NEUROLOGY

Far  Eastern  University  –  Dr.  Nicanor  Reyes  Medical  Foundation  

Institute  of  Medicine

NEUROCYTOLOGY  AND  THE  PATHOLOGIC  REACTIONS  OF  THE  NERVOUS  SYSTEM  (1.1/4)  
 
The  NERVOUS  SYTEM  is  composed  of:   MECHANISM  OF  CELL  DEATH  IN  THE  NERVOUS  SYSTEM    
§ Neurons  and  glial  cells  derived  from  the  neuroectoderm    
§ Supporting  cells  derived  from  the  mesoderm       Neurons,  Glial  cells,  and  Endothelial  cells  
§ Neurons  -­‐  functional  units  of  the  nervous  system   -­‐ may   follow   at   least   two   separate   pathways   for   cell  
§ Signaling   and   Trophism   -­‐   two   important   and   death,  which  differ  morphologically  and  biochemically  
interrelated  functions      
§ Mature   neurons   do   not   proliferate,   but   undergo   NECROSIS   APOPTOSIS  
 adaptive  changes  in  response  to  injury       Reflects  underlying  pathologic   § programmed  cell  death  
§ Most   disease   processes   that   affect   neurons   produce   process  that  produces:   § essential   for   normal  
 neuronal  degeneration  or  neuronal  loss       § abrupt  and  severe  loss  of   development   and   tissue  
  supply   of   oxygen   or   homeostasis  
CELLULAR  ELEMENTS  OF  THE  NERVOUS  SYSTEM       glucose   for   ATP   Triggered  by:  
  production   (hypoxemia,   § DNA  mutations  
a. Neurons   hypoglycemia/  ischemia)   § inflammatory  mediators  
-­‐ from  ectoderm   § excessive   mechanical   § abnormal   accumulation  
-­‐ functional  units  of  the  nervous  system   strain  (traumatic  injury)   of  intracellular  proteins  
-­‐ mature   neurons   do   not   undergo   proliferation;   § excessive   increase   in   § oxidative  stress  
only  neuronal  degeneration  and  loss   neuronal   energy  
  demands   (prolonged  
b. Supporting  Cells  (Neuroectodermal  Origin)   seizures)  
§ Oligodendroglia  –  forms  myelin  sheaths  in  CNS    
§ Schwann  cells  –  forms  myelin  sheaths  in  PNS    
§ Astrocytes   -­‐   widely   distributed   throughout   the     PATHOLOGIC  REACTIONS  OF  NEURONS    
CNS;   lie   near   both   the   neurons   and   blood        
 vessels   I.  Nonspecific    
  § Any  disease  leading  to  a  patient’s  death  
c. Ependymal  cells     § Associated   with   changes   in   body   chemistry   and  
-­‐ form   a   single   layer   of   ciliated    columnar   physiology  affecting  the  appearance  of  neurons    
epithelial   cells   that   lines   the    entire   ventricular   § Catabolic   processes   that   proceed   after   death  
system   (autolysis)  and  the  mechanical  procedures  can  distort  
-­‐ provide   selective   barrier   between   the   the  appearance  of  neurons    
 ventricular  fluid  and  the  brain    substance   § Neuronal  loss    
-­‐ gives  rise  to  the    choroid  plexus  which  produces    
the  CSF   II. Specific    
  § Ischemic  cell  change  
d. Supporting  Cells  of  Mesodermal  Origin     § Deprivation   of   oxygen   and   cessation   of   oxidative  
§ Microglia   metabolism  which  leads  to  morphologic  changes  
-­‐ cells   of    monocyte   lineage   that   migrate   into   the   § In  8-­‐12  hours,  
CNS   along   with   blood   vessels   from   the   -­‐ neurons  become  smaller;  outline  becomes  more  
mesoderm  surrounding  the  neural  tube   sharply  angular      
-­‐ migrate   into   the   CNS,   proliferate   to   become   -­‐ cytoplasm  becomes  eosinophilic      
scavenger   cells   or   macrophages,   removing   -­‐ nucleus  shrinks  and  becomes  darkly    stained      
damaged  tissues   -­‐ complete  (irreversible)  dissolution  of    the  neuron    
-­‐ normally  present  in  small  numbers       § Causes:  
§ Connective  Tissue  Cells     -­‐ loss  of  blood  flow      
-­‐ meninges  surrounding  the  nervous  system     -­‐ lack  of  oxygen  in  the  blood      
-­‐ fibrous   connective   tissue   surrounding   the   -­‐ lack   of   substances   necessary   for    oxidative  
peripheral  nerves     metabolism    
  -­‐ poison  (Cyanide)  blocking  oxidative    metabolism    
   
