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'''Neuropathology''' is the bane of many anatomical pathologists in teaching hospitals... 'cause they have to fill in for the neuropathologist when he or she is on vacation.
[[Image:MCA-Stroke-Brain-Human-2.JPG|thumb|right|Gross image showing changes of a [[stroke]]. (WC/Marvin 101)]]
This article is an introduction to '''neuropathology'''. There are separate articles for [[brain tumours]], the [[pituitary gland]], the [[spine]], the [[eye]], [[muscle pathologies]], [[neurohistology]] and [[neuroanatomy]].


This article is an introduction to neuropathology.  There are separate articles for [[brain tumours]], the [[pituitary gland]] and [[muscle pathologies]].
Neuropathology is the bane of many anatomical pathologists in teaching hospitals... 'cause they have to fill in for the neuropathologist when he or she is on vacation.


==Gross==
==Neuroanatomy==
*Uncus (as in ''uncal herniation'').
{{Main|Neuroanatomy}}
*Cerebellar tonsils (as in ''tonsillar herniation'').
This is a large topic. It covered in a separate article, that also covers grossing.


*Longitudinal fissure - divides cerebrum into hemispheres.
==Neuroradiology==
*Central sulcus - separate ''parietal lobe'' from ''frontal lobe''.
Key factors to consider in evaluation:
*Lateral sulcus (Sylvian fissure).
# Location.
# Number of lesions - single versus multiple.
# Cystic versus solid lesion.
# Enhancement.


===Less important===
==Lesion location==
*Glomeruli of Arnold.
In neuroradiology and neuropathology, real estate is crucial. Lesion location can often narrow your differential.
**Over lies hippocampus.
 
Cortical lesions (gray matter):
* [[Oligodendroglioma]].
* [[DNET]].
* [[Ganglioglioma]].
* [[Pleomorphic xanthoastrocytoma]].
* Extraventricular [[ependymoma]].
 
Cortical-subcortical junction:
* [[brain metastasis|Metastases]].
* Abscesses (hematogenous spread).
 
Subcortical lesions (white matter):
* [[Glioblastoma]].
* Diffuse gliomas.
* Demyelinating plaques.
 
Deep gray matter lesions (e.g. basal ganglia):
* Gliomas.
* [[Hypertensive hemorrhage]]
 
Cerebellar lesions:
* [[Medulloblastoma]].
* [[Pilocytic astrocytoma]].
* [[AT/RT]].
 
Intraventricular lesions:
* [[Ependymoma]].
* [[Subependymoma]].
* [[Pilocytic astrocytoma]].
* [[Central neurocytoma]].
* Rosette forming glioneuronal tumour of the fourth ventricle.
 
Suprasellar (above the pituitary):
* [[Craniopharyngioma]].
* [[Germinoma]].
* [[Pilomyxoid astrocytoma]].
 
==Number of lesions==
If ''single'' lesion = think primary, neoplastic
If ''multiple'' lesions = think metastatic, neoplastic or infectious
'''NB: glioblastoma can be multifocal''' (and the foci can be quite far apart)
 
==Cystic vs. solid lesions==
Some tumours are classically cystic with a small solid component (so-called cyst with a mural nodule) -- e.g. pilocytic astrocytoma, ganglioglioma, hemangioblastoma
 
==Enhancing vs. non-enhancing:==
*In adults, enhancing generally = high grade.
*In pediatrics, it often depends on the pattern.
Two main patterns to be mindful of -- ring enhancing lesions, and cystic lesions with a mural nodule.
 
===Ring enhancing lesions===
In [[HIV]]/AIDS patients... mass on CT if infection:
*[[Toxoplasmosis]] - most common.<ref>MUN. Feb 3, 2009.</ref>
 
Ring enhancing lesion (DDx) - mnemonic ''MAGICAL DR'':<ref>{{Ref TN2005 |NS7}}</ref>
*Metstasis.
*Abscess.
*[[Glioblastoma]].
*[[Infarct]].
*Contusion.
*AIDS-related.
*[[Lymphoma]] + [[HIV]] assoc. disease (toxoplasma).
*Demyelination (e.g. [[multiple sclerosis]]).
*Resolving hematoma.
 
===Cyst with enhancing mural nodule===
*hemangioblastoma (#1 in adults)
*pilocytic astrocytoma (#1 in peds)
*pleomorphic xanthoastrocytoma
*ganglioglioma
 
==Grossing==
This is covered in the ''[[neuroanatomy]]'' article.
 
===Gross pathology===
The gross usually useless for arriving at a definitive diagnosis.
 
