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CNS FUNGI Predisposing factors

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					                                           10 e
                                         20 nc
                                       8, re
                                     -2 nfe
Chronic Meningitis




                                   27 Co
                                 ry e
                               ua as
with an emphasis on fungal




                             br ise
                           Fe D
meningitis

                          n s
                       , o ou
                     ia cti
                   op fe
                 hi in
        Joseph R. Berger, M.D.
               Et uro
             a, e
           ab al N




        Department of Neurology
         Ab n
        s io




         University of Kentucky
      di nat
    Ad ter
      In
Chronic Meningitis Definition




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
                                    27 Co
                                  ry e
                                ua as
                              br ise
 A meningeal inflammatory



                            Fe D
                           n s
 process persisting under

                        , o ou
                      ia cti
                    op fe
 observation for at least 4 weeks
                  hi in
                Et uro

 with failure of clinical
              a, e
            ab al N




 improvement or with clinical
          Ab n
         s io
       di nat




 worsening.
     Ad ter
       In




                             Ellner and Bennett Medicine 1974;55:341
Ainslee B.




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   24 year old woman in horse industry




                                    27 Co
                                  ry e
   June 2004 – admitted with severe headaches




                                ua as
                              br ise
    and diplopia




                            Fe D
                           n s
                        , o ou
    – Travel to SW USA

                      ia cti
    – Exam shows papilledema and R 6th n palsy
                    op fe
                  hi in
                Et uro
    – CSF OP 50; WBC 50 (lymphs); glucose 17/90;
              a, e


      protein 66; +OCBs and ↑IgG
            ab al N
          Ab n




    – All microbiological studies negative
         s io
       di nat




    – Discharged as viral meningitis
     Ad ter
       In




   Recovers   w/o treatment
Ainslee B.




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   August 2008 – returns with headaches,




                                    27 Co
                                  ry e
    imbalance, and visual problems




                                ua as
                              br ise
    – Exam shows papilledema




                            Fe D
                           n s
    – CSF OP 25; WBCs 5; protein 121; glucose 10;


                        , o ou
                      ia cti
      +OCB; ↑IgG
                    op fe
                  hi in
    – MRI, MRA, and MRV negative
                Et uro
              a, e


    – All studies negative but CSF histoplasma CF 1:8
            ab al N




      yeast and 1:1 for mycelial phase
          Ab n
         s io
       di nat




   Five weeks of IV Ambisome followed by
     Ad ter




    Voriconazole and Diamox indefinitely
       In




   February 2010 – doing well
Chronic Meningitis
Epidemiology




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Dependent      on population risk factors




                                    27 Co
                                  ry e
                                ua as
    – New Zealand study representative of




                              br ise
      developed world




                            Fe D
                           n s
                        , o ou
    – < 1% of all meningitis

                      ia cti
                    op fe
       » 83 cases v. 1000 bacterial or viral meningitis
                  hi in
                Et uro

    – Causative agent identified in 66%
              a, e
            ab al N




       » TB (60%)
          Ab n
         s io
       di nat




       » Carcinoma (13%)
     Ad ter




       » Cryptococcus neoformans (11%)
       In




                          Anderson and Willoughby Q J Med 1987;63:283
Chronic Meningitis
Epidemiology




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
  Dependent         on geography




                                    27 Co
                                  ry e
                                ua as
  Examples




                              br ise
                            Fe D
    – Coccidioidmycosis in American Southwest


                           n s
                        , o ou
                      ia cti
    – Histoplasmosis in Ohio River Valley
                    op fe
                  hi in
                Et uro

    – Cysticercosis in Mexico and South and
              a, e
            ab al N




      Central America
          Ab n
         s io




    – Angiostrongylus cantenensis in China
       di nat
     Ad ter
       In
Chronic Meningitis
Infectious etiologies




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
    Viral   meningitis (HIV, Mollaret’s {HSV-




                                     27 Co
                                   ry e
     2})




                                 ua as
                               br ise
                             Fe D
    Tuberculous meningitis




                            n s
                         , o ou
                       ia cti
    Syphilis and neuroborreliosis (Lyme)
                     op fe
                   hi in
                 Et uro

    Nocardiosis
               a, e
             ab al N




    Parameningeal infection
           Ab n
          s io
        di nat




    Fungal meningitis
      Ad ter
        In




    Parasitic infection
Chronic Meningitis
Non-infectious etiologies




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
    Neoplastic meningitis




                                     27 Co
                                   ry e
    Sarcoidosis




                                 ua as
                               br ise
    Granulomatous angiitis




                             Fe D
                            n s
                         , o ou
    SLE and other vasculitides

                       ia cti
                     op fe
                   hi in
    Behcet’s disease
                 Et uro
               a, e
             ab al N




    Vogt-Koyanagi-Harada syndrome
           Ab n
          s io




    Allergic and hypersensitivity meningitis
        di nat
      Ad ter




    Chronic meningitis of unknown etiology
        In
Fungi




                                               10 e
                                             20 nc
                                           8, re
                                         -2 nfe
      Eukaryotic organisms




