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A. Characteristics

  1. Occurs in majority of patients with AIDS
  2. Focal Diseases
    1. Toxoplasmosis
    2. Primary CNS Lymphoma
    3. Progressive Multifocal Leukoencephalopathy (PML)
    4. Uncommon: abscess, tuberculoma, other neoplasms
  3. Diffuse Infections
    1. Meningitis - cryptococcal, bacterial, syphilis
    2. Encephalitis - CMV, HSV, others
  4. Diffuse Disease
    1. Autoimmune - demyelinating disease (multiple-sclerosis like), vasculitic
    2. AIDS Dementia Complex [2]
  5. Peripheral Nervous System Disease
    1. Inflammatory Neuropathy
    2. Myopathy
    3. Predominantly (Painful) Sensory Neuropathy
    4. Vacuolar Myopathy

B. CNS Infection

  1. Toxoplasmosis
  2. Cryptococcosis
  3. CMV - encephalitis, retinitis, cauda equina syndrome
  4. CNS Lymphoma (most associated with EBV Infection)
  5. PML - JC Virus infection
  6. Syphilis

C. Cryptococcus Infection

  1. Many HIV+ patients present with cryptococcal meningitis (meningoencephalitis)
  2. Symptoms
    1. Headache and Fever in >65%
    2. Nausea and Vomiting 42%
    3. Altered mentation
  3. Diagnosis
    1. Serum cryptococcal antigen
    2. CSF analysis for cryptococcal antigen (ELISA)
  4. Therapy
    1. Initially, amphotericin B iv is used at 0.5-0.7mg/kg/d for 2-4 weeks
    2. Nearly equal efficacy with decreased side effects using oral Fluconazole (100mg bid)
    3. Maintenance therapy with Fluconazole 100mg qd more effective than amphotericin

D. Toxoplasmosis

  1. Obligate intracellular protozoan
  2. Causes necrotic / inflammatory abscess formation
  3. Multifocal, may affect brainstem, 75% of lesions in cerebral hemispheres
  4. AIDS Defining illness in 3% of HIV+ patients
  5. Occurs overall in ~15% of all HIV+ patients
  6. Presentation
    1. Fever (~35%)
    2. Change in Mental Status
    3. Seizures
    4. Focal Neurologic Signs
  7. Diagnosis
    1. Positive toxoplasma serology
    2. Ring enhancing lesions on CT scans (usually multiple)
    3. Specific MRI findings
  8. Toxoplasmosis Therapy
    1. Pyrimethamine 200mg loading dose; then 75mg po qd
    2. Given with Leukovorin® (Folinic Acid) 5mg qd
    3. Sulfadiazine 1.5gm q6 hours
    4. If not tolerated, replace Sulfadiazine with clindamycin 900mg q6 hours
  9. Prophylaxis Therapy
    1. Lifelong
    2. Pyrimethamine 25mg daily
    3. Clindamycin 150-300mg q6-12 hours
    4. TMP/SMX (Bactrim®, Septra®) probably has adequate coverage (Bactrim DS 1 po qd)
  10. Toxoplasmosis is also important in organ transplantation [18]

E. Cytomegalovirus (CMV) Disease

  1. Typically occurs with CD4 counts <50-100/µL
  2. Disease Classification
    1. Retinopathy is most common (see below)
    2. Encephalitis - second most common cause after HIV encephalopathy
    3. Cauda equina syndrome
    4. Also causes gastrointestinal and pulmonary infections
    5. Major problem in organ transplantation, particularly liver transplants [18]
  3. Cauda Equina Syndrome
    1. CD4+ T cell count usually <50µL
    2. Caused by CMV
    3. Severe and rapid loss of lower extremity strength ± sensation
    4. Poor response to single agent anti-CMV Therapy
    5. Ganciclovir (DHPG) + Foscarnet may be used (poorly tolerated)
  4. CMV Encephalitis [3]
    1. Majority of cases occur in patients with advanced AIDS; <5% are immunocompetent
    2. In advanced HIV, pathology shows ventriculoencephalitis, a unique entity
    3. Over 50% of patients also have CMV retinitis
    4. Lethargy and confusion are most common symptoms
    5. Average CD4 count at presentation was 20/µL
    6. Spinal fluid analysis should include a polymerase chain reaction for CMV DNA
    7. Combination ganciclovir and foscarnet therapy is recommended but unproved
  5. Anti-CMV Agents
    1. Ganciclovir
    2. Foscarnet
    3. Cidofovir

