                   AIDS INFORMATION NEWSLETTER
                   Michael Howe, MSLS, Editor
                     AIDS Information Center
                VA Medical Center, San Francisco
                     (415) 221-4810 ext 3305
                          July 26, 1996

             Opportunistic Infections (Part XXVIII)
                   Neurological Complications

[From:  AIDS/HIV Treatment Directory, February 1996, Vol. 8, No.
1, pp. 131-135.  Published by the American Foundation for AIDS
Research.] 

     Central nervous system (CNS) and peripheral nervous system
(PNS) disorders in HIV-infected individuals may result from
opportunistic infections, neoplasms, and processes that appear to
be primary effects of human immunodeficiency virus (HIV) itself. 
The nervous system may also be damaged as a result of the toxic
effects of various treatments.  Indeed, the majority of AIDS
patients will eventually manifest one or more of these neurological
conditions.

             Opportunistic Infections and Neoplasms

     Opportunistic infections of the central nervous system
eventually develop in one-third or more of patients with AIDS.  The
most common opportunistic infections of the CNS are cerebral
toxoplasmosis developing in 5-10% of AIDS patients depending on
geographic location, cryptococcal meningitis in perhaps 5-10% of
AIDS patients, and progressive multifocal leukoencephalopathy (PML)
in 2-5% of AIDS patients.  Cytomegalovirus commonly infects the
brain, although usually this is not of major clinical significance;
however, 5% of patients may develop more severe CMV infection of
brain or nerves.  Much less common are mycobacterial (M.
tuberculosis) infections, neurosyphilis and viral (herpes simplex
encephalitis or myelitis) infections.  Other fungal (Aspergillus
and Candida) infections are rare.  In the case of CMV, infection
of peripheral nerves (more accurately, infection of nerve roots)
presents as an acute condition causing weakness and numbness
beginning in the legs which then affect urinary and bowel
functions.  Diagnosis is assisted by examination of the
cerebrospinal fluid (CSF), which shows a characteristic cell
response (Polymorphonuclear leukocytes); many patients have been
reported to respond to ganciclovir treatment or combination
treatment with ganciclovir and foscarnet.  Hence, diagnostic
evaluation and rapid implementation of such treatment should be
pursued aggressively.
     HIV-infected patients are susceptible to the development of
lymphomas, including primary CNS lymphomas (i.e., originating in
the CNS rather than spreading secondarily from the body).  Whole-
brain radiotherapy is the treatment of choice.  Lymphomas can also
spread to the CNS, usually to the meninges (the membranes covering
the brain) rather than to the brain tissue.  Treatment of systemic
lymphomas, which may develop earlier in HIV infection than primary
CNS lymphomas, usually involves intensive systemic therapy and
sometimes intrathecal (into the spinal fluid) chemotherapy (See
Part XXIV of this series, Lymphomas, dated 17 May 1996).

                Primary Effects of HIV on the CNS

     While it is clear that the CNS may be exposed to HIV early in
the course of infection, this does not characteristically result
in clinically evident neurological dysfunction until much later. 
Thus, studies of asymptomatic seropositives have shown that the CSF
is frequently mildly abnormal (elevated white blood cells and
protein, locally produced antibody, and, in up to 30%, detectable
virus), yet the study subjects remained clinically normal even when
evaluated using careful quantitative neuropsychological testing. 
Additionally, prospective studies (including the Multicenter AIDS
Cohort Study) have shown that systemically asymptomatic subjects
remain neurologically intact.  Nonetheless, HIV does cause
symptomatic neurological disease later in HIV infection, although
the mechanisms involved remain uncertain.  Very early in the course
of HIV infection, at or near the time or seroconversion, some
patients develop acute encephalitis, aseptic (nonbacterial)
meningitis, or various neuropathies.  These unusual syndromes
appear to relate either to direct viral infection of the nervous
system or to host immune responses (immunopathology triggered by
the virus).  They are generally self-limiting and usually resolve
with little or no residual effect.
     HIV-infected individuals may develop aseptic meningitis at the
time of seroconversions or after, which is presumed to be caused
by HIV itself.  Presenting symptoms are headache and stiff neck,
and the diagnosis is made by spinal tap and examination of the CSF
that reveal an increased number of cells but negative cultures for
bacterial and absence of cryptococcus.  This generally benign
condition must be differentiated from more important causes of
headache (such as toxoplasmosis) or CSF cell abnormality (such as
cryptococcal meningitis).  It also should be differentiated from
the more common headache that complicates and is common in HIV
infection.  Such headache may be severe and persistent, yet no
cause is established after through evaluation.  Some patients
appear to respond to low doses of the anti-depressant
amitriptyline, while others may require the use of narcotic
analgesics.

