normativeguidelines that are appropriate to the patient be-ing examined (i.e., ideally norms would be avail-able for the patient’s country and demographicpeer group). Available questionnaires assess thefrequency with which patients experience diffi-culties with various aspects of cognition in theireveryday lives, and increased dependence uponothers in their IADLs.17 Also, standardized tasksare available to objectively assess abilities to, forexample, manage medications, manage finances,shop, cook, perform job-related activities, anddrive an automobile.17-22

Objective, laboratory-based assessment offunctional impairment adds time to the diagnosticevaluation and may require specialized test mate-rials or equipment.

Also, such assessment is not needed in allcases. Objective assessment of functional skills islikely to be most informative when a patientmeets other criteria for an HIV-related neurocog-nitive disorder, but denies being aware of anychange in everyday functioning.

Mild functional decline requires at least two ofthe following that are not readily attributable tocomorbid conditions in the judgment of theexaminer:

1) Self report or other report of some increasedassistance with at least two IADLs such as medi-cation management, financial management,shopping, meal preparation, light housekeeping,laundry, driving, use of public transportation,maintaining personal schedules, understandingmedia events, and child care. (More IADLs couldbe considered as appropriate to the individual.)

2) Patient is unable to perform some aspects ofa previous job. This is not due to medicalsymptoms.

3) Although patient may maintain employ-ment and/or full IADL independence, he or shereports less efficiency, reduced productivity, moreerrors in performing tasks, more difficulty meet-ing expectations, or greater effort expended per-forming the same activities.

4) In the absence of significant depression (e.g.,Beck Depression Inventory � 1723),1 which maybias reporting of symptoms, patient reports thathe or she is experiencing increased difficulty with�2 aspects of cognition in daily life. These mayinclude difficulties with memory for recent events(people, conversations, names, commitments,where things are placed), understanding conver-sations or reading materials, word finding, plan-ning activities, problem solving, concentrating,thinking clearly or logically, finding his or herway about, calculating, or following directions orinstructions. Reports of these difficulties also maybe obtained from a knowledgeable informant.(Instruments to assess depression that allow oneto separate out items concerning somatic symp-toms from those describing depressed mood arepreferred for this purpose, as somatic symptomsassociated with depression may also be caused byHIV itself.)

5) If performance-based, standardized func-tional tests are administered, patient scores �1SD below an appropriate normative mean on atleast one such task.

Neurology 69 October 30, 2007 1797 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

Major functional decline requires two or moreof the following that are not readily attributableto medical or other comorbid conditions in thejudgment of the examiner:

1) Patient is unable to maintain former em-ployment and this is not due to systemic illness orother factors not related to cognitive impairment(e.g., healthcare coverage being dependent upondisability status).

2) Patient requires substantially greater assis-tance (or is dependent) with more than two IADLs,as listed above.

3) Patient or a knowledgeable informant re-ports that he or she experiences/shows signifi-cantly greater difficulty with �4 aspects ofcognition, as listed above. However, self report isnot sufficient (would need confirmation by an-other informant) if patient is significantly de-pressed (e.g., BDI � 17).

4) If performance-based, standardized func-tional tasks are administered, patient scores �2SD below an appropriate normative mean on atleast one such task, or �1 SD below the mean onat least two tasks.

Questionnaires and performance-based testsfor measuring functional decline have been stan-dardized in Western countries, and many havebeen used in published studies of HIV-infectedgroups. As is the case with NP testing, measuresof everyday functioning (and available normativestandards for them) cannot be assumed to bevalid across populations having substantially dif-ferent linguistic, cultural, and educationalbackgrounds.

ADLs themselves may be different in differentcultures (e.g., reflecting differences in commonmodes of transportation, shopping, and financialtransactions). Thus, compared to NP testing,which is intended to measure more fundamentalhuman abilities, measures of functional declinemay require even more adaptation for cross-cultural use. Before they are selected for use in anew (different) population, IADL tests and ques-tionnaires should be carefully screened for rele-vance to the everyday lives of the people involved.

There is an additional consideration for cross-cultural use of the current algorithm: HIV-1 relatedchanges in cognitive ability may be much less likelyto causemeaningful functional decline in cultures orliving situations that pose fewer demands for suchabilities. Ifmore severe cognitive changes are neededto cause meaningful functional declines in some set-tings, the prevalence of symptomatic neurocognitivedisorders (MND and HAD) may be significantlylower in those settings. This could have unfortunate

consequences if excessive numbers of patients inthese settings who do have HIV-1 associated braindysfunction fail to be identified as such. The currentnomenclature’s addition of an asymptomatic cate-gory of neurocognitive impairment may help pre-vent such cases from being missed.

