Approach to neurodevelopmental and neurologic complications in pediatric HIV infection

Carolyn Butler, MD, Joan Hittelman, PhD, and Sarmistha B. Hauger, MD

From State University of New York Health Science Center, Brooklyn, New York, and the College of Physicians and Surgeons of Columbia University and New York State Department of Health AIDS institute

Neurodevelopmental delays in infants and neuropsycho- logic deficits in older children have been documented in 75% to 90% of children with HIV infection. Common neurologic and/or developmental findings include1"5:

1. Mental and motor delays 2. Loss of previously acquired milestones 3. Acquired microcephaly 4. Progressive bilateral pyramidal tract signs 5. Short-term memory problems and attentional diffi-

culties in older children The neurologic dysfunction in pediatric HIV infection is

believed to represent an active and primary infection of the brain by HIV. In addition, factors such as in utero exposure to drugs, long-term hospitalizations, and chaotic social en- vironments have an effect on neurologic function. HIV in- fection probably occurs early and is persistent. In children with perinatal infection, the clinical signs of neurologic dysfunction may appear as early as 2 months of age and as late as 5 years or longer. Although the clinical picture of progressive encephalopathy most commonly has been noted in children with documented HIV infection and symptom- atic disease, it has been reported to be the initial manifes- tation of AIDS as well. Although the natural history of this finding is not known, longitudinal studies suggest that after a period of normal development, three distinct neurologic- developmental courses can be followed1: rapid progression; steady, subacute progression; or stepwise decline with rel- atively stable periods. In the last category, it has been well documented that some pediatric HIV-infected patients ex- perience an indolent course with variable periods of time during which no new milestones are acquired but without the loss of attained milestones.

Other presentations of neurologic disease may be related to opportunistic infection or central nervous system tumors. Reactivated latent or opportunistic infections and primary lymphoma of the brain are not so common in HIV-infected children as in adults. They do occur, however, and should be watched for. Tuberculosis, toxoplasmosis, and cytomeg-

alovirus are the most common opportunistic infections. Clinical manifestations are varied; patients often have focal neurologic signs, seizures, or chorioretinitis.

Children with HIV infection can develop neurologic ill- ness, as can any other child. Thus clinical suspicion of non- HIV-related neurologic disease should be fully assessed and appropriately managed by accepted pediatric neurology standards. In addition, many of the children at risk for HIV infection are also at risk for developmental delays and def- icits by virtue of the fact that they have been exposed to drugs in utero and are growing up in deprived social envi- ronments.

I FTA-ABS HIV VDRL

Fluorescent treponemal antibody absorption test [ Human immunodeficiency virus [ Venereal Disease Research Laboratories (test) I

S T A N D A R D D E V E L O P M E N T A L / P S Y C H O L O G I C E V A L U A T I O N

To identify developmental delays as early as possible, HIV-infected children need to be assessed developmentally at regular intervals, at least once during the first year of life. Most children who will have delays during the first year will do so by 6 to 9 months of age; therefore an evaluation scheduled at this time will be effective in identifying chil- dren with delay. To determine baseline rates, children should be assessed on initial encounter or at 6 to 9 months of age. They should be reevaluated every 6 months there- after until 2 years of age, after which they should be seen yearly. At any time, if the pediatrician or the parent or caretaker sees changes or a decline in the child's function- ing, the child should be reevaluated expeditiously.

Appropriate evaluation in these children requires assess- ment of mental development, motor development, language, attention and short-term memory skills, and social and emotional functioning.

The tools for age-specific developmental evaluation are

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S 4 2 Butler, Hittelman, and Hauger The Journal of Pediatrics July 1991

Tab le [. Tools for age-specific developmental evaluation

Developmental scales for children younger than 30 months of age Bayley Scales of Infant Development Cattell Infant Intelligence Scale Gesell Developmental Schedules

Tests for children older than 30 months of age Standardized intelligence scales

Stanford-Binet Intelligence Scale Wechsler Preschool and Primary Scale of Intelligence Wechsler Intelligence Scale for Children--Revised McCarthy Scales of Children's Abilities Kaufman Assessment Battery for Children

Tests of both fine and gross motor development Peabody Developmental Motor Scales and Purdue Pegboard (for 3- and 4-year old children use the