F. CMV Retinopathy [4]

  1. Affects about 20% of all AIDS patients (most common intraocular infection in HIV)
  2. CD4<100/µL in majority of cases
    1. CD4>200/µL has been reported and may increase with antiretroviral therapy [5]
    2. Screening for asymptomatic disease recommended q3-6 months with CD4<100/µL [6]
  3. Presentation
    1. White granular lesions with associated hemorrhage; "pizza-pie fundus"
    2. Retinal detachment often requires silicone oil tamponade to repair
    3. Will progress to blindness if left untreated
  4. Treatment Overview
    1. Prophylaxis with oral ganciclovir has shown efficacy [7]
    2. Therapy with Foscarnet or Ganciclovir initially (combinations being investigated)
    3. Maintenance therapy, usually poorly tolerated, is always required in AIDS patients
    4. Maintenance therapy is lifelong; relapse frequent, requiring re-induction
    5. Oral ganciclovir, intravenous agents, or vitreous implants are used for maintenance
    6. Cidofovir (Vistide®) is a new nucleoside analog highly active against CMV
  5. Treatment Induction [8]
    1. Ganciclovir 5mg/kg iv q12 hours or
    2. Foscarnet 60mg/kg iv q8 hours or 90mg/kg iv q12 hours or
    3. Cidofovir (usually for resistant disease)
    4. Cidofovir (Vistide®) intravenously prevents progression and maintains eyesite [9,10]
    5. Cidofovir, given with probenecid, may be better tolerated than foscarnet
    6. These therapies require indwelling central venous line and renal dosing adjustments
    7. Intravitreous injections of 20µg cidofovir is safe and effective in CMV retinitis [10]
    8. Low risk of retinal detachment with multiple injections of cidofovir
    9. Vitrasert® is a local implant slow release ganciclovir approved for therapy also
    10. Slow release intraocular (Vitrasert®) ganciclovir more effective than IV therapy [11]
    11. However, intraocular ganciclovir treated patients have more CMV systemic disease
  6. Maintenance [8]
    1. Ganciclovir 5-10mg/kg/d or
    2. Foscarnet 90-120mg/kg/day or
    3. Cidofovir (Vistide®) - maintenance therapy q1-2 weeks
    4. Oral ganciclovir (1-2gm tid) is safe and effective [12]
    5. Ganciclovir (Vitrasert®) slow-release (6-8 months) vitreous implant also effective [11]
  7. Prophylaxis with 1000mg po tid ganciclovir reduced risk of CMV retinitis ~50% [7]

G. CNS Lymphoma

  1. Symptoms
    1. Lethargy, Confusion, Memory loss
    2. Hemiparesis, Aphasia
    3. Crosses corpus calossum
    4. Multifocal neurologic defects
  2. Etiology
    1. Linkage to Epstein-Barr virus (EBV)
    2. Most are non-Hodgkin's Lymphomas
  3. Therapy
    1. Radiation therapy most commonly used and well tolerated
    2. High dose steroids (dexamethasone 10mg iv q4°-6°) for mass effect, symptoms
    3. May use chemotherapy for rapidly growing tumors
    4. Hydroxyurea (400-700mg/m2) daily was effective in EBV+ primary CNS lymphoma [13]
  4. Prognosis
    1. Exceptionally poor untreated (death within days-weeks)
    2. Radiation therapy probably most effective with the least side effects
    3. Chemotherapy increasingly better tolerated by most patients (along with antiretrovirals)

