Treatment Issues; Vol. 9, No. 3 - March 1995
George van Baelen

Early, aggressive treatment is often necessary for neurological conditions, since mortality and irreversible damage rates can be very high for untreated individuals. But, as we shall find in the following review of the six conditions the MACS analyzed, treatment of both symptoms and underlying disease process has had erratic results at best. Many studies and clinical trials are in progress or in the planning stages to further explore treatment strategies.

Opportunistic Infections

Toxoplasmosis encephalitis is the most common brain infection in people with AIDS, affecting from two to 40 percent of different patient groups.[2] Toxoplasma protozoa from contaminated meat or cat feces enter the body through the mouth and digestive tract. They then travel through the blood to the brain, where they invade and kill neuronal cells. Symptoms include fevers, headaches, confusion and lethargy, and seizures. Diagnosis is obtained by determining toxoplasma antibody levels, magnetic resonance imaging (MRI) and computed tomography (CT) scans.

There are no accepted prophylaxes for toxoplasmosis, although cotrimoxazole (Bactrim or Septra) and dapsone have been tried with good results. First-line therapy for active toxoplasmosis is oral pyrimethamine (starting with a loading dose of 50 to 200 mg/day and followed by 25 to 75 mg/day) and sulfadiazine (4 to 8 grams/day) for two to six weeks. This regimen is usually effective, but lifelong maintenance therapy to prevent recurrence is advised.[3]

Renal and dermatologic complications due to sulfadiazine occur in about 40 percent of the treated patients, however. Alternative therapy in that case is a combination of pyrimethamine (75 mg/day) and clindamycin (600 mg/day). Azithromycin is an option in patients who are intolerant to pyrimethamine, sulfadiazine or clindamycin. (Azithromycin's manufacturer, Pfizer, has a compassionate clinical trial for this purpose. For more information, physicians may call 800/742-3029.)

Atovaquone (Mepron) as salvage therapy (750 mg four times a day) has resulted in clinical improvement in 54 to 88 percent of clinical cases, depending on serum levels obtained.[4] Atovaquone/pyrimethamine/folinic acid is being compared to atovaquone/sulfadiazine in the NIH-sponsored ACTG trial 237. Intravenous cotrimoxazole at 40 to 50 mg per kilogram of body weight per day was reported to be beneficial in 72 percent of treated patients.[5] Other alternative therapies include the antibiotics doxycycline and minocycline.

Cryptococcal meningitis is the most common fungal infection attacking the central nervous system in HIV-infected persons. Five to ten percent of people with AIDS, and perhaps more,[6] contract this disease. Symptoms can be subtle: 75 to 90 percent of patients present with minimal inflammation, malaise, nausea and headaches. Diagnosis is established by cerebral spinal fluid tests or high serum cryptococcal antigen titer. A major problem is elevated intracranial pressure. Various drainage techniques (intraventricular shunts or repeated lumbar punctures) can relieve this pressure. Treatment with acetazolamide also has been effective. In addition, trials are assessing the use of corticosteroids for this purpose.

Acute cryptococcal infection can be treated with intravenous amphotericin B (0.7 mg per kilogram of body weight per day) for two to three weeks followed by oral fluconazole (200 to 400 mg/day). Life-long maintenance therapy, usually with fluconazole, is necessary to inhibit resurgence of the cryptococcus fungus.

Oral flucytosine (100 to 150 mg per kilogram of body weight per day) may be used in conjunction with the amphotericin, but both drugs have side effects that can limit their use. Liposomal amphotericin has been tried as a safer alternative. (See Treatment Issues, April 1994, pages 6, 9-12.)

Fluconazole and itraconazole are other possible options. A group at the University of California San Diego reported last summer that it had successfully treated cryptococcal meningitis in eight people through the use of high-dose fluconazole (800 mg/day).[7] The fungus was eliminated from patients' spinal fluid in a median of 21 days, and symptoms resolved.

Progressive Multifocal Leukoencephalopathy (PML) is caused by the infection of oligodendrocytes (specialized support cells in the brain) by the JC virus. It affects less than five percent of people with AIDS. Symptoms are changes in mental status, speech and vision disturbances, hemiparesis (paralysis on one side of the body), difficulty in walking and growing inability to coordinate limb movement. Care should be taken not to confuse PML with AIDS dementia. Magnetic resonance imaging - MRI - is the preferred tool for diagnosis, though biopsy remains necessary to establish a definitive diagnosis of PML. The disease has a median survival time of two to four months. Approximately ten percent of patients experience prolonged survival.