Wilson Norms) Tests of perceptual motor skills

Beery Development Test of Visual-Motor Integration Bender Visual Motor Gestalt Test

Standardized questionnaires and clinical instruments for chil- dren aged 2 years and older Conners Parent and Teacher Rating Scales Aehenbach Child Behavior Checklist Matching Familiar Figures Test The Gordon Diagnostic System

listed in Table I. Before 30 months of age, children should be assessed on an infant developmental scale, which pro- vides separate scores for mental and motor development. After 30 months of age, children should be assessed on an age-appropriate standardized intelligence scale, and should also be evaluated for fine and gross motor development and tests of perceptual motor skills. In addition, children older than 2 years should be evaluated for attentional difficulties by use of an age-appropriate standardized questionnaire or

clinical instrument. Because of the poor discriminative ability of tests for

children who are between 30 and 40 months of age, espe- cially for the purpose of identifying children with disabili- ties, caution must prevail in interpreting test scores in this age group. Whenever a delay is noted, children should be referred for a neurologic consult and, if needed, further evaluation and appropriate referral (see below). All test scores should be corrected for gestational age until the age of 2 years, when the child is eligible for early intervention programs without corrected scores.

N E U R O L O G I C E V A L U A T I O N

A neurologic consultation should be requested for infants and children by the primary care physician or the develop- mental psychologist who has noted any abnormal neuro- logic signs and symptoms. The primary care physician should pay special attention to the appearance of develop-

Table II. Laboratory tests* for patients with focal neurologic examinations or progressive neurologic dysfunction

Complete blood cell count, VDRL test (if not previously done)

Cerebrospinal fluid examination for protein, glucose, cells, VDRL test, cultures (mycobacterial, bacterial, fungal, and viral such as herpes simplex virus, enterovirus, and HIV, if available)

Ophthalmologic examination for presence of rctinitis Precontrast CT scan (postcontrast CT or magnetic reso-

nance imaging should be done in those patients who have evidence of cortical lesions or obstructive hydrocephalus on the precontrast scans)

Possible brain biopsy for tissue diagnosis

*Testing should be done as deemed appropriate by the physician.

mental delay or loss of previously acquired milestones, mi- crocephaly, abnormal tone, focal findings, and delay of speech and language development. The purpose of a neuro- logic evaluation is to identify and document the abnormal neurologic findings correctly, identify the presence or absence of non-HIV-related neurologic illness, and, when possible, to categorize the neurologic course that the disease

seems to be following (e.g., rapidly progressive, subacute, static).

Patients with non-HIV-related neurologic illness should be evaluated according to standard pediatric neurology guidelines. Those patients who manifest focal and/or pro- gressive neurologic dysfunction may undergo the following laboratory testing, as deemed appropriate (Table II): (1) complete blood cell count, VDRL test (if not previously done); (2) cerebrospinal fluid examination for protein, glu- cose, cells, VDRL test, cultures (mycobacterial, bacterial, fungal, and viral [e.g., herpes simplex virus, enterovirus, and HIV, if available]); (3) ophthalmologic examination for presence of retinitis; (4) precontrast computed tomog- raphy (postcontrast CT or magnetic resonance imaging should be done in those patients who show evidence of cor- tical lesions or obstructive hydrocephalus on the precontrast scans); (5) possible brain biopsy for tissue diagnosis.

Correlation and interpretation of the neurologic exami- nation and diagnostic studies should be discussed with the primary care physician. The necessity and timing of repeat evaluations should be individually based, depending on the severity of the neurologic involvement at the time of the initial assessment, the value of repeat neurologic examina- tions in terms of available therapeutic intervention and prognostic measures, and the appearance of new neurologic symptoms.

Repeat laboratory tests should be done as clinically indi- cated. Patients with seizures should have electroencephalo-

Volume 119 Approach to neurodevelopmental and neurologic complications S 4 3 Number 1, Part 2

graphic testing in addition to CT and lumbar puncture. Anticonvulsants should be prescribed if indicated. Patients who are found to have a developmental delay but no other neurologic findings should be reassessed in 6 months. If at that time there is no change in the neurologic evaluation, no further evaluations are needed unless a change in the neu- rologic status is noted by the primary care physician. Ap- propriate referrals to early intervention programs should be

made.