H. AIDS Dementia Complex [1,2]

  1. Subcortical Dementia
  2. Early Symptoms
    1. Apathy, Depression, Agitation
    2. Decreased memory, concentration, mental acuity
    3. Motor Function: unsteady gait, leg weakness, poor coordination, tremor
    4. Responds to anti-viral agents
  3. Late Symptoms
    1. Severe apathy, disorientation, decreased awareness, negative ideation
    2. Progressive (non-dementia) Disease: diffuse hyperreflexia, hypertonia, seizures
    3. Peripheral Effects of HIV: Myelopathy, sensory neuropathy
  4. Pathogenesis
    1. Probably related to production of lymphokines in CNS by activated monocytes
    2. These lymphokines, IL1, IL6, are toxic to neurons
    3. HIV protein gp120 also appears to be directly neurotoxic
    4. N-methyl-D-aspartate (NMDA) production is increased and this is also toxic
  5. Diagnosis
    1. Clinical suspicion with symptoms
    2. Crucial to rule out other causes of brain disease
    3. MRI shows marked diffuse white-matter changes with increased T2 signal
    4. Cortical atrophy with ventricular enlargement
    5. Cerebrospinal fluid (CSF) may show leukocytes with negative cultures
  6. Treatment
    1. Generally poor response to therapy
    2. ZDV (zidovudine, AZT) at high dose (1000-2000mg/day) may improve condition
    3. Lamovudine has good penetration to the cerebrospinal fluid (CSF)
    4. Lamovudine + stavudine or zidovudine reduced CSF HIV levels to undetectable [17]
    5. Unclear efficacy of other reverse transcriptase or protease inhibitors

I. Vacuolar Myelopathy

  1. Vacuoles within spinal cord
  2. Occurs in ~20% of advanced HIV Disease
  3. May be presenting manifestation
  4. Hyperreflexia in legs, spastic weakness, decreased rapid alternating movements
  5. Sensory ataxia WITHOUT sensory level

J. Progressive Multifocal Leukoencephalopathy (PML) [14,20,21]

  1. Rare progressive demyelinative disorder
  2. Usually occurs as late complication of severe (cellular) immunodeficiency
    1. Most common in late stage HIV infection
    2. Also occurs in leukemia (CLL), Hodgkin's disease
    3. Reported in organ transplant patients
    4. Very rare in patients treatmed with natalizumab (Tysabri®), an alpha4 integrin blocker (disrupts lymphocyte trafficking; Crohn's disease and multiple sclerosis) [21,22,23,24]
    5. May be found with systemic lupus, sarcoidosis, immunosuppression
  3. Caused by JC Virus [21]
    1. JC polyomavirus is a relative of the simian virus SV40
    2. JC virus antibodies (evidence of presence of agent) in 60-80% of adults
    3. Immunosuppression appears necessary for pathogenesis of JC Virus
    4. Virus normally remains quiescent in kidney and lymphoid organs of immunocompetent
    5. In normal persons, virus may be found in urine
    6. With immunosuppression, hematogenous dissemination occurs and CNS infection possible
    7. Normally, lymphocytes (probably CD8+) suppress virus
  4. Cytarabine failed to stem progression of PML [16]
  5. No known treatment at the present time
  6. However, withdrawal of immunosuppression may lead to some improvement

K. Indications for Brain Biopsy in HIV Disease

  1. Failed empiric anti-toxoplasmosis therapy ~10 days
  2. Accessible lesion
  3. No Coagulopathy
  4. No immediate life-threatening systemic disease