                                       27 Co
  




                                     ry e
      – Include yeasts, molds, and mushrooms




                                   ua as
                                 br ise
     Cell walls contain chitin




                               Fe D
      – Versus cellulose in plant cell walls




                              n s
                           , o ou
      – Chitin combined with glucans unlike arthropod


                         ia cti
                       op fe
      May grow as single celled yeasts reproducing by
                    hi in
                   Et uro

      budding or binary fission
                 a, e
               ab al N



     Most grow as hyphae (cylindrical structures 2-10μm
             Ab n




      in diameter
            s io
          di nat




      – Dimorphic fungi can switch between yeast and hyphal forms
        Ad ter




      All have a common ancestor
          In




  
                                       Fungi
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e
                                       Classification of Disease Causing
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                                       relative to other types




                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e
                                       Percentage of fungal meningitis
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
                                       related to wealth




               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                       Fungal meningitis inversely




                                   8, re
                                     20 nc
                                       10 e
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                       Higher mortality with fungal




                                   8, re
                                     20 nc
                                       10 e
                                       meningitis than with other forms
CNS FUNGI - Predisposing
factors




                                              10 e
                                            20 nc
                                          8, re
                                        -2 nfe
                                      27 Co
Predisposing factor             Typical fungi
                                candida




                                    ry e
prematurity




                                  ua as
                                candida, cryptococcus,




                                br ise
inherited immune deficiency -
                                aspergillus




                              Fe D
CGD, SCID, etc




                             n s
                                cryptococcus, candida



                          , o ou
corticosteroids
                                aspergillus, candida

                        ia cti
cytotoxic agents
                      op fe
HIV/AIDS            hi in       cryptococcus, histoplasmosis
                  Et uro
alcoholism                      sporothrix
                a, e


iron chelator therapy           zygomycetes
              ab al N




IV drug abuse                   zygomycetes, candida
            Ab n




                                zygomycetes
           s io




diabetic ketoacidosis
         di nat




trauma, surgery, FB             candida, dematiaceous fungi
       Ad ter




near-drowning                   pseuodallescheria
         In
Pathological spectrum of CNS
fungal infection




                                               10 e
                                             20 nc
                                           8, re
                                         -2 nfe
 SPECIES         Meningitis Abscess              Infarct




                                       27 Co
                                     ry e
                                   ua as
                                 br ise
 True yeast      ++++         +                  +




                               Fe D
 cryptococcus,




                              n s
                           , o ou
 histoplasmosis,

                         ia cti
 blastomycosis
                       op fe
                     hi in
 Pseudohyphae ++              ++                 -
                   Et uro

 candida                      microabscesses
                 a, e
               ab al N




                 +            +++            ++++
             Ab n




 True hyphae
            s io
          di nat




 aspergillus,                 macroabscesses
        Ad ter




 zygomycetes
          In
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e       True Yeast
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e
Cryptococcus neoformans
History




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
    1861- C. neoformans first identified




                                     27 Co
                                   ry e
                                 ua as
    1894 - Busse isolates the organism




                               br ise
                             Fe D
    1895 - Buschke describes tibial gumma



                            n s
                         , o ou
                       ia cti
    1914 - Verse describes C. neoformans
                     op fe
                   hi in
                 Et uro

                     meningitis
               a, e
             ab al N




    1956 - Introduction of amphotericin
           Ab n
          s io
        di nat
      Ad ter
        In
Cryptococcus neoformans
Synonyms




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Cryptococcus    neoformans




                                    27 Co
                                  ry e
                                ua as
   Cryptococcus histolytica




                              br ise
                            Fe D
   Torulopsis neoformans



                           n s
                        , o ou
                      ia cti
   Torula histolytica
                    op fe
                  hi in
                Et uro

   European blastomycosis
              a, e
            ab al N




   Saccharomyosis
          Ab n
         s io
       di nat




   “Champignon” (French)
     Ad ter
       In
Cryptococcus neoformans
Epidemiology




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Ubiquitous




                                    27 Co
                                  ry e
                                ua as
    – var. neoformans A-D: worldwide




                              br ise
                            Fe D
    – var. gatti: Australia, SE Asia, Central



                           n s
                        , o ou
      Africa, Southern California

                      ia cti
   prior           op fe
          to AIDS: 3 M:F
                  hi in
                Et uro
              a, e



   age range: 30-50 years (>2/3s)
            ab al N
          Ab n




   all races affected
         s io
       di nat
     Ad ter
       In
Cryptococcus neoformans
Associated disorders




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   AIDS  (1.9-11% of all AIDS patients)