D E V E L O P M E N T A L - P S Y C H O L O G I C A S S E S S M E N T S A N D R E F E R R A L S

Children with developmental delays may require further developmental assessment to clarify the types of disabilities or be referred to other services in addition to the neurologic consult. Children with motor delays, a common sequelae of HIV infection, may require additional developmental test- ing to assess cognitive functioning independent of motor status. For young children these assessments may be impossible because of the limitations of diagnostic tests. Diagnosis of cognitive functioning must be considered ten- tative or inconclusive. Parents need to be counseled accord- ingly.

Children aged 2 years and older can be assessed on psy-

chometric tests that minimize the impact of motor deficits on the findings. Children aged 2 years and older with hear- ing, language, and perceptual-motor deficits and those with academic difficulties in school may be evaluated with the tests listed in Table III. Children with language delays should be referred to an audiology specialist to rule out hearing impairment and for a speech and language evalu- ation. Children with a perceptual motor deficit should be referred to an ophthalmologist and undergo a detailed oc- cupational therapy evaluation.

Because attentional deficit hyperactivity disorders are common in school-aged HIV-infected children, they may require appropriate intervention and therapy.

If a deficit or delay is recognized, the child is entitled to enrollment in an appropriate early intervention program if younger than 3 years of age. Older children, 3 to 5 years of age, should be referred to their school district committee for preschool special education. Rehabilitation services can be useful for children with a specific deficit.

For the child 5 years and older with a delay or deficit, the psychologist should discuss with the parent or guardian the advisability of a Committee for Special Education referral for appropriate special educational services at the school. In New York City, the psychologist and parent should consider using the Physicians Advisory Services for Children with HIV Infection (School Review Panel) for assessing appro- priate classroom placement.

Table I l l , Tests for evaluation of motor- and

hearing-impaired children aged 2 years and older

Tests to Determine Cognitive Functioning in a Motor-Impaired Child The Leiter International Performance Scale (>2 years) Peabody Picture Vocabulary Test (>30 months) The Raven Progressive Matrices (3~/2 to 11 years) The Motor-free Visual Perception Test (5 to 7 years)

Tests for children with documented or suspected language de- lays Peabody Picture Vocabulary Test The Token Test Test of Early Language Development Test of Language Development The Carrow Auditor--Visual Abilities Test

Psychoeducational tests for children with academic difficulties The Woodcock-Johnson Psychoeducational Battery The Detroit Tests of Learning Aptitude

I N F E C T I O N S OF C E N T R A L N E R V O U S S Y S T E M

The true prevalence of central nervous system infections in children with HIV infection is not known; however, it is thought that such infections are much less frequent in chil- dren than in adults. The neurologic impairment most frequently seen in children may be attributed primarily to

HIV infection itself rather than to opportunistic infection or central nervous system tumors. However, several distinct infections need to be considered when a child is being eval- uated for neurologic dysfunction. 6

Toxoplasma gondii. The clinical presentation of cerebral toxoplasmosis is variable, and may include focal neurologic findings of recent onset, generalized seizures, or subtle dysfunction.V, s Serologic diagnosis of toxoplasmosis infec- tion may not be adequate in patients with HIV infection. Although patients with serum antibody are at high risk for toxoplasmosis, the greatest value of a negative IgG test is that it virtually rules out the diagnosis. Radiographic imaging of the brain usually reveals one or more ring- enhancing mass lesions. Although these lesions are charac- teristic of toxoplasmosis, they are not pathognomonic. Therefore, various other etiologic agents should be ruled out via lumbar puncture and blood testing, unless contraindi- cated. Definitive diagnosis can be made only with histologic confirmation from brain biopsy tissue. Current standard therapy allows for presumptive antibiotic therapy, followed by life-long medication if favorable response occurs. In those patients in whom no improvement is documented, further invasive diagnostic procedures may be indicated to rule out other opportunistic infections, brain abscess, or tu- mor.

