The disorders presenting with more general or diffuse brain dysfunction and without focal features can be further divided into those in which consciousness remains fully preserved and those accompanied by a concomitant decrease in alertness. Most important among the former is the AIDS dementia complex, a clinical syndrome characterized by cognitive, motor, and, at times, behavioral dysfunction.

Both the incidence and severity of the AIDS dementia complex increase with advancing immunosuppression. Although thought to relate to an effect of HIV-1 brain infection, the mechanisms linking this infection to neurologic dysfunction are uncertain. Most speculation centers on the activation of cytokines and related endogenous neurotoxins. Its early, mild form is usually characterized by impaired concentration and attention along with reduced mental agility, resulting in complaints of forgetfulness and slowness in performing complex mental tasks. In those who progress to more severe involvement, cognitive dysfunction worsens and involves other domains, and motor dysfunction becomes clinically manifest with gait unsteadiness and difficulty with rapid, fine movements of the hands. Personality change with apathy, lack of initiative, or, at times, hyperactivity and agitation may be part of the syndrome.

In its most severe form, global dementia, paraplegia, and virtual mutism may evolve with resultant incapacity. Although it is in part a diagnosis of exclusion, the symptoms and signs of the AIDS dementia complex are sufficiently distinct to allow bedside diagnosis in most patients on the basis of their stereotypy. Neuroimaging characteristically reveals cerebral atrophy, and MRI may additionally demonstrate increased signal in white matter or basal ganglia. Several studies have shown that zidovudine (AZT) can prevent and partially reverse the signs and symptoms of the AIDS dementia complex. This precedent suggests that combination HAART might be even more effective in this regard, although evidence for this is only beginning to be reported anecdotally or in case series.

In the AIDS dementia complex there is relative preservation of alertness in relation to cognitive loss. This contrasts with most metabolic encephalopathies developing as sequelae of the systemic diseases suffered by AIDS patients; for example, hypoxia and sepsis are characteristically accompanied by a degree of lethargy and confusion which parallels the decline in cognition. Likewise, CNS-active drugs often cloud mentation and alertness together. Although such metabolic and toxic disorders may present alone, they may also have an exacerbating or unmasking influence on the AIDS dementia complex, resulting in a mixture of the two conditions. HIV-1-infected patients may also be more sensitive to neuroleptics and thereby manifest parkinsonian or other movement disorders as side effects at seemingly low doses.

Brain infections may also produce diffuse brain dysfunction. Most important is CMV, which can be difficult to diagnose. Clinical features that raise suspicion include clouded consciousness, ataxia and nystagmus or seizures, whereas MRI findings of contrast enhancement or increased attenuation of the ventricular ependyma also support this diagnosis. CSF PCR detection of CMV sequences provides diagnostic confirmation in this setting. Although CNS toxoplasmosis characteristically causes focal neurologic symptoms and signs, in some patients generalized encephalopathy predominates. Similarly, CNS lymphoma may infiltrate deep structures and impair cognition and motor function without prominent focal symptoms or signs. Herpes simplex virus types 1 and 2 may also cause subacute nonfocal encephalitis.