There is no accepted treatment for PML. High-dose antiretroviral therapy is one possibility. Intravenous and intrathecal (spinal) infusions of cytarabine (commonly known as ara-C, a cancer therapy with many side effects) has been reported to stabilize or reduce PML in some patients.[8,9] Both forms of cytarabine are currently under investigation in ACTG trial 243, a 90-person trial that began enrolling a year ago.

Two other cancer drugs, topotecan and irinotecan, are also thought to be active against PML (Next month's Treatment Issues will carry an article on topotecan.) There has also been occasional interest in beta interferon (due to a 1987 journal article on the stabilization of one patient[10]) and peptide T.

Some activists have proposed a "kinder, gentler" approach involving various combinations of acyclovir, heparin, interferon, dexamethasone and n-acetylcysteine (NAC). (A lay report describing the range of potential treatments for PML can be obtained from Peter Brosnan at 213/874-7885 or 1709 North Fuller Ave., Los Angeles, CA 90046. Cost is $30 to the public and $20 to people with AIDS.)

Malignancy

Primary CNS lymphoma (PCNSL) is composed of B-cell tumor growth which occurs most often as a complication of late- stage AIDS. B-cells' normal task is to selectively produce antibodies when stimulated by CD4+ helper T-cells. Factors that may contribute to their unrestrained proliferation in HIV infection include chronic stimulation, loss of T-cell control mechanisms and infection by Epstein-Barr virus (EBV), which is highly associated with the development of PCNSL.

Historically, this lymphoma was thought to affect a few percent of people with AIDS, but in the MACS survey, this condition was increasing at a rate faster than any of the four AIDS-defining neurologic disorders. (The study found a 47 percent yearly increase in incidence.)

Symptoms include focal neurologic signs such as hemiparesis, aphasia (loss of ability to speak or understand speech), seizures, loss of cranial nerve function, lethargy, confusion and memory loss.

Presumptive diagnosis is established through MRI and CT scans, complemented with lumbar puncture and cytologic examination of spinal fluid. Epstein-Barr Virus (EBV) in spinal fluid has been suggested as a marker.[11]

Primary CNS lymphoma is unusually aggressive in people with AIDS. Survival time after the onset of PCNSL depends on CD4 count, and even with treatment, averages as little as five or six months in people with advanced symptomatic AIDS. Therapy consists of whole-brain irradiation, sometimes along with short-term administration of steroids to control and shrink tissue swelling and tumors. Relapse is frequent.

Use of chemotherapy for PCNSL is under investigation. ACTG 252 is evaluating the efficacy of preceding whole-brain irradiation with one cycle of "CHOD" - a combination of chemotherapeutic agents plus corticosteroid (dexamethasone) - and G-CSF (to maintain white blood cell levels). Intrathecal cytarabine also will be administered in trial participants with detectable Epstein-Barr virus in their cerebral spinal fluid. Such people may be less responsive to therapy or particularly prone to relapse.

Another chemotherapeutic agent is MGBG (mitoguazone). It is undergoing testing in a 25-person trial at the University of Southern California. This compound, which readily penetrates the blood-brain barrier, will be administered both before and after radiotherapy.

Cognitive Disorder

AIDS Dementia Complex (ADC) has been attributed to the direct results of HIV infection. It may represent a complex of several disease processes involving inflammatory immune sytem cytokines and oxidative stress as well as HIV itself. Some 30 percent of people with AIDS experience minor cognitive impairment while twenty percent have a serious deficit. Symptoms include apathy, decreased concentration and memory, and slowness of thought and motor movements. ADC appears as a late complication of HIV-infection in adults. The incidence rate for the condition apparently has not increased, according to the MACS.

Standard treatment consists of high-dose regimens of AZT. ACTG trial 005 found that people on 2,000 mg of AZT per day had significant improvements in neuropsychological test scores by week sixteen.[12] (See comments on the use of AZT for ADC in the accompanying article by Derek Link.) ddI is another potential treatment, but data from a 1,775-person European trial of people intolerant to AZT indicates that ddI is not very effective - the incidence of ADC was 11.1 percent.[13] The lack of efficacy may be due to ddI's poor penetration of the blood-brain barrier.

Another possibility is AZT plus ddC, which reduced neurocognitive dysfunction and CSF HIV levels in a small pilot study reported at last year's International Conference on AIDS.[14] Also at the Conference was a similar study involving ateviridine, a reverse transcriptase inhibitor under development by Upjohn that could be used in people intolerant to nucleoside analogues.[15]

Nimodipine, pentoxifylline and peptide T are among the drugs that might improve neurologic functions without affecting HIV replication.

Nimodipine, a calcium channel blocker, was studied in ACTG 162. The study ended in October, 1994. Five patients completed the protocol, and data from the trial are not yet available. The rationale for using a calcium channel blocker comes from the observation that a surface protein of HIV, gp120, can cause nerve cell death in the test tube.[16] Death was associated with the opening of calcium channels in the cells' membranes. Nimodipine prevented this process and seemed to save the cells.