Diagnosis. A presumptive diagnosis of toxoplasmosis can be based on (1) recent onset of focal neurologic abnormal-

S 4 4 Butler, Hittelman, and Hauger The Journal of Pediatrics July 1991

ity consistent with an intracranial lesion, (2) radiographic imaging studies indicative of ring-enhancing mass single or multiple lesions, (3) lumbar puncture excluding meningitis or encephalitis caused by various agents, such as crypto- coccus, bacteria, or herpesvirus (lumbar puncture should be done if not contraindicated), (4) elevated serum antibody to Toxoplasma, and/or (5) favorable response to antimicro- bial therapy for toxoplasmosis.

Definitive diagnosis requires the identification of the or- ganism on histologic examination of brain tissue. A defin- itive diagnosis does not need to be made in a patient with documented HIV infection who meets the presumptive cri- teria and who is responsive to therapy for toxoplasmosis that has already been initiated. Patients who are being treated empirically should be frequently reassessed for clinical de- terioration and the need for further diagnostic procedures. In addition, a definitive diagnosis is not required for a pa- tient who is either unable to tolerate or whose guardian re- fuses the diagnostic procedure. If a definitive diagnostic procedure is not performed, the reason should be noted in the medical record.

Therapy. Neurologic consultation should be obtained for patients with toxoplasmosis. Consultants should be involved especially with patients who fail to improve with empiric therapy and in whom further invasive diagnostic procedures are contemplated.

The standard regimen of therapy consists of sulfonamide drugs (sulfadiazine, trisulfapyrimidines at 100 to 150 mg/ kg/day divided in two doses) and pyrimethamine (loading dose 2 mg/kg/day divided in two doses for 2 days, followed by a maintenance dose of 1 mg/kg/day divided in two doses delivered orally). Folinic acid (1 to 2 mg/day in infants and 5 to 10 mg/day in older children, delivered orally) should be given to patients receiving pyrimethamine.

Some authorities follow the above regimen with alter- nating 3- to 4-week cycles of spiramycin at 100 mg/kg/day divided in two oral doses. This drug can be acquired from the Food and Drug Administration.

Pyrimethamine alone or in combination with clindamy- cin has been used as alternative therapies; the effectiveness is unproved in pediatric patients. Acceptable reasons for using alternative regimens include participation in a re- search protocol and inability to tolerate or failure to respond to standard therapeutic regimens.

Because the risk of relapse is high, treatment usually is maintained for life. Close monitoring is required to prevent adverse drug reactions, if therapy is stopped the reason should be indicated in the medical record.

Patient management. Major toxicities may occur during therapy or after the drug has been discontinued. Sulfona- mides can cause skin rashes, hematuria, crystalluria, neu-

tropenia, and anemia. Pyrimethamines are associated with bone marrow suppression and also act as folic acid antag- onists. To detect possible toxic effects, complete blood cell counts, platelet counts, and liver function tests should be performed one to two times per week while the patient is in the hospital. For outpatients, the above tests may be done once per month.

Cryptococcus neoformans infection. Cryptococcus neo- formans infection is common in HIV-infected adults) Symptoms may include headache, fever, meningismus, fo- cal findings, or subtle neurologic dysfunction. Cryptococcal meningitis should be considered in any HIV-infected pa- tient with new neurologic findings, and ruled out by lumbar puncture. Localized extraneural lesions may also occur in the liver, lung, and other organs. Diagnosis is confirmed by identification and isolation of the organism from normally sterile tissue. Special staining (India ink) and cerebrospinal fluid antigen testing are useful adjuncts for diagnosis and for following response to therapy.

Diagnosis. There are no indications for presumptive di- agnosis; definitive diagnosis is indicated for therapy of this illness. Definitive diagnosis requires the isolation of C. neo- formans by culture and its identification by India ink stain or by histologic examination of tissue specimens. Detection of cryptococcal capsular polysaccharide (cryptococcal an- tigen) correlates well with culture results, although several cultures may be needed to confirm the diagnosis. There are no exceptions to the need for a definitive diagnosis.

