Note from the National Guideline Clearinghouse: This guideline references a drug(s) for which important revised regulatory and/or warning information has been released.

Baseline Neurologic Evaluation

At routine visits, the primary care physician should be particularly vigilant for the appearance of the following conditions:

• Developmental delay or loss of previously acquired milestones
• Microcephaly/deceleration in head growth
• Abnormal tone and reflexes (especially clonus and cross adductor reflex)
• Focal findings
• Speech and language delay

A baseline neurological consultation should be obtained for all children with developmental delay or neurological signs and symptoms (e.g., focal weakness, seizures, altered mental status, or microcephaly) and for any human immunodeficiency virus (HIV)-infected child with a high viral load (>100,000 copies/mL) at baseline.

The neurologic specialist should discuss correlation and interpretation of neurologic examination and diagnostic studies with the primary care physician.

A routine ophthalmologic evaluation, including a yearly retinal examination, should be performed in all HIV-infected children. Clinicians should be aware that HIV-infected children with significant immune suppression are at risk for ocular infections, including cytomegalovirus (CMV) retinitis, toxoplasmosis, and herpes infections.

The necessity and timing of further evaluations should be determined by the following:

• Severity of neurologic involvement at the time of initial assessment
• Value of repeated neurologic examinations in terms of available therapeutic intervention and prognostic measures
• Appearance of new neurologic symptoms

Children with well-controlled HIV disease and isolated developmental delays without other neurologic findings should be reassessed 3 months after detection of the delay. If there is no change in neurologic examination and development is proceeding, follow-up should occur according to routine neurological care practice.

Specific Complications

HIV Encephalopathy

HIV should be considered in any child with progressive neurological deterioration who has not been previously tested for HIV or who might have it despite a previous negative test.

Treatment

HIV encephalopathy should be treated with the same antiretroviral (ARV) agents used to treat symptomatic HIV disease, with the goal of achieving low to undetectable viral load and reversal of immune suppression.

HIV-infected children with neurologic impairments and developmental delays should be referred to early intervention programs.

Infections of the Central Nervous System

A pediatric HIV Specialist should be consulted whenever a central nervous system infection is suspected.

Various etiologic agents should be excluded via lumbar puncture and cerebrospinal fluid (CSF) testing, unless contraindicated (see Table 1 in the original guideline document).

Cryptococcus neoformans

Diagnosis

Isolation of Cryptococcus neoformans by culture, serum, and CSF cryptococcal antigen test, or histologic examination of tissue specimens should be performed to obtain a definitive diagnosis.

Cryptococcal meningitis should be considered in any HIV-infected patient who has new neurologic findings and should be excluded by lumbar puncture.

Treatment

Treatment for cryptococcosis should be initiated if the organism is identified by stain or by increased levels of cryptococcal antigen (see standard and alternative regimens below). Waiting for culture results is not advisable before initiating therapy because it may take days or weeks to grow.

Cryptococcal meningitis should be treated with amphotericin B (with or without flucytosine) or fluconazole depending on severity of disease and immune suppression (see below for standard and alternative drug regimens for treatment of cryptococcosis).

Therapeutic lumbar punctures should be used to control symptoms of increased intracranial pressure secondary to communicating hydrocephalus caused by cryptococcal meningitis.

Because HIV-infected patients cannot be cured of cryptococcosis, most patients should be maintained on lifelong chronic therapy.

Standard Regimen for Cryptococcosis

Amphotericin B intravenously (0.7-1.0 mg/kg per day of the standard preparation or liposomal amphotericin 3-5 mg/kg per day) in one daily dose for 2 weeks or until clinically stable

with or without

5-fluorocytosine (100-150 mg/kg per day orally [po]), divided into four daily doses for 2 weeks or until clinically stable,

then

Fluconazole (10-20 mg/kg intravenously [IV] or po for 1 day up to 800 mg, then 5-10 mg/kg per day up to 400 mg indefinitely)

Alternative Regimens for Cryptococcosis

For very mild disease:

Fluconazole alone for 6 to 10 weeks

For very severe disease or in severely immune deficient children:

Amphotericin B + 5-fluorocytosine for 6 weeks prior to beginning fluconazole suppression

Clinical and Laboratory Monitoring

The neurologic status of patients with cryptococcosis should be monitored daily.

Lumbar puncture should be repeated within 1 week (sooner if clinically indicated), and cryptococcal antigen level should be monitored. Antigen level should decrease with successful therapy. Opening pressure should be measured at each lumbar puncture.

For patients receiving amphotericin B, complete blood count and tests for electrolytes, blood urea nitrogen (BUN), creatinine, and liver function should be performed at least once weekly to monitor for toxicities and more frequently at the beginning of therapy (see Table 3 in the original guideline document).

For patients receiving 5-fluorocytosine, complete blood count, platelet count, creatinine, and serum liver enzyme levels should be obtained. Serum drug levels should be monitored, if available (see Table 2 in the original guideline document).

A patient with cryptococcosis may be discharged from the hospital when neurologic status, especially intracranial pressure, is stable and adequate arrangements have been made for therapy at home.

After successful therapy for cryptococcal meningitis, the patient should be maintained on lifelong suppressive therapy. Suppressive therapy regimens include daily oral fluconazole or weekly intravenous amphotericin.

