HIV dementia is a serious neurological condition characterized by increasing forgetfulness, difficulty with concentration, loss of libido, apathy, inertia, and waning interest in work and hobbies resulting in social withdrawal. Patients complain of losing track of conversations and the plots of books and films and of taking longer to complete more complex daily tasks. Impaired short term memory causes difficulty with remembering appointments, medications, and telephone numbers. Motor complaints include poor handwriting, insecure balance, and a tendency to drop things easily. Gait difficulty is a relatively early symptom. Friends and partners report change in personality with apathy and social withdrawal and blunting of emotional responsiveness. The early symptoms are often subtle and may be overlooked or confused with psychiatric complaints, the effects of substance abuse, or delirium (click here to view McArthur, Neurology, 1993 (PDF format)).

Since the introduction of HAART in developed countries around 1996 the incidence of HIV-associated dementia in patients with good medication compliance has been decreasing. However, cognitive impairment eventually develops in about 30% of people with AIDS and frank dementia in about 15%, with an annual incidence after AIDS of approximately 5%. Typically, dementia develops after constitutional symptoms, immune deficiency and systemic opportunistic processes.

The diagnosis is made by experienced neurologists after carefully ruling out other causes for cognitive impairment. A thorough neurological exam and history, brain MRI scan, and sometimes lumbar puncture to evaluate the cerebrospinal fluid are performed. Neuropsychological testing can add useful information about the nature, severity, and progression of cognitive deficits.

For patients who have not undergone treatment with anti-HIV medications, initiation of a CNS penetrating, highly active antiretroviral regime can be effective in improving cognitive performance. The delineation of the pathophysiologic steps contributing to HIV dementia has suggested that antiretroviral therapies alone may not be sufficient to prevent the self-sustaining macrophage activation, and the subsequent release of neurotoxic factors. This concept has led to the testing of several adjunctive therapies aimed at interrupting or blocking these aberrant pathways. These include inflammatory antagonists, such as Lexipafant, an antagonist of platelet activating factor, and neuroprotective agents, such as memantine, an open-channel NMDA antagonist. Other compounds have been tested in small Phase I/II trials in patients receiving stable ART and have shown promising results. In one study of the licensed agent selegiline, significant improvements in memory were seen and a larger trial is  in the planning stages.







Up to 30% of patients with AIDS develop a neuropathy characterized by painful sensory symptoms in the feet. This disorder can be recognized by characteristic complaints of "burning feet." Numbness and paresthesias are also frequency reported. Reduced or absent ankle reflexes are found, along with elevated vibratory thresholds. Electrophysiological studies are helpful, but not essential for diagnosis and usually reveal a neuropathy affecting sensory more than motor fibers suggestive of a dying back axonopathy.

Consideration should be given to contributing factors, including nutritional and toxic causes of sensory neuropathy, such as alcohol, diabetes, pyridoxine excess, and B12 deficiency. The dideoxynucleosides ddI, ddC, and d4T cause toxic painful neuropathy in 15 to 20% of patients, usually after several weeks of treatment.

Symptomatic relief with pain modifying agents, such as the tricyclic antidepressants amitriptyline (Elavil) or nortriptyline (Pamelor) may be useful. New anticonvulsants such as lamotrigine (Lamictal) and gabapentin (Neurontin) have also shown efficacy in reducing the pain associated with HIV neuropathy.  Trials of regenerative agents have been conducted, including a recent trial of nerve growth factor for HIV-SN (click here to view McArthur, Neurology, 2000 (PDF)).







Myelopathy is generally seen in advanced HIV disease, sometimes but not always associated with cognitive dysfunction and or neuropathy. Symptoms include weakness in both legs, bladder and bowel control problems, and variable sensory symptoms including numbness in the feet or problems with balance.  Treatment usually includes HAART and rehabilitation.





About 3% of patients with AIDS will develop progressive multifocal leukoencephalopathy (PML) which typically presents with a progressive accumulation of focal neurological deficits - cognitive dysfunction, limb weakness, gait disturbance, coordination difficulties and visual loss.