Therapy. Therapy should be initiated if the presence of the organism is identified by stain or by increased levels of cryptococcal antigen. The physician should not await cul- ture results before therapy initiation. Therapy consists of amphotericin B at 0.5 to 1.0 mg/kg/day (higher dose pre- ferred) or amphotericin B plus 5-fiuorocytosine at 75 to 100 mg/kg/day in four divided doses,

Alternative therapies are intrathecal or intraventicular amphotericin B, intravenous miconazole, or fluconazole. The efficacy of these therapies in the pediatric population is unknown. Acceptable reasons for using alternative regi- mens are participation in a research protocol and an inabil- ity to tolerate or failure to respond to standard therapeutic regimens.

Because patients with HIV infection cannot be cured of this infection, most should be maintained with therapy for life, with weekly infusions. If such is not the case, the rea- son should be documented in the medical record.

Patient management. The patient's neurologic status should be monitored daily and documented in the medical record, Lumbar puncture should be repeated. Cryptocoecal antigen levels should be monitored, and should decrease with successful therapy.

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Antifungal drugs are associated with a number of toxic- ities. Toxicities for amphotericin B include renal toxicity, hypokalemia, liver and bone marrow dysfunction, fevers, hypotension, and chills. Treatment with 5-fluorocytosine can result in marrow dysfunction. Renal excretion also may be affected; serum levels of this drug may rise when simul- taneously administered with amphotericin B.

In patients who are being given amphotericin B, complete blood cell counts and electrolyte, BUN, and creatinine val- ues should be determined and liver function tests done at least once weekly. In those receiving 5-fluorocytosine, com- plete blood cell and platelet counts and creatinine tests should be done. Serum drug levels should be monitored, if available.

A patient may be discharged when neurologic status is stable and adequate arrangements have been made to receive therapy either at home or at the hospital on a weekly basis. These arrangements should be documented in the medical record.

Bacterial meningitis. Various bacteria may cause menin- gitis in the HIV-infected child. Patients may have nuchal rigidity, fever, headache, and focal or generalized signs of neurologie dysfunction. The encapsulated organisms, Streptococcus pneumoniae and Haemophilus influenzae type b, are of special importance in causing such central nervous system infections. A lumbar puncture is needed to make a correct diagnosis; definitive diagnosis is made only when the organism is isolated and identified from cere- brospinal fluid or from blood culture.

Diagnosis. A presumptive diagnosis can be made only in cases with a consistent clinical presentation and in which the patient is awaiting lumbar puncture or lumbar puncture is contraindicated. A definitive diagnosis is made only when the organism is isolated and identified from cerebrospinal fluid or from blood culture.

Therapy. Antimicrobial therapy should be aimed at the most common etiologic agents mentioned above. Duration of therapy is usually from 10 to 14 days.

Corticosteroids may be used in conjunction with antibi- otics for initial therapy of H. influenzae type b and pneu- mococcal meningitis, because some authorities have shown that they may have a beneficial effect in preventing hearing loss.l~ 11 Their use in meningitis caused by other organisms is unproven.

Patient management. The patient's neurologic status should be monitored daily and documented in the medical record. Lumbar puncture should be repeated if the diagno- sis is in doubt and to document sterility. Laboratory mon- itoring will depend on the various antibiotics chosen. The patient should receive hearing tests (audiogram, auditory evoked responses) prior to discharge. Hearing should be

monitored after therapy. A patient may be discharged when neurologic status is stable and adequate arrangements have been made for follow-up care. These arrangements should be documented in the medical record.

Syphilis (Trepnnema pallidum). HIV infection may alter the course of Treponema pallidum infections. In pediatric patients, two situations may occur: presentation of the in- fection acquired perinatally (congenital syphilis) or new acquisition of the infection.

Clinical symptoms are protean. A diagnosis usually is es- tablished by serologic diagnosis (nontreponemal and treponemal tests) or by identification of the organism by dark-field microscopy. In the adult population, T. pallidum infection has been reported in which these tests yielded negative results. The actual frequency of this occurrence is not known.

Diagnosis. A presumptive diagnosis may be made when the clinical symptoms are consistent with congenital syph- ilis, primary syphilis (genital, oral, or rectal chancres), sec- ondary syphilis (characteristic rash), or neurosyphilis (may or may not be symptomatic). Neurosyphilis should be con- sidered in the differential diagnosis of neurologic dysfunc- tion in an HIV-infected patient, regardless of serologic ev- idence of syphilis.