   
     
Prepared  by  Joan  Marie  Sales   1  
MD  2017  -­‐3D    
 
 § Biochemical  and  molecular  events  after  oxygen   delicate   connective   tissue   sheath   called  
deprivation:   endoneurium   (both   these   structures   maintain  
  the   integrity   even   as   the   axon   and   myelin  
    In  several  (2-­‐5)  minutes,   degenerate)  
-­‐ respiratory   chain   process   on   the   inner   § Schwann  cells  proliferate  along  the  entire  length  
 mitochondrial   membrane   ceases   that   depletes   of  the  degenerating  fiber      
the   sotred   ATP   and   impairs   the   ion   channels   § Distal   portion   of   a   damaged   nerve   provides   a  
there  by  leading  to  anaerobic  glycolysis,    lactate   superstructure   that   is   ready   to   receive   and  
production   and   further   inhibition   of   myelinate  new  axonal  sprouts  growing  from  the  
mitochondrial  function     proximal  portion;  If  these  axonal  sprouts  can  find  
-­‐ irreversible   changes   that   ultimately   lead   to   cell   their   way   into   one   of   these   tubes,   they   will  
death   are   excitotoxicity    (glutamate),   continue   to   grow   at   a   rate   of   3   mm/   day   and  
accumulation   of   intracellular    calcium   and   function  may  eventually  be  restored    
generation  of  free  radicals      
  4. Regeneration  in  the  CNS  is  not  Possible  
  § No   basement   membranes   or   collagen   sheaths  
A. PATHOLOGIC  REACTIONS  OF  NEURON  (specific)   (endoneuriums)  surrounding  nerves  
  § Oligodendroglia  are  incapable  of  proliferation  
1. Central  Chromatolysis   § New  axonal  growth  has  no  path  to  follow    
§ Also   called   axonal    
reaction   5. Neurofibrillary  Degeneration  
§ Change   in   neuronal   cell   § Formation   of   clump  
bodies   after   severe   masses   of   neurofibrils  
injury  to  the  axons   within   the   cytoplasm  
§ Seen  in  large  motor  cells   (CNS  neurons)  
§ Begins   2-­‐3   days   after   § Seen   in   Alzheimer’s  
injury   (maximum   in   2-­‐3   Disease  (dementia)  -­‐  neurodegenerative  disease    
weeks):     § In   the   brain   of   a   patient   with   Alzheimer’s  
-­‐    swelling  of  the  cell  body       disease:   Neurons   have   neurofibrillary   tangles  
-­‐    dissolution  of  the  Nissl  granules       consisting   of   an   accumulation   of  
-­‐    nucleus  migrates  to  the  periphery       hyperphosphorylated   tau   proteins.   Also   with  
§ Reversible;   normal   appearance   of   the   neuron   neuritic   plaques,   which   consists   of   extracellular  
may  be  restored  in  a  few  months     accumulation   of   B-­‐   amyloid   peptide   surrounded  
  by  dystrophic  neurites    
2. Wallerian  Degeneration    
§ Occurs   in   the   6. Neuronal  Inclusions  (Inclusion  Body  Formation)  
distal  part  of  the   § Abnormal  discrete  deposits  in  neurons  
axon   when   the   § Lewy   Bodies   in   the   cytoplasm   of   pigmented  
parent   body   is   dopaminergic   neurons   of   the   substantia   nigra  
destroyed   or   pars  compacta  in  Parkinson  disease  
separated   from   § These   cytoplasmic   inclusions   consist   of  
the   axon   by   accumulations   of   alpha-­‐synuclein   which   are  
disease  or  injury  (both  the  CNS  and  PNS,  an  axon   identified   in   routine   preparations   by   their  
cannot  survive  when  it  is  separated  from  its  cell   eosinophilic  core  surrounded  by  a  pale  “halo”  
body)   § The   distinguishing   features   of   several   important  
§ Unlike   in   the   CNS,   occurs   more   rapidly   in   neurodegenerative  diseases    
peripheral   nerves;   degenerative   changes   are   -­‐  Pick  bodies  in  the  neurons  of  hippocampus    
completed  in  a  few  weeks     -­‐  Cowdry  type  A  intranuclear  inclusion      
  -­‐    impairment  of  axonal  transport        
  -­‐    disappearance  of  neurofibrils       7. Storage  Cells  
  -­‐   breaking   up   of   axons   into   short    fragments   § Accumulation   of   metabolic   products   within   the  
that  eventually  disappear       nerve  cells  
  § Metabolic  diseases  involving  storage  of  lipids;  As  
3. Regeneration  in  the  PNS       these   lipid   products   accumulate,   the   cell   body  
§ Regeneration   of   the   nerve   is   possible   if   the   swells,  and  is  referred  to  as  “balloon”  cell    
parent   cell   body   survives   (does   not   occur   in   the   § Neuron   in   Tay-­‐Sach’s   disease   (lipid-­‐storage  
CNS  )   disease):   ballooning   of   cytoplasm   with   stored  
§ Each   axon   and   myelin   sheath   in   a   peripheral   material   forcing   the   nucleus   and   Nissl   granules  
nerve   is   surrounded   by   a   basement   membrane   to  end  corner  of  the  cell    
which   belongs   to   the   Schwann   cell,   and   by   a    