Reactivation of latent papovavirus (usually the JC strain) under conditions of immune deficiency leads to this progressive demyelinating disorder. Serological studies have shown that about 70% of all adults have antibodies to JC virus, implying that the infection is common in humans, although the primary infection is usually silent. Prior to AIDS, the condition had been reported most frequently in patients with lymphoma or leukemia, or in those receiving immunosuppressive drugs for the treatment of rheumatoid arthritis, sarcoidosis, or following organ transplantation. AIDS is now the most common cause of PML. Diagnosis is made by careful clinical evaluation and MRI scan.

Recently dramatic improvements with combination antiretrovirals have been seen. Several drugs have been tried and found ineffective, including cytosine arabinoside (Ara-C), topotecan, and cidofovir.  There have been anecdotal reports of responses to alpha interferon and in one observational study of 21 patients treated with 3 mU alpha interferon daily, the median survival was over 300 days and 1/3 of the patients had definite remission (click here to view Huang, J Neurovirology 1998 (PDF)).








Central nervous system lymphoma occurs in about 2% of patients with AIDS. Most patients present with headache, mental change, seizures and focal neurological deficits. Single or multiple lesions, generally with significant mass effect and contrast enhancement, are seen on MRI. Thallium SPECT scan can help distinguish PCNSL from other brain lesions including toxoplasmosis. Therapy is with whole brain radiation therapy and HAART.  The prognosis had been very poor but with HAART appears to be improving.







Toxoplasma encephalitis is caused by reactivation of latent infection in more than 95% of cases. In the US, 12-50% of HIV-infected individuals are latently infected with Toxoplasma gondii, an intracellular parasite, and it is estimated that, without prophylaxis, at least one-quarter of these at-risk individuals will develop Toxoplasma encephalitis Toxoplasmosis typically presents with the development of fever, altered mentation, seizures, and focal neurological signs developing over a few days. Imaging studies demonstrate multiple contrast-enhancing mass lesions, however, the radiologic appearances are not definitive for toxoplasmosis and can be mimicked by lymphoma or bacterial brain abscess. Prompt initiation of antimicrobial treatment with pyrimethamine and sulfadiazine will lead to clinical improvement in 80% of cases within 1-4 weeks. After this induction therapy for 6 weeks, maintenance therapy of pyrimethamine 25 mg daily with folinic acid and a second agent, either sulfadiazine or clindamycin 300 mg every six hours needs to be continued life-long.








Cryptococcus neoformans, a ubiquitous encapsulated yeast, causes neurological disease in about 5% of AIDS patients. Incidence rates have dropped in the USA, both as a result of the widespread use of antifungals for treatment of oropharyngeal candidiasis and the introduction of HAART. HIV-infected patients with cryptococcal meningitis complain of fever, headache, nausea and vomiting, and cognitive dysfunction. Diagnosis is made readily by assay for CSF cryptococcal antigen, which is nearly 100% sensitive and specific. Treatment is with a combination of amphotericin B and 5-Fluorocytosine, with successful treatment in about 60%.








CMV is a common pathogen in the advanced stages of AIDS, producing disease when the CD4+ count is usually less than 100 cells/mm3. CMV-induced disease represents reactivation of latent infection. The introduction of protease inhibitors has reduced the incidence of CMV disease significantly in the USA. CMV retinitis, a common manifestation of CMV-induced disease and a main cause of visual loss and blindness, occurs in 15-28% of AIDS patients.

CMV encephalitis has been reported in up to 2% of AIDS patients, although it may be misdiagnosed for HIV dementia, and this figure may under-represent the true frequency. CMV encephalitis presents with acute or subacute confusion, disorientation, and memory loss, and tends to have a more rapid progression than HIV dementia. CMV polyradiculitis occurs in about 2% of AIDS cases and is characterized by the subacute onset of a flaccid paraparesis, sacral pain, paresthesias, and sphincter dysfunction. A major advance in the early diagnosis of CMV encephalitis and radiculomyelitis is the detection of CMV DNA in cerebrospinal fluid. The development of PCR evaluation of the CSF for CMV has facilitated early and more definitive diagnosis. Treatment is with ganciclovir or forscarnet, and in severe cases double therapy.

 


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