Neurologic Infectious Diseases

Tamara B. Kaplan

Nagagopal Venna

NERVOUS SYSTEM LYME DZ

Definition: Tick-borne spirochete infxn caused by Borrelia burgdorferi (Borrelia garinii or afzelii in Europe/Asia).

Epidemiology:

Most common vector-borne illness in the United States; peak incidence in summer (May-Aug)
Majority of cases in NY, NJ, CT, RI, WI, PA, MA, ME, NH, MI, MD, DE, northern CA

Clinical Manifestations
Stage	Manifestation
Stage 1: Early localized: Wks after infxn	General: flu-like illness. Derm (˜80%): Erythema migrans (EM)
Stage 2: Early disseminated: Wks to mos after infxn	General: Fatigue, malaise, LAN, HA; fever uncommon. Derm: Multiple (1-100) annular lesions ±EM. Rheum (˜10%) migratory arthralgias (knee & hip) & myalgias. Neuro (˜15%): Cranial neuropathies (esp, CN VII), aseptic meningitis, mononeuritis multiplex (±pain), transverse myelitis. Cardiac: (˜8%): Heart block, myopericarditis
Stage 3: Late persistent: Mos to yrs after infection	Derm: Acrodermatitis chronica atrophicans, panniculitis. Rheum (60%): Joint pain, recurrent mono- or oligoarthritis of large joints (classically knee), synovitis. Neuro: Subacute encephalomyelitis, polyneuropathy, dementia
Lancet 2003;362:1639; CID 2006;43:1089; NEJM 2007;357:1422.

Neurologic presentations of Lyme dz: (Neurology 1996;46:619). Neuro involvement in ˜15% untreated cases, typically in stages II-III. Even untreated, most cases of acute CNS Lyme improve or completely resolve in weeks-months; ˜5% untreated pts → chronic neurologic dz

Neurologic Presentations	Comments
Meningitis	± Cranial neuritis or acute radiculoneuritis: Up to 15% cases (si/sx: HA, neck stiffness, cranial neuropathies (esp CN VII palsy), painful radiculoneuritis w/motor & sensory involvement). Thoracic radiculitis w/segmental weakness of the abdominal wall. CSF antibodies almost always positive. CSF PCR unreliable
Peripheral neuropathy/chronic radiculoneuropathy	˜30% cases. Mononeuritis multiplex. Unlike early radiculoneuritis, not a/w meningitis, cranial neuropathy, or CSF abs
Chronic axonal polyneuropathy	With radicular pain, distal paresthesias
Encephalomyelitis	Rare, 0.1%-5% most commonly involves the spinal cord at the level of a radiculopathy and is usually apparent on MRI scans; assoc w/inflammatory CSF
Encephalopathy	Mild cog. dysfxn. Brain MRI & CSF usually nml likely 2/2 systemic infxn. Similar to “toxic metabolic” encephalopathy a/w chronic UTI, PNA
Optic neuritis	In pedi population 2/2 infl. or ↑ ICP
Chronic encephalomyelitis	W/spastic paraparesis, CN palsy, cognitive &Dgr;s, persistent CSF abs (seen in Europe w/B. garinii infxn). Subtle cognitive dysfxn w/o inflammatory &Dgr;s in CSF but w/+ CSF abs.

Diagnostic eval: CLINICAL dx w/lab data as supportive. High suspicion if h/o tick exposure & typical skin lesion. LP: Do if e/o CNS involvement, incl severe, prolonged HA, nuchal rigidity, AMS, or subacute meningoradiculitis, multiple cranial neuropathies. Pts w/isolated neuropathy (e.g., Bell palsy) do not automatically require LP.

Diagnosis of CNS Lyme: Need (1) & (2) & one of (3): (1) One of the neurologic entities described above & (2) Possible tick exposure in endemic area & (3a) EM (or histopathologically proven Borrelia lymphocytoma or acrodermatitis) OR (3b) +immunologic e/o exposure in serum OR (3c) +isolation of B. burgdorferi from cx, histology or PCR. Ideally also find immunologic e/o exposure in CSF (unless strictly PNS involvement or chronic dz). Definite dx of CNS Lyme difficult (low Se of cx from specimens other than skin lesions).