                                    27 Co
                                  ry e
                                ua as
   Corticosteroid therapy




                              br ise
                            Fe D
   Leukemia and lymphoma



                           n s
                        , o ou
                      ia cti
   Diabetes mellitus, cirrhosis, renal
                    op fe
                  hi in
                Et uro

    disease
              a, e
            ab al N




   Sarcoidosis, SLE
          Ab n
         s io
       di nat




   TB
     Ad ter
       In




   Idiopathic CD4 lymphopenia
Cryptococcus neoformans
Characteristics




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
    Variety neoformans capsular types (A-




                                     27 Co
                                   ry e
     D) and gatti (B and C)




                                 ua as
                               br ise
                             Fe D
    Commonest fungal infection of CNS




                            n s
                         , o ou
                       ia cti
    Bird excreta, soil, fruits, animals, man
                     op fe
                   hi in
                 Et uro

    dairy workers and immunosuppressed
               a, e
             ab al N




    Lesions of lung, skin, mucous
           Ab n
          s io




     membranes, bone
        di nat
      Ad ter
        In
Cryptococcus neoformans
Identification




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
    Grows    at 27oC, but not at 44oC




                                     27 Co
                                   ry e
                                 ua as
    Hydrolyzes urea




                               br ise
                             Fe D
    Virulent in mice



                            n s
                         , o ou
                       ia cti
    Ability to assimilate carbon and nitrogen
                     op fe
                   hi in
                 Et uro

     compounds
               a, e
             ab al N




    Mucinous capsule (only encapsulated
           Ab n
          s io




     fungus to invade the CNS)
        di nat
      Ad ter
        In
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       Cryptococcus neoformans




                                       10 e
Cryptococcus neoformans
Pathogenesis




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Respiratory tract is usual portal of entry;




                                    27 Co
                                  ry e
    occasionally skin or mucous membrane




                                ua as
                              br ise
                            Fe D
   CNS most common site of clinical




                           n s
                        , o ou
    infection
                      ia cti
                    op fe
                  hi in
   Other organ systems affected:
                Et uro
              a, e
            ab al N



    – respiratory (“coin” lesion of lungs)
          Ab n
         s io




    – lymph nodes
       di nat
     Ad ter




    – skin and eyes
       In




    – bone
  In
Ad ter
  di nat
    s io
     Ab n
                                       Pathogenesis



       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                                 Cryptococcus neoformans




                                       10 e
Cryptococcus neoformans
Properties enabling CNS invasion




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Receptor   on CNS cells for yeast ligand




                                    27 Co
                                  ry e
                                ua as
   Ability to grow at 37o C




                              br ise
                            Fe D
   Melanin production by yeast



                           n s
                        , o ou
                      ia cti
    (antioxidant)
                    op fe
                  hi in
                Et uro

   Production of capsule (protective)
              a, e
            ab al N




   Resistance against C. neoformans
          Ab n
         s io




    chiefly CMI: corticosteroid therapy and
       di nat
     Ad ter




    HIV
       In
Cryptococcal meningitis
Signs and symptoms (Sabetta and Andriole




                                               10 e
1985)




                                             20 nc
                                           8, re
                                         -2 nfe
    Headache                          87%




                                       27 Co
                                     ry e
                                   ua as
    Fever                             60%




                                 br ise
                               Fe D
    Nausea   and vomiting                    53%


                              n s
                           , o ou
                         ia cti
    Altered mental status             52%
                       op fe
                     hi in
                   Et uro

    Meningeal signs                   50%
                 a, e
               ab al N




    Visual disturbances                      33%
             Ab n
            s io
          di nat




    Cranial nerve palsies                    32%
        Ad ter
          In
Cryptococcal meningitis
Signs and symptoms (Sabetta and Andriole




                                               10 e
1985)




                                             20 nc
                                           8, re
                                         -2 nfe
    Papilledema                       28%




                                       27 Co
                                     ry e
                                   ua as
    Ataxia                            26%




                                 br ise
                               Fe D
    Seizures                                 15%


                              n s
                           , o ou
                         ia cti
    Aphasia              10%
                       op fe
                     hi in
                   Et uro

    No signs or symptoms 10%
                 a, e
               ab al N
             Ab n
            s io
          di nat
        Ad ter
          In
Cryptococcal neoformans
Radiographic findings




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
   CT   and MRI usually normal




                                     27 Co
                                   ry e
                                 ua as
     – meningeal inflammation typically minimal




                               br ise
                             Fe D
   rarely   focal mass lesions


                            n s
                         , o ou
                       ia cti
     – cryptococcomas: indistinguishable from
                     op fe
                   hi in
       pyogenic abscess
                 Et uro
               a, e


     – pseudocysts: CSF equivalent w/o
             ab al N




       contrast+, “soap bubble” appearance
           Ab n
          s io
        di nat




     – choroid plexus granulomas
      Ad ter
        In
                             In
                           Ad ter
                             di nat
                               s io
                                Ab n
                                  ab al N
                                    a, e
                                      Et uro
                                        hi in
                                          op fe
                                            ia cti
                                              , o ou
                                                                  Radiographic findings