Pentoxifylline, a reputed antagonist of tumor necrosis factor (TNF), also is being assessed in its capacity to alleviate ADC. The underlying rationale is that TNF, an inflammatory molecule secreted by the immune system, promotes brain injury. Another potential TNF blocker is OPC-14127, a vitamin E-like compound that may scavenge the free radicals that TNF induces within cells. OPC will be the subject of the first trial organized by a new university consortium devoted to investigating treatments for ADC. Three centers - at the University of Rochester, Johns Hopkins University and Columbia University - will participate.

Peptide T, a synthetic peptide that mimics the cell binding site on HIV's surface protein gp120, has been mired in controversy for years. It was originally supposed to protect cells from penetration by HIV. New data suggests that peptide T inhibits TNF.[17] A phase I study with intranasal peptide T reported some improvement in neurocognitive functions. No side effects were reported.[18]

A new phase II trial of peptide T is planned for HIV-positive individuals with cognitive impairment. The study will soon be underway at eleven sites nationwide and is sponsored by Peptech, a peptide T licensee.

In patients with psychomotor slowing, use of psychostimulants, such as Ritalin may be helpful. Agitation and mania can be treated with neuroleptics or lithium, starting at low doses.

Nerve Damage

Peripheral neuropathies common to HIV-infection may be categorized as two types.

The first type is a complication arising in the early stages of the infection, inflammatory demyelinating polyneuropathy (IDP). Morbidity stems from the progressive breakdown of the fatty envelope around the neurons - the myelin sheet.

Conduction of signals to and from the brain is impaired. This complication appears in most cases even before individuals become susceptible to opportunistic pathogens and is thought to be an autoimmune disease. Patients experience mild sensory problems, decreased clinical reflexes and chronic progressive weakness, similar to Guillain-BarrÄ syndrome in HIV-negative patients. Symptoms can be managed with corticosteroids.

The second type is predominantly sensory axonal polyneuropathy, a late stage complication of HIV-infection. The major symptom is painful tingling or burning sensations. AZT is ineffective in treating the symptoms. Tricyclic antidepressants are indicated, particularly low-dose amitriptyline. Brief bursts of pain can be treated with phenytoin or carbamazepine, which are anticonvulsants. Topical capsaicin has also been tried.

Mexiletine failed to relieve pain in a nineteen-person clinical trial by the AIDS Research Community Research Consortium in Redwood City, California. Results were presented at the Second Annual Human Retrovirus Conference (abstract no. LB21) described elsewhere in this issue. Peptide T also failed to relieve neuropathy during a trial. (See Treatment Issues, February, 1994. Acupuncture now is under evaluation, alone or in combination with amitriptyline, by the Community Programs for Clinical Research on AIDS (CPCRA trial 022).

1 Bacellar H et al. Neurology. Oct 1994; 44(10): 1892-1900.

2 Wong SY and Remington JS. AIDS. Mar 1993; 7(3): 299-316.

3 Luft BJ and Remington JS. Clinical Infectious Diseases. 1992; 15(2): 211-222.

4 Torres R et al. Ninth International Conference on AIDS. Jun 1993; I(abstract PO-B10-1453):377.

5 Canessa A et al. Sixth International Conference on AIDS. Jun 1990; 1(abstract Th.B.477):241.

6 Currie BP and Casadevall A. Clinical Infectious Diseases. Dec 1994; 19(12):1029-33.

7 Haubrich R et al. Journal of Infectious Diseases. 1994; 170(1): 238-41.

8 Nicoli F et al. Lancet. 1992; 339(8788):306.

9 Novak IS et al. Neurology. 1989; 39(S1):379-80.

10 Tashiro K et al. Journal of Neurology. Aug 1987; 234(6):427-9.

11 MacMahon EME et al. Lancet. 1991; 338(8733):969-73.

12 Sidtis JJ et al. Annals of Neurology. Apr 1993; 33(4):343- 9.

13 Portegies P et al. Lancet. Sept 10, 1994; 344(8924):759.

14 McIntyre K et al. Tenth International Conference on AIDS. Aug 1994; I(abstract PB0233):201.

15 Brew BJ et al. Tenth International Conference on AIDS. Aug 1994; I(abstract 232B):70.

16 Dreyer EB et al. Science. Apr 20, 1990; 248(4953):364-7.

17 Phipps DJ et al. Ninth International Conference on AIDS. Jun 1993; I(abstract PO-A13-0232):173.

18 Bridge P et al. Seventh International Conference on AIDS. Jun 1991; II(abstract T.H.B.90):79.

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