Diagnostic studies

Serology (in right clinical setting): Screen w/ELISA, but false+ due to other spirochetal diseases, SLE, RA, EBV, HIV, etc.; false- due to early abx therapy or w/in 6 wk of infxn. IgM response first, then declines. IgG+ after ˜1 mo. Confirm ELISA results w/Western blot Se 20%-30% in first weeks (IgM) but >80% after 6 wk; Sp > 95%
CSF if suspected neuro disease: Intrathecal Ab if (IgGCSF/IgGserum)/(albCSF/albserum) >1 (Compare CSF and serum specific Abs, correcting for total IgG concentration in both compartments).
If only PNS involvement, there is no reason to expect CSF Ab to be positive
Active CNS infection—CSF pleocytosis ± increased prt, should improve w/Abx.

Other Laboratory Dx of Lyme Dz
	Comments Sensitivity/Specificity
Western blot	Confirmatory, usu not helpful if seroneg; IgG blot + if 5/10 bands present; IgM blot + if 2/3 bands present	CDC recs: “Two tier” test w/ELISA & Western blot 56%-100% Se, 100% Sp; Se lower during acute period (<6 wk)
CSF ab detection	Less useful in nonacute presentation of CNS Lyme	Sensitivity ranges from 50%-100%, often near 90% for meningitis; up to 95% specific
Culture	Difficult to cx; low sensitivity of specimens other than skin	Skin cx: Se 80%, Sp 100% CSF cx: Se 10%, Sp 100%
PCR (serum, CSF or synovial fluid)	High rate of false +; useful mainly if classic clinical presentation in endemic area & serum Lyme ab is neg	Se, Sp not well established; may be ˜100% but clinical signif. +PCR unclear; may detect DNA from dead bacteria
Cell-mediated immunoassay	Useful if suspicion high in seroneg pt (due to antibiotic use around time of exposure)

Treatment: Approp abx can → dramatic improvements even w/severe forms of meningoradiculitis. Consider repeat LP after 2 wk to eval response of pleocytosis, protein, & antibodies to Rx. IgG ab in CSF often persists for years after Rx. No known benefit of concurrent steroid administration. Vaccine 76% effective in preventing Lyme infxn.

Prophylactic doxycycline 200 mg recommended if able to give w/in 72 h of removing tick that can be identified as Ixodes scapularis & is attached for >36 h (NEJM 2001;345:79).

Prognosis: Good Rx response in 90% of appropriate pts. No proven benefit of additional abx for “post-Lyme syndrome” (chronic fatigue, diffuse pain, cognitive impairment).

Treatment of Lyme Dz
	Antibiotic	Dose	Side effects
Parenchymal CNS Lyme (e/o infxn crossing blood-brain barrier^a)	IV ceftriaxone (first line) IV cefotaxime IV PCN G	2 g/day × 2-4 wk. 2 g/day q8h 18-24 MU/day q4h	Rash, n/v/d, pseudomemb. colitis, ↑ LFTs Rash, n/v/d, HA, pseudomembranous colitis GI upset, n/v/d, black or hairy tongue
Peripheral neuropathy, isolated cranial neuropathies	Oral doxycycline (children >8 yo, nonpregnant F Oral amoxicillin (children <8 yr & pregnant F)	200 mg/day × 14-21 days 500 mg tid × 14-21 days	Photosensitivity rash in sun, pseudomembranous colitis Rash, diarrhea, pseudomembranous colitis, hemolytic anemia
CNS Lyme w/e/o infxn crossing blood-brain barrier^a	IV ceftriaxone (first line) IV cefotaxime IV PCN G	2 g/day × 2-4 wk 6 g/day 18-24 MU/day div q4h	Rash, n/v/d, pseudomemb. colitis, ↑ LFTs. Rash, n/v/d, HA, pseudomembranous colitis GI upset, n/v/d, black or hairy tongue
Early localized or disseminated infxn	Same as for periph. neuropathy/isolated cranial neuropathy, Alt: cefuroxime 500 mg bid × 14-21 days		Same as above
Serious cardiac or joint involvement	Same as for CNS Lyme		Same as above
^aIn Europe, oral doxycycline may be sufficient for CNS Lyme (Lancet Neurol 2008;7:690.)
Oral Abx are probably effective for meningitis and other neuro involvement, w/the exception of parenchymal CNS infection