Exceptions:<ref>R. Kiehl. 8 November 2010.</ref>
*Sausage shape lesion of filum terminale = [[myxopapillary ependymoma]].
*Soft & tan colour = [[pituitary adenoma]].


==Normal histology==
==Normal histology==
===Normal cells===
{{main|Neurohistology}}
*Neuron:
This is a big topic.  It is covered in a separate article called ''[[neurohistology]]''.
**Abundant cytoplasm - '''key feature'''.
 
**Often very large cells, with angled edges.
==Histopathology==
**Prominent nucleolus.
===Neuronal changes===
**Nissl substance (granular perinuclear material - rough ER).
====Anoxic neurons====
*Glial cells.
*[[AKA]] ''red neurons''.
**Oligodendrocyte.
 
***Small round nuclei (lymphocyte-like nucleus) - '''key feature'''.
Features:
***May resemble a ''fried egg'' on H&E (clear cytoplasm, central nucleus).
*Intensely red cytoplasm.
**Astrocyte.
*Pyknosis = nuclear shrinkage + darker staining.
***Irregular non-ovoid nucleus - '''key feature'''.
 
***Nuclei less dense than in oligodendrocyte.
=====Images=====
***Close to blood vessels.
<gallery>
***Form blood-brain barrier.
Image:Alzheimer_type_II_astrocyte_high_mag_cropped.jpg | Anoxic neurons (WC)
***Cytoplasm normally ''not'' visible.
Image:AcuteStroke_HE400x.jpg | Neurons in an acute stroke. (WC)
***Image: [http://embryology.med.unsw.edu.au/histology/endocrine/pin42he.jpg astrocyte (med.unsw.edu.au)] (in [http://embryology.med.unsw.edu.au/notes/endocrine12.htm endocrine development]).
</gallery>
**Microglia - macrophage of the brain (derived from monocyte).
www:
***May be large.
*[http://neuropathology-web.org/chapter2/images2/2-anoxic.png Anoxic neurons (neuropathologyweb.org)].<ref>URL: [http://neuropathology-web.org/chapter2/chapter2aHIE.html http://neuropathology-web.org/chapter2/chapter2aHIE.html]. Accessed on: 10 December 2014.</ref>
***May have vesicles.
*[http://moon.ouhsc.edu/kfung/iacp-olp/APAQ-Images/N1-MS-01-16.gif Anoxic neurons (ouhsc.edu)].<ref>URL: [http://moon.ouhsc.edu/kfung/iacp-olp/apaq-text/N1-MS-01-16-Ans.htm http://moon.ouhsc.edu/kfung/iacp-olp/apaq-text/N1-MS-01-16-Ans.htm] and [http://moon.ouhsc.edu/kfung/iacp-olp/apaq-text/n1-ms-01.htm http://moon.ouhsc.edu/kfung/iacp-olp/apaq-text/n1-ms-01.htm]. Accessed on: 31 October 2010.</ref>
***Rarely seen in normal tissue.
 
*Ependyma.
====Central chromatolysis====
**Simple ciliated cuboidal epithelium.
Features:<ref>URL: [http://www.neuropathologyweb.org/chapter1/chapter1aNeurons.html http://www.neuropathologyweb.org/chapter1/chapter1aNeurons.html]. Accessed on: 22 December 2010.</ref>
**Image: [http://www.stonybrookmedicalcenter.org/sbumcfiles/images/221-001.jpg Ependyma (stonybrookmedicalcenter.org)].
*Central clearing.
**Nucleus and Nissl substance are pushed to cell periphery.
 
DDx:
*Axonal injury (traumatic).<ref name=pmid8909880>{{cite journal |author=Holland GR |title=Experimental trigeminal nerve injury |journal=Crit. Rev. Oral Biol. Med. |volume=7 |issue=3 |pages=237–58 |year=1996 |pmid=8909880 |doi= |url=}}</ref> 
*Vitamin deficiency ([[pellagra]]).<ref name=pmid15577526>{{cite journal |author=Piercecchi-Marti MD, Pélissier-Alicot AL, Leonetti G, Tervé JP, Cianfarani F, Pellissier JF |title=Pellagra: a rare disease observed in a victim of mental and physical abuse |journal=Am J Forensic Med Pathol |volume=25 |issue=4 |pages=342–4 |year=2004 |month=December |pmid=15577526 |doi= |url=}}</ref>
 
=====Images=====
<gallery>
Image:Central_chromatolysis_-_intermed_mag_-_cropped.jpg | Central chromatolysis - intermed. mag. (WC)
Image:Central_chromatolysis_-_nf_-_very_high_mag.jpg | Central chromatolysis - NF stain - very high mag. (WC)
</gallery>
====Axonal swellings====
H&E:
*Eosinophilic (light pink) - ground glass-like appearance.
*Shape:
**Round if sectioned perpendicular to axis of axon.
***Bound by cell membrane.
***Large ~ typically 2-4x RBC diameter.
**Sausage-shaped if cut in along axis.
 