                                                 n s
                                                  Fe D
                                                    br ise
                                                      ua as
                                                        ry e
                                                          27 Co
                                                            -2 nfe
                                                              8, re
                                                                                    Cryptococcal neoformans




                                                                20 nc
                                                                  10 e
Lacunar infarct of right basal ganglia on CT scan
                                                         In
                                                       Ad ter
                                                         di nat
                                                           s io
                                                            Ab n
                                                              ab al N
                                                                a, e
                                                                  Et uro
                                                                    hi in
                                                                      op fe
                                                                        ia cti
                                                                          , o ou
                                                                                              Radiographic findings




                                                                             n s
                                                                              Fe D
                                                                                br ise
                                                                                  ua as
                                                                                    ry e
                                                                                      27 Co
                                                                                        -2 nfe
                                                                                          8, re
                                                                                                                Cryptococcal neoformans




                                                                                            20 nc
                                                                                              10 e
Contrast enhanced FLAIR (A and C) and T1WI (B and D)
 Cryptococcal neoformans
 Radiographic findings – IRIS in AIDS




                                                          10 e
                                                        20 nc
                                                      8, re
                                                    -2 nfe
                                                  27 Co
                                                ry e
                                              ua as
                                                                          Meningeal




                                            br ise
Small cerebellar                                                         enhancement




                                          Fe D
    lesion




                                         n s
                                      , o ou
                                    ia cti
                                  op fe
                                hi in
                              Et uro

                                                                    2 weeks after
                            a, e
                          ab al N




                                                                   the initiation of
                        Ab n
                       s io




                                                                       HAART
                     di nat
                   Ad ter
                     In




                                     Riedel DJ et al. (2006) Nat Clin Pract Neurol 2: 557
Cryptococcal meningitis
CSF findings




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
      WBC (<800 cells;lymph)                97%




                                     27 Co
  




                                   ry e
                                 ua as
   protein (<600 mg/dl)                    90%




                               br ise
                             Fe D
   opening pressure                                64%


                            n s
                         , o ou
                       ia cti
   glucose (15-35 mg/dl)                   55%
                     op fe
                   hi in
                 Et uro

   +India ink                              57%
               a, e
             ab al N




   +culture                                        75%
           Ab n
          s io
        di nat




   +crypt Ag (latex agg>CF)                        >95%
      Ad ter
        In
Cryptococcal meningitis
AIDS vs. non-AIDS:[+<25%; ++<50%; +++<75%; ++++<100%]




                                                10 e
                                              20 nc
                                            8, re
                                          -2 nfe
   Findings                    AIDS           non-AIDS




                                        27 Co
   symptoms<1-2 weeks          +              ++




                                      ry e
                                    ua as
   +India ink                  ++++           ++




                                  br ise
                                Fe D
   CSF Ag titer>1:1024         +++            +



                               n s
                            , o ou
                          ia cti
   +serum Ag                   +++            ++
                        op fe
                      hi in
    CSF WBC                    ++++           +
                    Et uro
                  a, e


    CD4 count                  ++++           +
                ab al N




   cryptococcemia              +++            +
              Ab n
             s io
           di nat
         Ad ter
           In
Cryptococcal meningitis
AIDS vs. non-AIDS:[+<25%; ++<50%; +++<75%; ++++<100%]




                                                 10 e
                                               20 nc
                                             8, re
                                           -2 nfe
  Findings                   AIDS               non-AIDS




                                         27 Co
                                       ry e
  extracranial sites         +++                +




                                     ua as
                                   br ise
  parenchym. lesions         ++                 +



                                 Fe D
                                n s
                             , o ou
  increased ICP              ++                 +

                           ia cti
  var neoformans         op fe
                             ++++               +++
                       hi in
                     Et uro

  suppressive Rx             ++++               +
                   a, e
                 ab al N




  + initial response         ++++               ++++
               Ab n
              s io
            di nat




  relapse                    +                  +
          Ad ter
            In
Cryptococcus neoformans
Histopathology




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Meningitis/meningoencephalitis




                                    27 Co
                                  ry e
       67%




                                ua as
                              br ise
                            Fe D
   Cysts                                          18%


                           n s
                        , o ou
                      ia cti
   Granulomas (cryptococcomas)
                    op fe
                  hi in
       8%
                Et uro
              a, e
            ab al N




   Encephalitis                                   4%
          Ab n
         s io




   Abscesses                                      2%
       di nat
     Ad ter
       In
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
                                       Histopathology



         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                                   Cryptococcus neoformans




                                       10 e
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                                                  Cryptococcal meningitis




                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e
                                       A Proposed Management Algorithm
Cryptococcal meningitis
Treatment




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Induction   (2 weeks)




                                    27 Co
                                  ry e
                                ua as
    – Amphotericin B 0.7 mg/dk/d




                              br ise
                            Fe D
    – +/- flucytosine



                           n s
                        , o ou
   Maintenance       (8 weeks)
                      ia cti
                    op fe
                  hi in
    – fluconazole 400 to 800 mg/d or
                Et uro
              a, e
            ab al N