Other sources of NP impairment and functional lim-itations (comorbid conditions). The algorithm fordiagnosing the three HIV-1–associated neurocog-nitive disorders (table E-2) requires the clinicianto make the judgment that these disorders reflectthe effects of HIV-1 infection on the brain. As de-scribed above, in Section 1, the observed NP im-pairments and functional limitations cannot beexplained on the bases of CNS opportunistic dis-eases, medications with CNS effects, or develop-mental or acquired conditions unrelated toHIV-1. The number of such potential confounds,in all of their manifestations, is exceedingly large,so it would be impossible to specify how to ratethe importance of each of them. A second level ofcomorbid condition is considered to be a contrib-uting condition. This means that the conditionprobably has had some substantive contributionto the observed NP impairments or functionallimitations, but that the effect of HIV-1 also isconsidered to be significant. For example, in the caseof a serious developmental disorder or previoustraumatic brain injury, subsequent progression ofNP impairment or functional declinemay have beendocumented within the context of HIV-1 infection.This would demonstrate a significant role forHIV-1. It is emphasized that the presence of a con-tributing condition does not preclude the diagnosisof an HIV-1–associated neurocognitive disorder, al-though the severity of theHIV-1 component may bemore difficult to ascertain.

Received July 12, 2006. Accepted in final formMay 24, 2007.

REFERENCES1. Janssen RS, Cornblath DR, Epstein LG, et al. Nomen-

clature and research case definitions for neurologicalmanifestations of human immunodeficiency virustype-1 (HIV-1) infection. Report of a Working Groupof the American Academy of Neurology AIDS TaskForce. Neurology 1991;41:778–785.

2. Cherner M, Cysique L, Heaton RK, et al. Neuropatho-logic confirmation of definitional criteria for humanimmunodeficiency virus-associated neurocognitive dis-orders. J Neurovirol 2007;13:23–28.

3. Cherner M, Masliah E, Ellis RJ, et al. Neurocognitivedysfunction predicts postmortem findings of HIV en-cephalitis. Neurology 2002;59:1563–1567.

4. Wojna V, Skolasky RL, Hechavarria R, et al.. Prevalenceof human immunodeficiency virus-associated cognitiveimpairment in a group ofHispanicwomen at risk for neu-rological impairment. J Neurovirol 2006;12:356–364.

1798 Neurology 69 October 30, 2007 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

5. Arendt G, Hefter H, Hilperath F, von Giesen HJ, Stro-hmeyer G, Freund HJ. Motor analysis predicts pro-gression in HIV-associated brain disease. J Neurol Sci1994;123:180–185.

6. Brew BJ. Evidence for a change in AIDS dementia com-plex in the era of highly active antiretroviral therapyand the possibility of new forms of AIDS dementiacomplex. AIDS 2004;18 suppl 1:S75–S78.

7. Dore GJ, Correll PK, Li Y, Kaldor JM, Cooper DA,Brew BJ. Changes to AIDS dementia complex in the eraof highly active antiretroviral therapy (in process cita-tion). AIDS 1999;13:1249–1253.

8. Dore GJ, McDonald A, Li Y, Kaldor JM, Brew BJ.Marked improvement in survival following AIDS de-mentia complex in the era of highly active antiretrovi-ral therapy. AIDS 2003;17:1539–1545.

9. Dore GJ, McDonald A, Li Y, Kaldor JM, Brew BJ.Marked improvement in survival following AIDS de-mentia complex in the era of highly active antiretrovi-ral therapy. AIDS 2003;17:1539–1545.

10. Brew BJ. Evidence for a change in AIDS dementia com-plex in the era of highly active antiretroviral therapyand the possibility of new forms of AIDS dementiacomplex. AIDS 2004;18 suppl 1:S75–S78.

11. Woods SP, Rippeth JD, Frol AB, et al. Interrater reli-ability of clinical ratings and neurocognitive diagnosesin HIV. J Clin Exp Neuropsychol 2004;26:759–778.

12. Folstein MF, Folstein SE, McHugh PR. Mini-MentalState: a practical method for grading the cognitive stateof patients for the clinician. J Psychiatr Res 1975;12:189–198.