                      AIDS Dementia Complex

     The most important CNS complication, that has been attributed
to a primary effect of HIV, has been described using a variety of
terms including the AIDS dementia complex (ADC), subacute
encephalitis and HIV encephalitis.  This syndrome may represent
more than one type of disease process.  It is characterized by
decreased concentration and rapidity of thought, loss of interest
in activities, and slowness of motor movements.  The link between
HIV infection in the brain or in the body and this neurological
condition still remains uncertain.  While it is clear that patients
severely affected by this disorder have HIV-infected macrophages
within the brain, those with milder disease have not been shown to
have active virus infection within the brain.
     TREATMENT RESULTS:  AZT has been demonstrated to improve and
possibly prevent HIV-induced cognitive dysfunction in certain
patients.  Sidtis and co-workers enrolled 39 patients with AIDS
dementia in a placebo-controlled study (ACTG Protocol 005) of AZT
(1,000 or 2,000 mg/d).  Final analysis showed neuropsychologic
function improved in those patients receiving AZT compared with
placebo, and raised the question of whether the very high dose of
AZT (2,000 mg daily) might have been most effective.  This result
is consistent with those of earlier studies in adults and children
showing similar AZT effect in both treatment and prevention.  An
open study of three doses of AZT (1,000 mg, 750 mg, or 500 mg/day)
in 30 patients with ADC was conducted by Tozzi et al.  Response to
treatment was sometimes transient, and was not associated with the
dose of AZT.
     Yarchoan et al. reported on five patients with HIV-related
neuropsychiatric impairment who received ddI in a dose-ranging
phase I study; all patients experienced significant improvement. 
A multicenter open label pilot trial of ddI (375 mg or 250 mg) in
mild or severe ADC is under way.  ACTG 140, a comparative trial of
ddI vs. AZT (ddI 250 or 375 mg qd or AZT 1,000 mg qd) is underway
at Tulane University and Washington University in St. Louis.  Clear
evidence of ddI, ddC, d4T, or other antiretroviral effect in AIDS
dementia complex awaits further study.  These results are anecdotal
and some clinicians report less favorable experiences particularly
when setting of AIDS dementia develops or recurs in patients
already being treated with AZT.  In such patients the choices
include:  1) raising the AZT dose to 1,000 mg per day or more if
there has not been evidence of drug intolerance or toxicity
(perhaps in concert with GM-CSF if needed); 2) switching to or
combining therapy with another antiretroviral drug; 3) adding an
adjunct therapy aimed at interfering with some of the toxic
processes underlying brain injury as described below.
     At least 3 drugs are being evaluated for their ability to
improve neurological function without directly inhibiting virus
replication.  These adjunctive therapies include:  cytokine
antagonists, antioxidants, and neuroprotective agents.  They are
in various stages of testing. Peptide T, which was thought to have
some promise as a potential therapy, was found ineffective in a
large randomized study.
     Some cell-culture studies suggest that the HIV envelope
protein gp120 is toxic to neurons by virtue of it effect on calcium
channels.  An ACTG trial (ACTG 162) with the calcium channel
blocker nimodipine is underway to study its effect in ADC.
     A parallel syndrome is very common in children with AIDS,
eventually causing major developmental delay, loss of milestones,
cognitive impairment, and motor deficits in perhaps 75% of
patients.  Therapeutic studies indicate that AZT is effective in
ameliorating neurological deficit in these patients.  Preliminary
studies suggest that ddI may also be helpful in children with AIDS. 
Wolters et al. evaluated the effects of ddI on 64 children with
symptomatic HIV infection.  All patients received ddI for at least
6 months.  42/64 patients received ddI for 12 months.  Age-
appropriate general intelligence tests were administered to
children prior to treatment and after 6 and 12 months of ddI. 
Overall there was no change in IQ scores associated with ddI. 
Individually, over the first 6 months of ddI treatment 21% of the
children showed significant improvement in IQ (10% change and 8
points), 9% declined, and 70% remained stable.  There was little
further change in IQ scores after the second 6 months of treatment. 
The investigators suggest a correlation between plasma ddI
concentrations and improved IQ scores.
     Psychostimulants such as methylphenidate hydrochloride
(Ritalin) may be helpful in some patients with characteristic
psychomotor slowing.  In those with agitation or frank mania,
lithium or neuroleptics may be helpful, although therapy should
start with very low doses.