EHRLICHIOSIS

Presentation (J Vector Borne Dis 2008;45:273): 1-2 wk post-tick exposure, develop malaise, low back pain, fever, HA, N/V, myalgias/arthralgias. Can also p/w pharyngitis, lymphadenopathy, encephalopathy.

Etiology: Ehrlichia chaffeensis = Obligatory intracellular tick-transmitted bacterium. Vector: Most commonly A. americanum (lone star tick); can be other ticks (e.g., Ixodes). Reservoirs: White-tailed deer. Most infxns occur in S. central, SE, & mid-Atlantic states.

Dx: IFA ab titer to E. Chaffeensis, or + PCR (blood, CSF) & confirmation of E. chaffeensis DNA, or immunostain + for E. chaffeensis Ag in bx, or +Cx (blood, CSF).

Rx: Doxycycline 100 mg bid PO or IV × 7-14 days; tetracycline 500 mg PO qid × 7-14 days.

NEUROSYPHILIS

Definition: Spirochete, Treponema pallidum, infxn. Varied presentation: “Great imitator.”

Epidemiology: Historically highest rates in southern states & in blacks. After decades of decline, rates of 1° & 2° syphilis on the rise, esp in HIV+ MSM.

Special considerations in HIV (Clin Infect Dis 2007;44:1222): (1) 1° syphilis infxn facilitates transmission & acquisition of HIV. (2) May see multiple, more persistent, or larger/deeper chancres, concurrent 1° & 2° stages at presentation, earlier development of gummas & more frequent CSF abnlities w/higher cell count, higher elevation of protein, lower glucose. (3) Transient ↑ in viral load & ↓ CD4 count w/syphilis infxn. (4) Neurologic dz seen earlier—HIV pts may be at ↑ risk for developing neurosyphilis. (5) Risk of neurosyphilis in HIV pts after adequate Rx for syphilis unknown. (6) More likely to have persistently + serologic & CSF tests despite Rx (unclear clin. significance). (7) If CD4 count ≤350 cells/mL or RPR titer ≥1:32 → need LP (Clin Infect Dis 2009;48:816).

Clinical Presentation
	Manifestations	Comments
1° (weeks after exposure)	Chancre: painless, indurated, nonpurulent ulcer	Resolves in 2-6 wk w/or w/o Rx.
2° (4-8 wk after chancre)	3-10 mm macular rash (flanks, shoulders, arms, chest, back); w/o Rx → maculopap. rash (esp palms/soles); malaise, fatigue, HA, lymphadenopathy, sore throat; ± fever, wt ↓, myalgias/arthralgias, condyloma lata	Resolves w/o Rx but 25% recur, usu in first year. Rash is most common presenting sx in syphilis (˜90% pts).
Latent (early L:<1 yr post-infxn, late L: >1 yr post-infxn)	Seroreactivity w/o other e/o dz	Infectious only via mother → child transmission
Early neurosyphilis (w/in weeks-years)	Meningitis (aseptic meningitis); cranial neuropathy; ocular dz (anterior uveitis, choroiditis, interstitial keratitis, retinitis, scleritis, optic neuritis); meningovascular dz w/strokes: typically brainstem & cerebral lacunar syndromes, 2/2 propensity for small arterioles; also ACA branch strokes.	25%-60% pts during 1° or 2° syphilis → early neurosyphilis; <5% symptomatic. Enters CNS early (→ CSF pleocytosis, ↑ protein, +CSF-VDRL or PCR). W/o Rx ˜25% do not clear organisms. W/Rx, most immunocompetent pts clear CSF infxn. BUT Rx does not preclude → neurosyphilis.
Tertiary syphilis, incl late neurosyphilis, usu years-decades after infxn	Cardiovascular syphilis (10%, ˜20-30 yr after exposure); Gummatous dz (15%, 1-46 yr); General paresis (˜5%, 2-30 yr): chronic dementia w/prominent behavioral ↓, delusions; Tabes dorsalis (˜5%, 3-50 yr): chronic spinal cord d/o, sensory gait & limb ataxia & ↓ bowel/bladder fxn; Rapidly progressive dementia w/psychosis (esp HIV pts).	Pts w/tertiary syphilis are not infectious. 1/3 untreated pts develop late sequelae.
JAMA 2003;290:1510.