    – itraconazole
          Ab n
         s io




   Secondary     prophylaxis (AIDS patients)
       di nat
     Ad ter




    – fluconazole 200 mg/d
       In
Cryptococcus neoformans
   Side effects of treatment




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
                                    27 Co
   Amphotericin




                                  ry e
                                ua as
    – fever, chills, H/A, N&V, phlebitis, cardiotoxicity,




                              br ise
      nephrotoxicity, hypomagnesemia, hypokalemia,




                            Fe D
      hepatotoxicity, cytopenias



                           n s
                        , o ou
                      ia cti
   5-Flucytosine
                    op fe
                  hi in
                Et uro
    – cytopenias, nephrotoxicity, hepatoxicity,
              a, e


      confusion, H/A, hallucinations
            ab al N
          Ab n
         s io




   Fluconazole
       di nat
     Ad ter




    – nausea and vomiting, headache, skin rash, abd
       In




      pain, diarrhea, hepatotoxicity, seizures
Cryptococcus neoformans
Prognostic factors




                                               10 e
                                             20 nc
                                           8, re
                                         -2 nfe
   ↑  CSF opening pressure




                                       27 Co
                                     ry e
                                   ua as
    + India ink test




                                 br ise
                               Fe D
    ↓ CSF leukocyte count



                              n s
                           , o ou
                         ia cti
    CSF hypoglycorrhachia
                       op fe
                     hi in
                   Et uro

    ↑ CSF cryptococcal Ag titer
                 a, e
               ab al N




    + blood culture
             Ab n
            s io
          di nat




    C. neoformans at extraneural sites
        Ad ter
          In




                                    Diamond and Bennett 1974
            0
                        50
                                    100




       0
  In
                                          Survival




       6
Ad ter
  di nat
    s io
     Ab n




       12
       ab al N
         a, e
           Et uro
             hi in



       18
               op fe
                 ia cti
                   , o ou
                      n s
       30
                       Fe D
                         br ise
                           ua as
                             ry e
                dead




                               27 Co
                       ill




                                 -2 nfe
                                          Cryptococcal meningitis -




                                   8, re
                                     20 nc
                                       10 e
                             well
                             ill
                             well
                             dead
Histoplasma capsulatum
Epidemiology




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
   Endemic  to Ohio River valley, central




                                     27 Co
                                   ry e
    Mississippi valley, Appalachian Mountains




                                 ua as
                               br ise
   Sources: soil, domestic and wild animals




                             Fe D
                            n s
                         , o ou
   Asymptomatic disease common:


                       ia cti
                     op fe
    – primary pulmonary infection
                   hi in
                 Et uro

    – RES affected
               a, e
             ab al N




   Most   commonly symptomatic in 1st year of
           Ab n
          s io




    life and 5-6 decades
        di nat
      Ad ter




   Incidence in AIDS is as high as 26% in
        In




    endemic areas to <1% in non-endemic
Histoplasma capsulatum
Systemic features




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
   Symptoms   develop              –   Dry Cough




                                     27 Co
                                   ry e
    in 3-17 days                    –   Headache




                                 ua as
                               br ise
    – typically 12-14 days          –   Sweats




                             Fe D
      following exposure



                            n s
                                    –   Chills


                         , o ou
                       ia cti
                of
   Constellation                   –   Fatigue
                     op fe
                   hi in
    symptoms include:               –   Hemoptysis
                 Et uro
               a, e


    – Fever                         –   Night sweats
             ab al N
           Ab n




    – Chest Pain
          s io
        di nat




    – Weight loss
      Ad ter
        In
  In
Ad ter
  di nat
                                       Chest X-ray


    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                                 Histoplasma capsulatum




                                   8, re
                                     20 nc
                                       10 e
Histoplasma capsulatum
Dissemination to the CNS




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Dissemination usual in




                                    27 Co
                                  ry e
    immunosuppression




                                ua as
                              br ise
                            Fe D
   CNS disease in 10-25% with




                           n s
                        , o ou
    dissemination
                      ia cti
                    op fe
                  hi in
    – meningitis (basal)
                Et uro
              a, e


    – IC mass lesions
            ab al N
          Ab n




   CNS   disease may occur many years
         s io
       di nat




    after apparent cure
     Ad ter
       In




   Culture negative biopsy may be
    mistaken for sarcoidosis
Histoplasma capsulatum
Clinical features




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
   Symptoms:




                                     27 Co
                                   ry e
                                 ua as
     – Headache, confusion




                               br ise
                             Fe D
   Signs:




                            n s
                         , o ou
                       ia cti
     – Altered LOC
                     op fe
                   hi in
     – Cranial neuropathies
                 Et uro
               a, e
             ab al N



     – Seizures, personality change, focal
           Ab n




       features in 10%
          s io
        di nat




     – Meningismus (10%)
      Ad ter
        In
Histoplasma capsulatum
Diagnosis




                                                10 e
                                              20 nc
                                            8, re
                                          -2 nfe
     Chest X-ray normal in 33%