         Other CNS Conditions Complicating HIV Infection

     In addition to the HIV-specific CNS complications of infection
discussed above, patients can develop a number of other
neurological disorders that occur in those with severe systemic
illness.  These include metabolic encephalopathies due to hypoxia,
hepatic insufficiency of disseminated intravascular coagulation. 
Strokes may also complicate the course of AIDS.  Likewise, many
medications may cause disturbances of cognition or alertness. 
Clinical experience suggests that AIDS patients may be particularly
sensitive to the side effects of antipsychotics and other CNS-
active drugs.  Because of this wide array of possible CNS
complications and the importance of clear cognition for the quality
of life, accurate diagnosis is an important part of patient
management.

                           REFERENCES

Tozzi V et al. Effects of zidovudine in 30 patients with mild to
end-stage AIDS dementia complex. AIDS 7:683-92, 1993.

Wolters P et al. The effects of dideoxyinosine (ddI) on the
cognitive functioning of children with HIV infection after 6 and
10 months of treatment. VII Intl Conf AIDS, Florence. Vol 2:
194(W.B.2051), 1991.

Yarchoan R et al. Long term toxicity/activity profile of 2',3'-
dideoxyinosine in AIDS or AIDS-related complex. Lancet 336:526-
29, 1990.

                          OTHER REPORTS

Aronow H et al. The management of the neurological complications
of HIV infection and AIDS. AIDS 2(suppl 1):S151-9, 1988.

Brouwers P et al. Effect of continuous-infusion zidovudine therapy
on neuropsychologic functioning in children with symptomatic human
immunodeficiency virus infection. J Pediatr 117:980-5, 1990.

De Girolami U et al. Neuropathology of the acquired
immunodeficiency syndrome. Arch Pathol Lab Med 114:643-655, 1990.

Gabuzda DH. Neurologic disorders associated with HIV infections.
J Am Acad Dermatol 22:1232-6, 1990.

Heyes MP et al. Quinolinic acid in cerebrospinal fluid and serum
in HIV-1 infection: relationship to clinical and neurological
status. Ann Neurol 29(2):202-9, 1991.

Ingraham L et al. Neuropsychological effects of early HIV-1
infection: assessment and methodology. J Neuropsych & Clin Neurosci
2:174-182, 1990.

Kramer E et al. Brain imaging in acquired immunodeficiency syndrome
dementia complex. Sem Nuc Med 20(4):353-63, 1990.

Lechtenberg R. AIDS in the brain. Int J STD & AIDS 1:311-317, 1990.