Diagnostic Evaluation of Syphilis
Syphilis cannot be cultured. Direct e/o infxn requires dark-field microscopic exam or fluorescent ab stains of genital or mucosal lesions; neither test is sensitive.
Test	Nontreponemal serologic lipid antigen tests	Treponemal serologic tests	CSF tests (non-TP & TP)
	RPR, VDRL	TPPA, FTA-abs	RPR, VDRL, FTA-abs
Se, Sp	Se: 1°: 78%-86%, 2°: 100%, latent: ˜95%; false+ 1%-2% (IVDU, TB, vaccinations, pregnancy, HIV, rickettsial infxn mononucleosis, endocarditis, other spirochetal infxns (titers usu <1:8 in false+’s); false- in HIV; VDRL→ +1-2 wk after chancre; rare false- w/↑ ↑ ↑ titers (prozone phenomenon)	False+ from other spirochetal infxns, malaria, leprosy; false-in HIV	CSF-VDRL Se 30%-70%, Sp 99% CSF-FTA-abs ˜100% Se, but low Sp
Note	Usu → neg after Rx, although up to 28% w/1° syphilis & 44% w/2° syphilis still + at 36 mo (Ann Intern Med 1991;114:1005)	Most + for life despite Rx 10%-25% → neg.	↑ protein, ↑ lymphs (>5) support dx +CSF-VDRL (any titer) = neurosyphilis
TPPA, Treponema pallidum particle agglutination; FTA-abs, fluorescent treponemal antibodies; Se, sensitive; Sp, specific; AI, autoimmune; TP, treponemal.
JAMA 2003;290:1510.

When to do an LP: (Clin Infect Dis 2009;48:816): (1) Neuro/ocular sx, (2) Late latent syphilis or ? duration in HIV pt, (3) Active tertiary syphilis, (4) Rx failure (see below), (4) Serum RPR ≥1:32 or CD4 count ≤350 cells/mm³ in HIV+ w/or w/o neuro sx.

Imaging: Variable: nl, ischemic strokes w/lacunar features, nonspecific WM lesions incl periventricular, mesiotemporal T2-weighted hyperintensities, meningeal enhancement, arteritis/vasculitis on angiography. Cases in recent years w/mesiotemporal T2-weighted hyperintensities resembling HSV or limbic encephalitis.

Syphilis Treatment (PCN, penicillin; MU, million units; doxy, doxycycline)

1°/2°/early latent dz: Benzathine PCN G IM 2.4 MU × 1. PCN allergic → doxy 100 mg bid × 14 days or tetracycline 500 mg qid × 14 days or ceftriaxone 1 g IV/IM qd × 10 days. Azithromycin may be effective in 1° & 2° syphilis but high % resistance in several major cities.
Late latent or nonneurologic tertiary syphilis: Benzathine PCN G IM 2.4 MU wkly for 3 wk. If PCN allergic: doxy 100 mg bid × 28 days or tetracycline 500 mg qid × 28 days.
Neurosyphilis, incl ocular or auditory dz: Aqueous crystalline PCN G 3-4 MU q4h × 14 days or 18-24 MU qd in continuous infusion × 10-14 days or procaine PCN3 2.4 MU IM qd + probenecid 500 mg PO qid × 14 days; desensitize pts w/PCN allergy.

Note: Beware Jarisch-Herxheimer reaction (fever/chills, HA, myalgias) from endotoxin release 4-12 h after first injection of PCN.