13. Crum RM, Anthony JC, Bassett SS, Folstein MF.Population-based norms for the Mini-Mental State Ex-amination by age and educational level. JAMA 1993;269:2386–2391.

14. Power C, Selnes OA, Grim JA, McArthur JC. The HIVDementia Scale: a rapid screening test. J AIDS 1995;8:273–278.

15. Sacktor NC,WongM, Nakasujja N, et al. The Interna-tional HIV Dementia Scale: a new rapid screening testfor HIV dementia. AIDS 2005;19:1367–1374.

16. Mattis S. Dementia Rating Scale (DRS). Odessa, FL:Psychological Assessment Resources, Inc., 1988.

17. Heaton RK, Marcotte TD, Mindt MR, et al. The im-pact of HIV-associated neuropsychological impair-ment on everyday functioning. J Int Neuropsychol Soc2004;10:317–331.

18. Albert SM, Weber C, Todak G, et al. An observed per-formance test of medication management ability inHIV: relation to neuropsychological status and adher-ence outcomes. AIDS and Behavior 1999;3:121–128.

19. Lowenstein DA, Bates BC. Manual for administrationand scoring the Direct Assessment of Functional Statusscale in older adults (DAFS). Miami Beach, FL: Mt.Sinai Medical Center, 1992.

20. Marcotte TD,Wolfson T, Rosenthal TJ, et al. A multi-modal assessment of driving performance in HIV infec-tion. Neurology 2004;63:1417–1422.

21. Patterson TL, Lacro J, McKibbin CL, Moscona S,Hughs T, Jeste DV. Medication management abilityassessment: results from a performance-based measurein older outpatients with schizophrenia. J Clin Psycho-pharmacol 2002;22:11–19.

22. Patterson TL, Goldman S, McKibbin CL, Hughs T,Jeste DV. UCSD Performance-Based Skills Assessment:development of a new measure of everyday functioningfor severely mentally ill adults. Schizophr Bull 2001;27:235–245.

23. Kalichman SC, Rompa D, Cage M. Distinguishing be-tween overlapping somatic symptoms of depressionand HIV disease in people living with HIV-AIDS. JNerv Ment Dis 2000;188:662–670.

24. Grant I The neurocognitive complications of HIV in-fection. In: Ramachandran VS, editor. Encyclopedia ofthe Human Brain. San Diego: Academic Press, 2002:475–489.

Neurology 69 October 30, 2007 1799 at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from

DOI: 10.1212/01.WNL.0000287431.88658.8b 2007;69;1789-1799; originally published online Oct 3, 2007; Neurology

R. Robertson, N. Sacktor, V. Valcour and V. E. Wojna Joseph, K. Marder, C. M. Marra, J. C. McArthur, M. Nunn, R. W. Price, L. Pulliam, K.Clifford, P. Cinque, L. G. Epstein, K. Goodkin, M. Gisslen, I. Grant, R. K. Heaton, J.

A. Antinori, G. Arendt, J. T. Becker, B. J. Brew, D. A. Byrd, M. Cherner, D. B. Updated research nosology for HIV-associated neurocognitive disorders

This information is current as of December 20, 2008

& ServicesUpdated Information

http://www.neurology.org/cgi/content/full/69/18/1789including high-resolution figures, can be found at:

Supplementary Material

8658.8b/DC1http://www.neurology.org/cgi/content/full/01.WNL.0000287431.8Supplementary material can be found at:

Subspecialty Collections

irmenthttp://www.neurology.org/cgi/collection/mci_mild_cognitive_impa

MCI (mild cognitive impairment) disorders_dementiahttp://www.neurology.org/cgi/collection/assessment_of_cognitive_

Assessment of cognitive disorders/dementia http://www.neurology.org/cgi/collection/hiv_dementia

HIV dementia aviorhttp://www.neurology.org/cgi/collection/all_neuropsychology_beh

Neuropsychology/BehaviorAll http://www.neurology.org/cgi/collection/hiv

HIVfollowing collection(s): This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.neurology.org/misc/Permissions.shtmlor in its entirety can be found online at: Information about reproducing this article in parts (figures, tables)

Reprints http://www.neurology.org/misc/reprints.shtml

Information about ordering reprints can be found online:

at UNIV CALIFORNIA SAN DIEGO on December 20, 2008 www.neurology.orgDownloaded from