In addition to these tests, definitive diagnosis also requires a positive nontreponemal (VDRL) and treponemal (FTA- ABS) test results. VDRL test results may be negative if the infection is early (30% of primary cases). The organism may also be identified by dark-field microscopy from lesions. In cases of neurosyphilis a cerebrospinal fluid examination is mandatory. Cerebrospinal fluid may or may not reveal pleocytosis, high protein levels, and positive VDRL; how- ever, if these findings are present, the diagnosis is more se- cure. In all patients with congenital syphilis born to a mother with HIV eoinfeetion, cerebrospinal fluid should be examined.

Therapy. The following guidelines for therapy are ex- cerpted from current CDC recommendations. 12 All chil- dren with congenital syphilis should be treated for the pres- ence of neurosyphilis with a 10- to 14-day course of intra- venous aqueous crystalline penicillin G at 100,000 to 150,000 U/kg/day divided in two doses or intramuscular procaine penicillin 50,000 U/kg/day. After the newborn period, an older child should receive 200,000 to 300,000 U/kg/day of aqueous penicillin G administered as 50,000 U/kg every 4 to 6 hours. Treatment for neurosyphilis is the same as for congenital syphilis.

For patients with early stages of syphilis, some authori- ties have recommended a cerebrospinal fluid examination and therapy for neurosyphilis in HIV coinfected patients. The CDC recommends no change in standard therapy. In

S 4 6 Butler, Hittelman, and Hauger The Journal of Pediatrics July 1991

a child, this therapy would be 50,000 U/kg /day in a single intramuscular injection up to the maximum adult dose of 2.4 million units of benzathine penicillin G.

Patient management. All patients should be monitored with quantitative nontreponemal antibody tests at 1, 2, 3, 6, and 12 months after therapy and at 3-month intervals until a two-dilution drop is seen. If such a decrease does not oc- cur by 6 months or if a sustained two-dilution or greater in- crease occurs, the patient should be reevaluated for treat- ment failure or reinfection. Cerebrospinal fluid should be examined in such cases. Patients treated for neurosyphilis should have cerebrospinal fluid reexamined every 6 months until normal, with close neurologic follow-up.

Viral infections. Several viruses can cause neurologic dysfunction in HIV-infected children. Members of the herpesvirus family, which includes cytomegalovirus, herpes- virus, and varicella-zoster virus, may cause encephalitis,

meningitis, or retinitis. Diagnosis is usually made by culture or tissue examination. Cerebrospinal fluid examination may show pleocytosis with elevated protein levels. Radiographic imaging and electroencephalograms are often helpful in lo- calizing lesions in herpes encephalitis. An eye examination should be done in all HIV-infected children when these agents are in the differential diagnosis of a neurologic finding.

Therapy with acyclovir is recommended for therapy of herpesvirus and varicella-zoster virus infections; therapy with gancMovir has shown little promise in treatment of cyt0megalovirus encephalitis, but has been effective in treatment of cytomegalovirus retinitis. The dosage of acy-

clovir for herpesvirus infection in the immunocompromised host is 750 mg/m2/day divided in three doses and admin- istered intravenously over 1 hour every 8 hours for 7 days. The dosage of acyclovir for varicella-zoster virus infections is 1500 mg/m2/day divided in three doses administered in- travenously Over 1 hour every 8 hours for 7 days.

Progressive multifocal leukoencephalopathy is a chronic demyelinating disease related to central nervous system in- fection with JC virus. The only specific method of diagnosis is by tissue biopsy from which viral particles may be iden-

tified. There is no known effective therapy.

Mycobacteria. Both Mycobacterium tuberculosis and atypical mycobacteria may cause central nervous system infection. Patients may present with meningitis or with mass lesions of the brain. Lumbar puncture may reveal high pro-

tein, low glucose, and a lymphocytic pleocytosis. A pre- sumptive diagnosis may be made if the patient has consis- tent clinical findings and has a PPD reaction. Because many patients with HIV infection are anergic, diagnosis often de- pends on recovering the organism by culture from normally sterile tissue. Definitive diagnosis of mass lesions may be made only by tissue diagnosis. For complete discussion of therapy of tuberculosis and atypical mycobacteria, refer to the article on pulmonary conditions.

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