Follow up: (1) Repeat serologic tests & clinical f/u at 1, 3, 6, & 12 mo (and 24 mo for late latent/tertiary dz or HIV pts). (2) Treatment failure = persistent si/sx & failure of nontreponemal tests to ↓ fourfold (two dilutions) w/in 6-12 mo of Rx in early syphilis & 24 mo in late syphilis, or fourfold ↑ at any stage; 5% in non-HIV vs. 20% in HIV pts. (3) Repeat LP: 3-6 mo after Rx & then q6mo until CSF normalizes.

NEUROLEPTOSPIROSIS

Epidemiology

Leptospirosis transmitted by urine of infected animal
Rats, mice moles, most common vector

General: Neurologic manifestations in 10%-15% of cases. Consider in pts w/acute hepatorenal dysfxn & altered MS in or from endemic areas. Consider in ddx of acute aseptic meningitis/meningoencephalitis a/w conjunctival suffusion & often w/jaundice, although these findings may be absent.

Presentation: Typically fever, chills, HA, vomiting, AMS; szs & focal deficits less common. May cause meningitis ± encephalitis

Dx: Imaging: nl or may show diffuse cerebral edema. CSF: ↑ lymphs common (<500 cells/mm3). Can detect serum & CSF antibodies. organism can be found in blood & CSF for first 7-10 days. After 7-10 days can be found in urine. Confirm w/ELISA and PCR. Gold standard for dx: MAT (microscopic agglutination test).

Rx: Options: PCN G, ampicillin, & doxycycline for less severe cases.

Prognosis: Significantly altered MS & ↑ ↑ CSF protein are poor prognostic findings.

HIV INFECTION OF THE NERVOUS SYSTEM

Epidemiology: >1/2 HIV pts have neuro si/sx; complications include opportunistic infxns, direct effect of HIV virus on nervous system, & adverse effects of antiretroviral Rx.

HIV-associated neuropathy

Presentation: 20%-60% HIV pts—Distal, symmetric, polyneuropathy, affects small ± large sensory fibers. Si/Sx: Combination of pos neuropathic sx (paresthesia, pain) and neg neuropathic sx (numbness, imbalance); usually no motor sx. Neuropathic pain 50%-90% of patients. Neuropathy does not correlate w/viral load or CD4 count. Also ↑ risk for entrapment neuropathy (e.g., carpal tunnel). DM, INH exposure, malnutrition ↑ risk. Older dideoxynucleotide antiretroviral agents: didanosine (ddI), stavudine (d4T), and zalcitabine (ddC) sensory polyneuropathy clinically indistinguishable from HIV-induced neuropathy. Less common presentations: AIDP, CIDP, mononeuritis multiplex w/and w/out concurrent CMV infxn

Exam: ↓ sensation (can be all modalities, esp pain & temp; JPS often ok); ↓ ankle reflexes; strength typically preserved. Diagnosis: Exclude other causes/mimics of axonal sensory polyneuropathy (DM, B12 def, renal/liver dz, thyroid dz, syphilis) & concomitant exposure to neurotoxic meds commonly used in HIV pts (e.g., antineoplastic drugs, INH, thalidomide). EMG: Axonal, length-dependent predominantly sensory polyneuropathy (but can be nl if mostly small unmyelinated fibers affected); uncommonly e/o demyelination/remyelination. AIDP/CIDP: (often w/CSF ↑ protein & mild pleocytosis), polyradiculopathy (often 2/2 CMV in late HIV dz, CSF ↑ polys, ↑ protein, ↓ glucose; send CSF for viral PCR; Rx w/IV ganciclovir, Foscarnet.

Treatment: Supportive. Symptomatic Rx: TCAs, gabapentin, pregabalin, lamotrigine, duloxetine. Identify & treat confounding factors such as DM.

Acute neuromyopathy mitochondrial toxicity: Resemble GBS, associated w/several NRTIs, particularly w/d4T, also zidovudine (AZT), ddI, and lamivudine (3TC), either alone or in combination. Lactic acidosis suggests acute mitochondrial toxicity possibly 2/2 metabolic effects of the nucleoside analogs. Acute cauda equina syndrome: Rapidly developing painful paraparesis w/bladder and bowel involvement; characteristic of CMV polyradiculitis in advanced immunodeficiency.