Lipton S. Models of neuronal injury in AIDS: another role for the
NMDA receptor? Trends in Neurosci, 15(3):75-79, 1992.

Maj M. Organic mental disorders in HIV-1 infection. AIDS 4:831-
840, 1990.

McArthur J. Low prevalence of neurological and neuropsychological
abnormalities in other-wise healthy HIV-1 infected individuals:
results from the Multicenter AIDS Cohort Study. Ann Neurol 26:601-
611, 1989.

McArthur J. Neurologic manifestations of AIDS. Medicine 66(6):407-
437, 1987.

McGrail M et al. Peptide T studies: neurophysiologic results. VII
Intl Conf AIDS, Florence. Vol 1:194(M.B.2049), 1991.

McIntyre K et al. Pilot study of zidovudine (AZT) and zalcitabine
(ddC) combination in HIV-associated dementia. X Intl Conf AIDS,
Yokohama. Vol 1:201(P.B.0233), 1994.

Perdices M et al. Neuropsychological investigation of patients with
AIDS and ARC. J AIDS 3:555-564, 1990.

Perry S. Organic mental disorders caused by HIV: update on early
diagnosis and treatment. Am J Psych 147(6):696-710, 1990.

Portegies P. Declining incidence of AIDS dementia complex after
introduction of zidovudine treatment. B Med J 299(6703):819-21,
1989.

Pulliam L et al. Human immunodeficiency virus-infected macrophages
produce soluble factors that cause histological and neurochemical
alterations in cultured human brains. J Clin Invest 87(2):503-12,
1991.

Price R et al. The brain in AIDS: central nervous system HIV-1
infection and the AIDS dementia complex. Science 239:586-92, 1988.

Price R et al. Central and peripheral nervous system complications
of HIV-1 infection and AIDS. In: DeVita VT, Hellman S and Rosenberg
SA, eds.,  AIDS: Etiology, Diagnosis, Treatment and Prevention,
Philadelphia: J.B. Lippincott Company, 3rd ed., 1992:237-257.

Satriano J et al. Central nervous system stimulants as symptomatic
treatment for AIDS dementia complex. VII Intl Conf AIDS, Florence.
Vol 1:195(M.B. 2053), 1991.

Sidtis et al. Zidovudine treatment of the AIDS dementia complex:
results of a placebo-controlled trial. Ann Neur 33(4):343-9, 1993.

Simpson DM et al. Neurologic manifestations of HIV infection, Ann
Intern Med 121:769-785, 1994.

Stover E et al. CNS aspects of HIV-1 infection and AIDS in infants
and children: a collaborative research agenda. Ped AIDS and HIV
Infection 1:109-119, 1990.

Wiley C et al. Human Immunodeficiency virus; infection of the
nervous system. Curr Topics Microbiol 160:157-72, 1990.

Worley JM et al. Clinical manifestations of the HIV-1 infection of
the nervous system. In: Stroop W and McKendall R, eds., Handbook
of Neurovirology, Marcel Dekker, 1992.

Worley JM et al. Management of neurologic complications of HIV-1
infection. In: Sande M and Volberding P eds., The Medical
Management of AIDS, Philadelphia: W.B. Saunders Co., 3rd ed,
1992:193-217.