Prepared  by  Joan  Marie  Sales   2  

MD  2017  -­‐3D    
 
B. PATHOLOGIC  REACTIONS  OF  OLIGODENDROGLIA     D. PATHOLOGIC  REACTIONS  OF  ASTROCYTES      
   
§ Extremely   sensitive   to   injury,   including   ischemia   and   § 2  Types  of  Astrocytes  
metabolic  disorders      
§ Have   a   range   of   responses   to   injury   that   vary    
according  to  the  type  of  lesion        
§ Nuclei  shrink  or  break  up  then   dissolve  when  affected   a. Protoplasmic  
by  pathologic  responses   Astrocytes   –  
  predominantly  in  
1. Demyelinating/  Myelinoclastic  Diseases    the   gray   and  
§ Normal   myelin   is   attacked   by   some   exogenous   subcortical   white  
agent   (usually   unknown)   and   broken   down   into   matter;  shorter  processes;  less  fibrils  
its  component  lipids  and  absorbed  (eg.  Multiple    
Sclerosis     b. Fibrillary   Astrocytes   –   are   predominantly   in   the  
§ Demyelination   may   be   a   nonspecific    white  matter;  long  processes,  abundant  fibrils    
manifestation   of   ischemic,   infectious,   toxic   or    
metabolic   injury   to   oligodendrocytes,   but   it   is   § Almost   any   CNS   injury   can   produce   reaction   of  
often  immune-­‐mediated   astrocytes  
§ Multiple   Sclerosis   -­‐   most   common   immune-­‐   § Astrocytosis/   Astrogliosis/   Gliosis   (proliferate   and  
related  demyelinating  disease    increase  in  number)      
  § Hypertrophy   and   Hyperplasia  –  in  acute  and  chronic  
2. Leukodystrophies/  Dysmyelinating  Diseases    diseases,   astrocytes   commonly   increase   in   size   and  
§ Myelin   is   abnormally   formed   owing   to   a    number      
genetically   determined   error   in   metabolism;   § Gemistocytic/   Hypertrophied   Astrocyte   -­‐   “plump”  
unstable  and  breaks  down    displays   a   large,   round   cytoplasm   with   short  
§ Genetically   determined   disorders   that   are   fibrillated    processes   and   a   vesicular,   eccentrically  
commonly   due   to   defects   of   lysosomal   or   displaced   nucleus;   cytoplasm   becomes   visible;   form  
peroxisomal  metabolism     longer   and   thicker   processes   which   form   a   dense  
§ Result   from   he   failure   to   form   and   maintain   network  in  the  damaged  tissue    
normal  myelin  sheaths     § Reactive  Astrocytosis    
  -­‐ Reactive   astrocytes   at   the   border   of   an   infarct.  
  Note   the   expansion   of   the   cytoplasm   producing  
C. PATHOLOGIC  REACTIONS  OF  SCHWANN  CELLS     a   plump   appearance   (gemistocysts)   and   the  
  dense  tangle  of  fibers  in  the  background    
1. Segmental  Demyelination    
§ Disease   processes   of    
Schwann   cells   affect   E. PATHOLOGIC  REACTIONS  OF  MICROGLIA    
peripheral  axon   § Microglial   cells,  
§ Immune-­‐mediated   derived   from   bone  
disorders,   such   as   acute   marrow   monocytes,  
or  chronic  inflammatory   enter   the   nervous  
neuropathies,   may   tissue   during   early  
produce   segmental   loss   brain  development    
of   myelin   (segmental   § Proliferate,   migrate,  
demyelination)     and   mature   into  
§ Guillain-­‐Barre   syndrome   resident  or  resting  microglia    
(acute)   § Major   function   is   the   surveillance   of   and   participation  
  in  immunologic  processes    
2. Repeated  Demyelination  and  Remyelination     § Activated  rod-­‐shaped  microglia  in  encephalitis:  
§ Hereditary  demyelinating  neuropathies  (Charcot-­‐   -­‐ Presence   of   many   rod   cells   indicate   low-­‐grade  
Marie-­‐Tooth  Disease  of  HSMN  I)     chronic   irritation   (e.g.   chronic   encephalitis  
§ Genetic   disorders   affecting   peripheral   nerves   associated  with  neurosyphilis)  
(mutations   of   genes   encoding   for   peripheral   -­‐ Prominent   in   viral   diseases   and   parenchymal  
myelin  proteins)     neurosyphilis,  are  distinguished  by  conspicuously  
§ Each   episode   leaves   a   layer   of   Schwann   cells   and   hypertrophied  rod-­‐shaped  nuclei    
collagen,   forming   concentric   layers   around   the   -­‐ React  in  a  stereotyped  way  to  most  diseases  that  
axon,  nerves  become  large     affect  the  CNS    
  -­‐ Recognized   by   their   elongated   rod-­‐shaped  
  nuclei,  hence  the  name  rod  cells    
  -­‐ Prominent  in  chronic  infections    