HIV-associated myopathy: (1) Zidovudine myopathy: Fatigue, prox muscle weakness & atrophy, myalgias. More common after cumulative dose >200 g. Ragged red fibers seen on electron microscopy. Ddx: preserved DTR and sensation unlike CIDP or other neuropathy. CK usu ↑. Rx: d/c zidovudine; CK and muscle pain dec first, later return of muscle strength. (2) Pyomyositis: Rare. Indurated, tender muscle mass. Dx: nl-high CPK. Ultrasound, CT scan, & MRI helpful. Aspirate & culture. Rx: IV abx & surgical drainage as needed. (3) Nemaline rod myopathy: Subacute development of weakness & atrophy. ↑ CPK. Nemaline rods on bx w/variable muscle necrosis & inflammation. Rx: steroids, ?IVIg. (4) HIV wasting illness: Prox weakness & atrophy w/diarrhea, fever, cachexia. CPK usu wnl. (5) Diffuse infiltrative lymphocytosis
syndrome: B/l salivary gland enlargement or xerostomia. CD8 polyclonal lymphocytic infiltrate on bx of minor salivary gland. May initially p/w myositis, neuropathy, or mononeuritis multiplex. Rx: steroids. (6) Opportunistic infxn or tumor infiltration of muscle.

HIV-associated myelopathy (“vacuolar myelopathy”): Pathologic diagnosis. Characteristic pathology at autopsy in ˜55% of patients dying from AIDS. Clinical myelopathy is less common. ↓ incidence due to ART; ˜5%-10% untreated pts affected; CD4 usu <350/mm³.

Presentation: Gradual onset weeks-months leg weakness, spasticity, gait ataxia 2/2 ↓ proprioception; urinary incontinence less common. Typically painless & mimics subacute combined degeneration of B12 deficiency. Commonly parallels development of HIV-associated dementia (HAD).

Exam: Symm. spastic paraparesis; hyperreflexia, often sparing upper extremities; upgoing toes. Less commonly: Impaired proprioception in legs less common. Typically no sensory level.

Dx: of exclusion clinically. B12 level, serum syphilis & viral testing, CSF analysis w/syphilis testing & viral PCRs, MRI spinal cord w/gado. CSF: Few cells. MRI: Of spine often nl or nonspecific hyperintensity; later → cord atrophy. Pathology: Axonal injury, macrophage infiltration, & vacuolation of lateral/dorsal columns; T > C, L spine.

Rx: Starting ART after vacuolar myelopathy usu does not improve sx. Symptomatic Rx of spasticity & neurogenic bladder. Physical therapy.

Other Causes of Myelopathy in HIV

HIV myelitis a/w seroconversion: Self-limited, transient paraparesis. HIV abs may be neg. Send HIV viral load

HTLV I & II: Progressive painful spastic paraparesis, develops over years; common coinfxn w/HIV in pts from HTLV endemic areas; more rapid decline in HIV+ than in HIV- pts. CSF = significant pleocytosis. Serum & CSF HTLV abs.

Epidural abscess: Fever, back pain, radicular sx. Rapidly → spastic paraparesis. MRI to visualize abscess. IV abx, ±surgical decompression.

VZV myelitis: Usu few weeks after skin eruption. Ipsil. weakness. Spinothalamic/dorsal column impairment. CSF pleocytosis. Dx w/CSF PCR or cx. MRI: Enhancement at infxn site.

CMV myelitis: Rare (more often causes radiculopathy). CD4 usu <50/mm³.

Rapidly progressive development of spinal cord lesion. CSF w/marked pleocytosis, ↑ protein, & often ↓ glucose. Dx w/CSF PCR; also r/o retinitis & viremia. MRI: Enhancement of affected area. Rx: IV ganciclovir or Foscarnet.

HSV myelitis: Rare, presentation similar to CMV myelitis. Unlike CMV myelitis, much less marked CSF pleocytosis. Dx w/CSF PCR &/or cx. Rx: IV high-dose acyclovir.