                      Peripheral Neuropathy

     Two types of neuropathy are common in HIV infection.  The
first type, subacute and chronic demyelinating polyneuropathies is
uncommon and occurs relatively early in HIV infection, before
susceptibility to major opportunistic infections.  A second type,
predominantly sensory axonal polyneuropathy, develops as a late
complication in up to 30% of people with AIDS.  The first is felt
to have an autoimmune pathogenesis.  Like subacute (Guillain-Barre
syndrome) or chronic idiopathic demyelinating polyneuropathy
(CIPD), which develops in non-HIV-infected persons, it responds
favorable to plasma exchange, IVIG or glucocorticoids, with the
former being the currently recommended treatment.
     The major morbidity of axonal predominantly-sensory
polyneuropathy relates to pain and to the fact that patients may
have to stop neurotoxic antiretrovirals (i.e. ddI, ddC, or d4T). 
In some cases, painful burning or tingling may be so severe that
the patient avoids shoes or bedclothes.  Treatment is symptomatic;
anecdotal experience suggests AZT is usually ineffective.  The
mainstay is amitriptyline (Elavil) or other tricyclics initiated
at low doses.  For patients with lancinating brief bursts of pain,
phenytoin, carbamazepine, and topical capsaicin can also be tried. 
In a study by Dejard and co-workers in 16 patients with chronic
painful diabetic neuropathy, mexiletine (10 mg/kg/d PO) relieved
the symptoms but not the signs of neuropathy.  Mexiletine is a
congener of lidocaine currently used as a treatment for ventricular
arrhythmias.  A placebo-controlled trial of mexiletine (10 mg/kg/d)
for HIV-related neuropathy is underway at the AIDS Community
Research Consortium in Redwood City, CA.  Preliminary results
indicate 8/10 evaluable patients experienced 50% pain relief on
subjective assessment.  Two did not improve.  One patient was
withdrawn due to disseminated MAC and CMV retinitis.  Improvement
was most likely to occur during the first 3 weeks of treatment, and
symptoms returned within 1 week of cessation of treatment.  Side
effects included transient GI upset, nausea and vomiting.
     ACTG 242 is a placebo-controlled trial comparing mexiletine
and amitriptyline for the treatment of peripheral neuropathy.  As
of January 1996, 117/240 patients have been enrolled.  Beginning
in May 1996, the ACTG will be conducting a trial of nerve growth
factor, which has the potential to stimulate the regeneration of
damaged nerve fibers (ACTG 291).
     ddC, d4T, and ddI induce a similar neuropathy in a dose-
dependent manner (most common with ddC, least with ddI).  Patients
on such drugs must be monitored for the onset of pain or numbness
in the feet.  When these therapies are stopped, the symptoms may
progress for a few weeks, but usually then gradually reverse.
     Chronic AZT therapy can lead to muscle weakness and wasting,
perhaps due to an effect on mitochondrial DNA polymerase.  Serum
creatine kinase is usually elevated and muscle biopsy may show
"ragged red" fibers.  Discontinuation of AZT allows gradual
recovery.
     A multi-center randomized clinical trial (CPCRA 022) is
underway to study acupuncture alone and in combination with
amitriptyline for the relief of the symptoms of peripheral
neuropathy.  260 patients will be enrolled.

                           REFERENCES

Doob PR et al., Role of peptide T in palliation of HIV-1 related
painful peripheral neuropathy. VII Intl Conf AIDS, Florence. Vol
2:225(W.B. 2173), 1991.

Gabuzda DH. Neurologic disorders associated with HIV infections.
J Am Acad Dermatol 22:1232-6, 1990.

Kent G et al. The safety and efficacy of mexiletine in HIV-
associated painful peripheral neuropathy (PPN). VII Intl Conf AIDS,
Florence. Vol 1:199(M.B. 2068), 1991.

Level D et al. Topical capsaicin in the treatment of painful
diabetic neuropathy. Lancet (letter) 324:776, 1991.

McGrail M et al. peptide T studies: neurophysiologic results. VII
Intl Conf AIDS, Florence. Vol 1:194(M.B 2049), 1991.

Parry GJ. Peripheral neuropathies associated with HIV infections.
Ann Neurol 23(suppl):49-53, 1988.

Price R et al. Central and peripheral nervous system complications
of HIV-1 infection and AIDS. In: DeVita VT, Hellman S, and
Rosenberg SA eds., AIDS: Etiology Diagnosis, Treatment and
Prevention, Philadelphia: J.B. Lippincott Company, 3rd ed.,
1992:237-257.
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