Prepared  by  Joan  Marie  Sales   3  

MD  2017  -­‐3D    
 
F. PATHOLOGIC  REACTIONS  OF  EPENDYMAL  CELLS     § Lesions:  
  a. Mass   lesion   –   considered   when   the   signs   and  
§ Ependymal  cells  react  in  a  very  limited  way  to  noxious   symptoms,   whether   acute,   subacute   or   chronic  
stimuli  (most  often  are  infectious)     in   onset,   suggest   progression   of   a   focal   lesion  
§ There   is   loss   of   ependymal   cells;   however,   the   (eg.  neoplasm,  hematoma)  
proliferation   of   subependymal   astrocytes   forms   b. Nonmass  lesion  –  considered  when  the  lesion  is  
“ependymal   granulations”   (not   actually   ependymal   diffuse   in   location   or   when   signs   and   symptoms  
cells)   suggest   a   nonprogressive   focal   abnormality   (eg.    
§ In   response   to   injury,   blood   vessels   may   respond   by   meningitis,  encephalitis)  
capillary  proliferation    
§ When   inflammation   is   present,   infiltration   of   DEGENERATIVE  DISEASE    
leukocytes  occurs     § Chronic,  progressive,  diffuse  
  § No   cause   is   apparent;   many   are   familial   biochemical  
  disorders  
CEREBRAL  EDEMA   § Characterized   by   a   gradual   decrease   in   neuronal  
a. Cytotoxic  Edema   function  
-­‐ More  likely  to  affect  gray  matter   § The  neurons  show  specific  changes    
-­‐ Failure   of   Na-­‐K   pump   leads   to   Na   retention   -­‐ Neurofibrillary  tangles  in  Alzheimer  disease    
intracellularly   then   water   is   attracted   leading   to   -­‐ Inclusion  body  (Lewy  body)  in  Parkinson  disease  
cellular  edema   § The  neurons  atrophy  and  disappear    
b. Vasogenic  Edema    
-­‐ Predominantly  in  the  white  matter   NEOPLASTIC  DISEASE    
-­‐ Loss  of  integrity  of  the  blood-­‐brain  barrier  leads   § Chronic,  progressive,  focal;  any  cell  type  can  undergo  
to   excessive   water   and   large   solutes   (serum   neoplastic  changes  and  proliferate  
proteins)   escape   the   capillaries   to   go   to   § Neurons   are   normally   incapable   of   cell   division   after  
extracellular  space   cell   differentiation   is   complete;   neoplasms  
c. Interstitial  Edema   (neurocytomas)  are  extremely  rare  
  § Astrocytes  –  most  reactive  cells  of  CNS  
  § Astrocytomaas  –  most  common  primary  CNS  Tumors  
CLINICOPATHOLOGIC  CORRELATIONS     § CNS  tumors  do  not  metastasize  outside  the  CNS  