Syphilis: Acute/subacute spastic paraparesis; impaired proprioception; bowel/bladder disturbance & sensory level. CSF: Pleocytosis, ↑ protein; +serum RPR, CSF VDRL or FTA abs.

Spinal tuberculosis: CD4 count usu <250/mm3. Often in conjunction w/TB meningitis.

Other: Vitamin B12 deficiency, idiopathic transverse myelitis, multiple sclerosis, lymphoma.

HAND, HIV-associated neurocognitive disorders.

References: Neurol Clin 2008;26:799; Lancet Neurol 2005;9:543.

Three conditions w/in the spectrum of HAND: Asymptomatic neurocognitive impairment (ANI); mild neurocognitive disorder (MND); HIV-associated dementia (HAD).

Epidemiology: Overall incidence ↓ w/widespread ART of HAD. Milder cognitive dysfxn, still common (20%-69%) in HIV+ pts. Presentation: Progressive cognitive, behavioral, & motor dysfxn, similar to a subcortical dementia. ↓ memory, attention; psychomotor slowing. Depressive sx, agitation, apathy, change in personality; less commonly psychosis & mania. Motor impairment (tremor, gait disturbance, spasticity); may resemble Parkinson dz. Frontal release signs, hyperreflexia. Sx may develop acutely over weeks-months. Milder forms of cognitive motor dysfxn, may precede HAD. Sx may wax and wane.

Risk factors: Low CD4 count, older age at seroconversion, anemia, ↑ age, duration of dz, low BMI, IVDU. CSF & plasma viral load (VL) do not clearly predict progression to HAD (but possible assn b/n CSF VL & severity of HAD). E4 isoform of apolipoprotein E is a/w severity of dementia (Neurology 2004;63:626).

Ddx: CNS lymphoma, CMV encephalitis, progressive multifocal leukoencephalopathy (PML), toxoplasmosis, TB, cryptococcal meningitis, neurosyphilis, depression, vascular dementia, neurodegenerative dementia.

Workup: Imaging: May be nl, esp early on; cerebral/basal ganglia atrophy, ventricular enlargement & diffuse white matter T2 hyperintensities, often isointense on T1. MR spectroscopy: ↑ Choline (astrocytosis) & decrease in N-acetylaspartate (neuronal injury). CSF: Often w/pleocytosis & ↑ protein & IgG. Neuropsych testing: Psychomotor & memory deficits.

Rx: ART improves neuropsych testing in HAD (J Neurovirol 2000;6:84; Neurology 2006;67:311). In some pts w/subacute HIV encephalitis, dementia improves markedly w/ART → should be considered reversible cause of dementia. Controversy re: Whether certain regimens superior; stavudine, zidovudine, abacavir, lamivudine, efavirenz, nevirapine, indinavir appear to have best CNS penetration. No clear role currently for neuroprotective agents (e.g., selegiline or minocycline) (Neurology 2007;69:1314). Ineffective Rx: Memantine (AIDS 2007;21(14):1877), transdermal selegiline (Neurology 2007;69:1314) minocycline (Neurology 2013;80:196)

Prognosis: Both HAD & HAND predict ↓’d survival regardless of whether on ART.

INTRACRANIAL OPPORTUNISTIC INFECTIONS

Toxoplasma gondii Cryptococcus neoformans Cytomegalovirus (CMV) Fungal Encephalitis

Progressive Multifocal Leukoencephalopathy (PML) Herpes Varicella-Zoster Virus (VZV)

Initial eval: (1) Detailed H&P, incl travel, exposures, meds. (2) Eval risk factors for opportunistic infxns. (3) Don’t forget usual infxns seen in non-HIV pts incl CD4 count, VL, current ART, prophylaxis, CBC w/diff, LFTs, hepatitis serologies, RPR, PPD, chest x-ray, crypto Ag, toxo serology.

Who needs brain imaging prior to LP? (NEJM 2001;345:1727)

(1) ^*Immunocompromised pts, incl all HIV pts. (2) ↓ level of consciousness. (3) Focal neuro findings incl papilledema. (4) Age ≥ 60. (5) Known CNS lesion. (6) sz in past wk.