                                        27 Co
     CSF with monocytic pleocytosis, ↑protein, ↓glucose




                                      ry e
                                    ua as
      – Occasionally persistent neutrophilic pleocytosis




                                  br ise
                                Fe D
     Positive CSF cultures in 50%-66%




                               n s
                            , o ou
     Blood culture + in 50%

                          ia cti
                        op fe
      Bone marrow culture + 33-60%
                     hi in
                    Et uro

      – Culture negative bx may be mistaken for sarcoidosis
                  a, e
                ab al N



     + Serum and CSF histoplasma Ag – specific
              Ab n




      – 95% of urine + and 85% of blood in HIV+
             s io
           di nat




     + Serum and CSF histoplasma Ab
         Ad ter
           In
Histoplasma capsulatum
Treatment




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   CNS   disease requires amphotericin




                                    27 Co
                                  ry e
                                ua as
    – Liposomal ambisome or ambisome lipid




                              br ise
      complex




                            Fe D
                           n s
                        , o ou
    – Decreases risk of renal toxicity

                      ia cti
   Itraconazole    op fe
                  hi in
                Et uro
              a, e


    – Oral itraconazole may be started after 2
            ab al N




      weeks
          Ab n
         s io
       di nat




    – Check liver functions
     Ad ter
       In




    – Check serum levels after 2 weeks
      (>1µg/ml)
Coccidioides immitis
Epidemiology




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
  Dimorphic yeast




                                    27 Co
                                  ry e
                                ua as
  Endemic to San Joaquin valley &




                              br ise
   Arizona



                            Fe D
                           n s
                        , o ou
  Found in soil - inhaled into lungs

                      ia cti
                    op fe
                  hi in
  Predisposing factors for dissemination:
                Et uro
              a, e


   – pregnancy, DM, immunodeficient states
            ab al N




   – More common in African Americans and
          Ab n
         s io
       di nat




     Latinos
     Ad ter
       In
  In
                                       In culture

Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                                               Coccidioides immitis




                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e
Coccidioides immitis
Clinical manifestations




                                                  10 e
                                                20 nc
                                              8, re
                                            -2 nfe
       Six main




                                          27 Co
   




                                        ry e
       presentations




                                      ua as
                                    br ise
       – Asymptomatic




                                  Fe D
                                 n s
             »   Most common



                              , o ou
                            ia cti
       –     Pulmonary
                          op fe
                        hi in
       –     Skin
                      Et uro
                    a, e


       –     Soft tissue
                  ab al N




       –     Skeletal
                Ab n
               s io
             di nat




       –     Meningitis
           Ad ter
             In
Coccidioides immitis
Features of severe infection




                                                10 e
                                              20 nc
                                            8, re
                                          -2 nfe
 Loss   of body weight >10% baseline




                                        27 Co
                                      ry e
 Intense night sweating >3 weeks




                                    ua as
                                  br ise
 Infiltrates involving >50% of one lung or portions




                                Fe D
                               n s
                            , o ou
  of both lungs

                          ia cti
                        op fe
   – prominent or persistent hilar lymphadenopathy.
                      hi in
                    Et uro

 Anti-coccidioidal      complement fixing antibody
                  a, e
                ab al N




  titer >1:16.
              Ab n
             s io




 Failure of dermal hypersensitivity to coccoidal
           di nat
         Ad ter




  Ags
           In




 Symptoms may also persist for >2 months.
Coccidioides immitis
Neuropathology




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
                                     27 Co
  Meningitis alone (13%)




                                   ry e
                                 ua as
  Meningitis with cerebritis (78%)




                               br ise
                             Fe D
  Scattered miliary granulomas (9%)



                            n s
                         , o ou
                       ia cti
                     op fe
                   hi in
                 Et uro
               a, e
             ab al N
           Ab n
          s io
        di nat
      Ad ter
        In
Coccidioides immitis
Diagnosis




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Brain   imaging




                                    27 Co
                                  ry e
    – Normal or meningeal features




                                ua as
                              br ise
   CSF




                            Fe D
                           n s
    – Presence of eosinophils (>10 eos/ml3 ) -

                        , o ou
                      ia cti
      ≤30%
                    op fe
                  hi in
    – Some eosinophils in 70%
                Et uro
              a, e
            ab al N




   Diagnosis
          Ab n
         s io




    – + CSF Complement fixations - Ab to C.
       di nat
     Ad ter




      immitis
       In




    – + CSF cultures for C. immitis
Coccidioides immitis
Treatment




                                                 10 e
                                               20 nc
                                             8, re
                                           -2 nfe
     Ambisome for meningitis or refractory cases




                                         27 Co
      – Direct port into the CSF may be required




                                       ry e
                                     ua as
      – Lifetime Rx with imidazole may be needed




                                   br ise
      Fluconazole is first line.