  § The  degree  of  malignancy  may  be  graded  considering  
§ To   arrive   at   a   neurologic   diagnosis,   detailed   history   the   degree   of   pleomorphism   (lack   of   uniformity   of  
taking  with  careful  and  correct  neurologic  examination   appearance   and   nuclear-­‐cytoplasmic   ratio)   of   tumor  
should  be  obtained       cells,   frequency   of   mitotic   figures,   proliferation   of  
  tumor  vessels,  and  necrosis  of  tumor  tissue  
§ Neurologic  disease  may  be  classified  as:   § In  children,  infratentorial  tumors  are  common  
a. Focal   –   involving   a   single   circumscribed   area   or   § Cerebellar  medulloblastoma  is  the  most  common  
group  of  contiguous  structures   § Among  adults,  supratentorial  tumors  are  common    
b. Multifocal   –   involving   more   than   one    
circumscribed   area   or   several   noncontiguous   VASCULAR  DISEASE    
structures     § Acute,   sudden   onset   ;   may   be   focal   or   diffuse   in  
c. Diffuse   –   involving   portions   of   the   nervous   distribution      
system  in  a  bilateral,  symmetrical  fashion   § Neurons   deprived   of   metabolic   support   (oxygen   and  
   glucose)   cease   functioning   in   seconds   and   undergo  
§ The  development  of  symptoms  can  be  classified  as:      pathologic  changes  in  minutes      
a. Acute  –  within  minutes   § Two  types:      
b. Subacute  –  within  days   a. Infarct  
c. Chronic  –  within  weeks  or  months     -­‐  Atherothrombotic  (most  common)  
  -­‐  Embolic  (Atrial  Fibrillation)  
§ The  evolution  of  symptoms  may  be  classified  as:   b. Hemorrhagic    
a. Transient  –  symptoms  have  resolved  completely   -­‐  Cerebral  (intra)  
after  onset   -­‐  Subarachnoid  (ruptured  aneurysm)  
b.  Improving   –   symptoms   have   decreased   from    
their   maximum   but   have   not   completely   TOXIC-­‐METABOLIC  DISEASE    
resolved   § Diffusely   distributed;   may   affect   the   nervous   system  
c. Progressive  –  symptoms  continue  to  increase  in   acutely,  subacutely  or  chronically    
severity  or  when  there  are  new  symptoms     § Various   chemical   agents;   vitamin   deficiencies;   genetic  
d. Stationary   –   symptoms   remain   unchanged   after   biochemical  disorders  
a  period  of  time   § Encephalopathies  of  kidney  and  liver  diseases      
 

Prepared  by  Joan  Marie  Sales   4  

MD  2017  -­‐3D