Toxoplasma gondii

Diagnosis

If Toxoplasma serology is positive, a child should be treated empirically with pyrimethamine/sulfa for 2 weeks before considering more invasive diagnostic procedures.

If Toxoplasma serology is negative or if CSF Epstein-Barr virus polymerase chain reaction (EBV PCR) is positive, invasive diagnostic procedures, such as a brain biopsy, should be considered to determine the diagnosis. A positive CSF EBV PCR indicates the likelihood of central nervous system (CNS) lymphoma.

If a favorable response to empiric treatment is documented, CNS toxoplasmosis is the presumptive diagnosis. In cases in which no improvement is documented, further invasive diagnostic procedures may be indicated to exclude other opportunistic infections, brain abscess, or tumor.

Treatment

Toxoplasma encephalitis should be treated with one of the regimens listed below for 4 to 6 weeks:

Standard Regimen

Sulfadiazine 120 to 200 mg/kg/day divided into four doses

and

Pyrimethamine [loading dosage of 2 mg/kg per day (max, 100 mg) divided into two doses for 3 days, followed by maintenance dosage of 1 mg/kg per day (max, 25 mg), delivered orally]

and

Folinic acid (1 to 2 mg per day in infants and 5 to 10 mg every 3 days in older children, delivered orally) for patients receiving pyrimethamine

Alternative Regimen*

Clindamycin (40 to 60 mg/kg/day IV divided into 4 doses) plus pyrimethamine plus folinic acid

*The effectiveness of the alternative regimen is unproven in pediatric patients. Acceptable reasons for using the alternative regimen are patient participation in a research protocol and patient inability to tolerate or failure to respond to the standard therapeutic regimen.

Laboratory Monitoring

Close monitoring of patients receiving treatment for toxoplasmosis, including complete blood count (CBC) and serum liver enzymes, is required to detect adverse drug reactions (see Table 5 in the original guideline document for major toxicities that may occur with treatment).

Herpes Virus

Herpes Simplex Virus (HSV)

HSV encephalitis should be treated with acyclovir. Beyond the neonatal period, the dosage is 30 mg/kg/day IV divided into three doses administered every 8 hours for 14 to 21 days. The neonatal dose is 60 mg/kg/day IV divided into three doses administered every 8 hours for 14 to 21 days.

Varicella Zoster Virus

Acyclovir at 1500 mg/m²/day IV divided into three doses administered every 8 hours for 7 to 10 days (or 30 mg/kg/day divided every 8h) should be used to treat varicella zoster virus infection.

Cytomegalovirus

Cytomegalovirus infection may be treated with intravenous ganciclovir (10 mg/kg per day divided into two doses every 12 hours), and maintenance therapy is needed until immune restoration occurs.

For ganciclovir-resistant retinitis, foscarnet should be used (limited data in pediatrics).

Routine retinal examinations should be performed every 6 months in children with severe immunosuppression.

JC Virus

Clinicians should recommend highly active antiretroviral therapy (HAART) for patients with progressive multifocal leukoencephalopathy (PML).

Bacterial Meningitis

Diagnosis

Definitive diagnosis of bacterial meningitis is made by isolating and identifying the organism from CSF or blood culture. Lumbar puncture is needed to make a correct diagnosis.

Treatment

Antimicrobial therapy directed at the most common etiological agents (i.e., Streptococcus pneumoniae, Haemophilus influenzae) should be used to treat bacterial meningitis. Both vancomycin and ceftriaxone at meningitic doses should be used in the empiric treatment of community-acquired bacterial meningitis. Antibiotic choice may be modified once an organism is identified and antimicrobial sensitivities are available. Duration of therapy is usually 10 to 14 days.

Clinical and Laboratory Monitoring

Neurologic status of patients with bacterial meningitis should be monitored daily.

If diagnosis is in doubt, lumbar puncture should be repeated to diagnose bacterial meningitis and to document sterility.

Hearing tests (audiogram, auditory evoked responses) should be performed in patients with bacterial meningitis before discharge and at 6-month follow-up visit after discharge.

Patients with bacterial meningitis may be discharged from the hospital when neurologic status is stable and adequate arrangements have been made for follow-up.

Syphilis (Treponema pallidum)

Diagnosis

Neurosyphilis should be considered in the differential diagnosis of neurologic dysfunction in an HIV-infected patient, regardless of serologic evidence.

Definitive diagnosis can be made by positive non-treponemal (Venereal Disease Research Laboratory [VDRL], Rapid Plasma Reagin [RPR]) and fluorescent treponemal antibody-absorption (FTA-ABS) tests; however, a VDRL may be negative if the infection is early. The organism may be identified by dark-field microscopy from lesions.

A CSF examination (opening pressure, cell count, total protein, glucose, and VDRL) is strongly recommended for all children and adolescents co-infected with HIV and syphilis.

Clinicians should perform a CSF examination in all infants with congenital syphilis born to mothers with HIV co-infection.

Treatment

The following are available:

• Neurologic complications in HIV-infected children and adolescents. Tables and recommendations. New York (NY): New York State Department of Health; 2003 Mar. 11 p.
• HIV clinical practice guidelines. New York (NY): New York State Department of Health; 2003. 36 p.

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