                                 Fe D
  




                                n s
                             , o ou
      – Good CSF penetration


                           ia cti
      – Effective in ~75% of patients
                         op fe
                       hi in
      Itraconazole is equally effective
                     Et uro
  
                   a, e


      – Poor CSF penetration
                 ab al N




      Voriconazole
               Ab n




  
              s io
            di nat




      –   Broad spectrum in vitro agent
          Ad ter




      –   Good efficacy either PO or IV
            In




      –   Efficacy is nearly as good as ambisome
      –   Visual changes (~20%) & hallucinations (~5%)
Actinomycosis




                                               10 e
                                             20 nc
                                           8, re
                                         -2 nfe
 Endemic    in Africa, India and




                                       27 Co
                                     ry e
  S. and C. America




                                   ua as
                                 br ise
 Most commonly skin




                               Fe D
                              n s
  infection following traumatic


                           , o ou
                         ia cti
  inoculation of organism
                       op fe
                     hi in
                   Et uro
   – Maduromycosis (mycetoma
                 a, e


     pedis)
               ab al N
             Ab n




 CNS   infection reported
            s io
          di nat
        Ad ter
          In
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
 P. Boydii in transplant patient
                               27 Co
                                 -2 nfe
                                   8, re
                                       Pseudoallescheria boydii




                                     20 nc
                                       10 e
Blastomycosis dermatitidis




                                                10 e
                                              20 nc
                                            8, re
                                          -2 nfe
    Uncommon infection




                                        27 Co





                                      ry e
   Most common in USA




                                    ua as
                                  br ise
   M:F ratio of ~10:1




                                Fe D
                               n s
    Transmission by inhalation from


                            , o ou




                          ia cti
    decomposing vegetation and
    rotting wood        op fe
                      hi in
                    Et uro

    Usually indolent with chronic
                  a, e



                ab al N




    progression
              Ab n
             s io




    Skin lesions in exposed areas
           di nat





         Ad ter




   CXR with nodular infiltrates in
           In




    ~65% of cases
Blastomycosis dermatitidis




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Uncommon   cause of meningitis




                                    27 Co
                                  ry e
                                ua as
   Also causes vertebral osteomyelitis




                              br ise
                            Fe D
   Treatment



                           n s
                        , o ou
                      ia cti
    – Liposomal amphotericin B
                    op fe
                  hi in
                Et uro
    – Voriconazole may be used as follow on
              a, e



      therapy or in amphotericin intolerant
            ab al N
          Ab n
         s io
       di nat
     Ad ter
       In
Sporotrichosis schenckii




                                                 10 e
                                               20 nc
                                             8, re
                                           -2 nfe
   Found worldwide




                                         27 Co
   In soil, moss, rose thorns, hay




                                       ry e
                                     ua as
    Typically chronic skin infection




                                   br ise





                                 Fe D
   Forms




                                n s
                             , o ou
    – Cutaneous


                           ia cti
                         op fe
    – Pulmonary        hi in
                     Et uro
    – Disseminated – including CNS
                   a, e
                 ab al N



   To 1987 – only 15 cases in world
    literature of CNS sporotrichosis
               Ab n
              s io
            di nat




   Dx:
          Ad ter




    – Difficult to culture
            In




    – CSF/blood Ab to Sporotrichosis
                                       Scott et al: N Engl J Med. 1987;317:935.
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
                    True Hyphae
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e
Mucormycosis
(phycomycosis)




                                            10 e
                                          20 nc
                                        8, re
   Mucoraceae       (Rhizopus, Mucor,




                                      -2 nfe
                                    27 Co
    Absidia)




                                  ry e
                                ua as
   ubiquitous bread & fruit mold, soil,




                              br ise
                            Fe D
    manure


                           n s
                        , o ou
                      ia cti
   1885- described with brain abscesses
                    op fe
                  hi in
   most aggressive fungal infection
                Et uro
              a, e
            ab al N




   worldwide distribution and all ages
          Ab n
         s io




   classic triad:
       di nat
     Ad ter




    – diabetic ketoacidosis
       In




    – naso-orbital necrotizing infection
    – meningoencephalitis
Mucormycosis
(phycomycosis)




                                            10 e
                                          20 nc
                                        8, re
   95%   immunocompromised:




                                      -2 nfe
                                    27 Co
    – diabetes mellitus 70%




                                  ry e
                                ua as
    – hematologic malignancy (lung or




                              br ise
      dissemin.)