L. Ocular Manifestations of AIDS [6,15,19]

  1. Over 60% of patients with AIDS will develop an ophthalmological problem
    1. There is some correlation between ocular manifestations and CD4+ T cell counts
    2. Antiretroviral therapies raise CD4+ counts
    3. However, numbers of "reconstituted" T cells may not correlate well with ocular disease
  2. CD4+ T Cell Count <500/µL
    1. Kaposi Sarcom (of eyelid)
    2. Lymphoma
    3. Tuberculosis
  3. CD4+ T Cell Count <250/µL
    1. Pneumocystis - retina and choroid infections
    2. Toxoplasmosis
  4. CD4+ T Cell Count <100/µL
    1. Retinal or conjunctival microvasculopathy
    2. CMV Retinopathy (see above)
    3. Keratoconjunctivitis sicca
    4. Varicella zoster retinitis
    5. MAI Infection
    6. Cryptococcus
    7. Microsporidiosis
    8. HIV encephalopathy
    9. PML
  5. Cotton Wool Spots
    1. These are nerve fiber layer infarctions (similar to that seen in diabetes)
    2. Most common ocular finding in AIDS
    3. Cause unknown; possible immune complex disease and/or HIV infection of endothelium
    4. Usually resolve without therapy; little risk of visual loss
  6. Rifabutin Uveitis
    1. Anterior uveitis, may begin months after rifabutin started
    2. May be potentiated by coadministration of clarithromycin or fluconazole
    3. Usually responds to discontinuation of drug and glucocorticoid eye drops
  7. Eyelid Disease
    1. Molluscum contagiosum
    2. Kaposi Sarcoma
    3. Herpes Zoster infection
  8. Corneal Disease
    1. Ulcerative keratitis
    2. Sjogren-like syndrome: dry eyes mainly
    3. Herpes simplex or Herpes zoster keratitis
    4. Microsporidiosis
  9. Retina / Choroid Infections [6]
    1. CMV Retinitis (see above)
    2. Syphilis
    3. Toxoplasmosis
    4. Cryptococcus
    5. Mycobacterial infection
    6. Pneumocystis carinii
    7. Candidiasis
    8. Histoplasmosis
  10. Conjunctivitis - nonspecific, probably autoimmune

References

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  3. Arribas JR, Storch GA, Clifford DB, Tselis AC. 1996. Ann Intern Med. 125(7):577 abstract
  4. Jacobson MA. 1997. NEJM. 337(2):105 abstract
  5. Jacoboson MA, Zegans M, Pavan PR, et al. 1997. Lancet. 349:1443 abstract
  6. Whitcup SM. 1996. JAMA. 275(2):142 abstract
  7. Spector SA, McKinley GF, Lalezari JP, et al. 1996. NEJM. 334(24):1491
  8. Drugs for Cytomegalovirus. 1997. Med Let. 39(1003):57 abstract
  9. Lalezari JP, Stagg RJ, Kuppermann BD, et al. 1997. Ann Intern Med. 126(4):257 abstract
  10. Studies of Ocular Complications of AIDS Research Group. 1997. Ann Intern Med. 126(4):264 abstract
  11. Musch DC, Martin DF, Gordon JF, et al. 1997. NEJM. 337(2):83 abstract
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  13. Slobod KS, Taylor GH, Sandlund JT, et al. 2000. Lancet. 356(9240):1493 abstract
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  15. Sarraf D and Ernest JT. 1996. Lancet. 348:525 abstract
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  17. Foudraine NA, Hoetelmans RMW, Lange JMA, et al. 1998. Lancet. 351(9115):1547 abstract
  18. Fishman JA and Rubin RH. 1998. NEJM. 338(24):1741 abstract
  19. Cunningham ET Jr and Margolis TP. 1998. NEJM. 339(4):236 abstract
  20. Koralnik IJ, Schellingerhout D, Frosch MP. 2004. NEJM. 350(18):1882 (Case Record) abstract
  21. Berger JR and Koralnik IJ. 2005. NEJM. 353(3):online (Case Report)
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  23. Kleinschmidt-DeMasters BK and Tyler KL. 2005. NEJM. 353(4):369 abstract
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