                            Fe D
                           n s
    – renal transplant


                        , o ou
                      ia cti
    – IVDA (m.c. cause of IC fungal abscess)
                    op fe
                  hi in
    – Rx with desferroxamine
                Et uro
              a, e
            ab al N




   Pathology:
          Ab n
         s io




    – hyphae invade arterial walls, spread into
       di nat




      brain
     Ad ter
       In




    – 1/3 thromb int carotid artery (hemorrh.
      infarct)
    – cavernous sinus thrombosis common
Mucormycosis
(phycomycosis)




                                             10 e
                                           20 nc
                                         8, re
                                       -2 nfe
   Symptoms: facial pain, diplopia, lacrimation,




                                     27 Co
                                   ry e
    nasal stuffiness or discharge, fever, lethargy




                                 ua as
                               br ise
   Signs: nasal ulcer, nasal discharge, facial




                             Fe D
                            n s
                         , o ou
    swelling, cranial nerve abn, ophthalmoplegia,

                       ia cti
                     op fe
    focal deficits, seizures
                   hi in
                 Et uro

   Radiographic       studies: bone erosion &
               a, e
             ab al N




    sinus opacification; BG m.c. site of abscess
           Ab n
          s io
        di nat




   CSF: non-specific; cultures negative
      Ad ter
        In
Mucormycosis
(phycomycosis)




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Morbidity   and mortality:




                                    27 Co
                                  ry e
    – >90% before amphotericin




                                ua as
                              br ise
    – now >70% DM and ~20% others




                            Fe D
                           n s
    – 70% with residual deficits

                        , o ou
                      ia cti
   Treatment       op fe
                  hi in
                Et uro

    – correction of metabolic abnormality
              a, e
            ab al N




    – exenteration of infected tissues
          Ab n
         s io




    – amphotericin B
       di nat
     Ad ter




    – ?hyperbaric O2
       In
Aspergillosis




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   “aspergillum”: sprinkles holy water




                                    27 Co
                                  ry e
                                ua as
   1897 - sphenoid lesion w/spread to




                              br ise
                            Fe D
    optic chiasm and internal carotid artery


                           n s
                        , o ou
                      ia cti
   ubiquitous: soil, water, organic debri
                    op fe
                  hi in
                Et uro

   >9 of 200 species cause CNS lesions
              a, e
            ab al N




   worldwide distribution
          Ab n
         s io
       di nat




   no sex or age predilection
     Ad ter
       In
Aspergillosis




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Risk   factors:




                                    27 Co
                                  ry e
    – neutropenia: hematologic neoplasms,




                                ua as
                              br ise
      organ & BM transplants




                            Fe D
                           n s
    – DM, IVDA,hepatic disease, Cushings


                        , o ou
                      ia cti
    – sarcoidosis, TB
                    op fe
                  hi in
                Et uro

   Pathology:
              a, e
            ab al N




    – vasculitis and infarct
          Ab n
         s io




    – cerebritis and abscess
       di nat




    – granuloma (rare)
     Ad ter
       In
Aspergillosis




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   lungssite of primary infection




                                    27 Co
   two patterns of CNS infection




                                  ry e
                                ua as
                              br ise
    – direct extension from paranasal sinuses




                            Fe D
                           n s
    – hematologic dissemination


                        , o ou
                      ia cti
       » CNS involved in 15% of pulmonary cases
                    op fe
                  hi in
       » CNS in 40-60% of all disseminated cases
                Et uro
              a, e


   stroke syndrome m.c. manifestation
            ab al N
          Ab n




   serological studies experimental
         s io
       di nat
     Ad ter




   Rx: extirpation/drainage and AmphoB
       In
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                    Pseudohyphae
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e
Candida




                                            10 e
                                          20 nc
                                        8, re
               >90%; other species <10%




                                      -2 nfe
   C.albicans




                                    27 Co
   Normal flora: skin, oropharynx, gut,




                                  ry e
                                ua as
    vagina




                              br ise
                            Fe D
    – blood seeded by gut, IV lines, endocarditis



                           n s
                        , o ou
                      ia cti
   Compromised   neutrophil function
                    op fe
                  hi in
                Et uro

   At autopsy, most common fungal brain
              a, e



    dis.
            ab al N
          Ab n
         s io




   Pathology:
       di nat
     Ad ter




    – microabscess - typical lesion
       In




    – full sized abscess in <14%
    – meningitis/ependymitis probably <15%
Candida




                                            10 e
                                          20 nc
                                        8, re
                                      -2 nfe
   Clinical   manifestations are non-specific:




                                    27 Co
                                  ry e
    – confusion, drowsiness, stupor, fever




                                ua as
                              br ise
   Meningiticsigns m.c. than w/other fungi



                            Fe D
                           n s
                        , o ou
   Focal signs with full-sized abscess

                      ia cti
                    op fe
   Usually very ill and on IV antibiotics
                  hi in
                Et uro
              a, e


   CSF non-specific; cultures negative
            ab al N
          Ab n




   Frequent presence of Candida at other
         s io
       di nat




    sites
     Ad ter
       In




   Rx: AmphoB w or w/o oral flucytosine
  In
Ad ter
  di nat
    s io
     Ab n
       ab al N
         a, e
           Et uro
             hi in
               op fe
                 ia cti
                   , o ou
                      n s
                       Fe D
                         br ise
                           ua as
                             ry e
                               27 Co
                                 -2 nfe
                                   8, re
                                     20 nc
                                       10 e

				
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