Images:
*[http://frontalcortex.com/gallery/pics/gliageek_VWMDx200.jpg Axonal swelling (frontalcortex.com)].<ref>URL: [http://frontalcortex.com/?page=oll&topic=24&qid=602 http://frontalcortex.com/?page=oll&topic=24&qid=602]. Accessed on: 3 November 2010.</ref>
*[http://www.neuropathologyweb.org/chapter3/images3/3-pvlaxonsweling.jpg Axonal swelling (neuropathologyweb.org)].
 
=====IHC=====
*APP.
 
Image:
*[http://vet.sagepub.com/content/37/6/677/F7.expansion.html Axonal swelling - APP (sagepub.com)].<ref>{{cite journal |author=Finnie JW, Manavis J, Blumbergs PC, Kuchel TR |title=Axonal and neuronal amyloid precursor protein immunoreactivity in the brains of guinea pigs given tunicamycin |journal=Vet. Pathol. |volume=37 |issue=6 |pages=677–80 |year=2000 |month=November |pmid=11105962 |doi= |url=http://vet.sagepub.com/content/37/6/677.full}}</ref>
 
===Glial changes===
====Astrocyte changes====
Reactive astrocytes:
*Approximately equally-spaced; distance between neighbouring astrocytes is ~2x (or more) the cell size.
*Well-defined cell border.
*Eosinophilic cytoplasm with many branching processes.
**Classically described as "funnel-shaped" in benign astrocytes.<ref>MUN. 15 November 2010.</ref>
*Peripheral nucleus.
<gallery>
Image:Reactive_astrocytes_-_lfb_-_high_mag.jpg | Reactive astrocytes - high mag. (WC)
</gallery>
 
Alzheimer type II astrocyte:<ref>URL: [http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html]. Accessed on: 2 July 2010.</ref>
*Large cleared nucleus - '''key feature'''.
*Indistinct cytoplasm.
*Found in the context of ''hepatic encephalopathy'' in basal ganglia and lower layers of cortex.<ref name=Ref_Klatt202>{{Ref Klatt|202}}</ref>
*Images:
**[http://neuroquiz.com/?page=image&topic=1&qid=2714 Alzheimer type II astrocytes (neuroquiz.com)].
**[http://www.neuropathologyweb.org/chapter10/images10/10-AlzIIl.jpg Alzheimer type II astrocytes (neuropathologyweb.org)] .
<gallery>
Image:Alzheimer_type_II_astrocyte_high_mag.jpg| Alzheimer type II astrocytes. (WC)
</gallery>
 
Creutzfeldt cell:<ref name=Ref_PSNP18>{{Ref PSNP|18}}</ref>
*Astrocyte that mimics a mitoses; has moderate (identifiable) cytoplasm.
*Finding associated with demyelinating disease.
*Image: [http://path.upmc.edu/cases/case336/images/fig03.jpg Crutzfeldt cell (upmc.edu)].<ref>URL: [http://path.upmc.edu/cases/case336.html http://path.upmc.edu/cases/case336.html]. Accessed on: 15 January 2012.</ref>
 
Gemistocytic astrocytes:<ref>URL: [http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html]. Accessed on: 7 November 2010.</ref>
*Distinct eosinophilic cytoplasm - with ground-glass appearance.
 
Tufted astrocytes:<ref name=Ref_MBNP173>{{Ref MBNP|173}}</ref>
*Cellular processes loaded with tau protein (as may be seen with tau [[IHC]] or Gallyas silver stain); Parisian-star-like appearance with special stain.
*+/-Multinucleated.
*A classic feature of ''[[progressive supranuclear palsy]]''.
 
====Other glial====
Bergmann gliosis (in the cerebellum):<ref name=Ref_PSNP18>{{Ref PSNP|18}}</ref>
*Thin layer of cells (2-3 cells) with open nuclei that are larger than granular cell layer nuclei; seen with Purkinje cell loss.
 
<gallery>
Image:Bergmann_gliosis_-_intermed_mag.jpg | Bergmann gliosis - intermed. mag. (WC)
Image:Bergmann_gliosis_-_high_mag.jpg | Bergmann gliosis - high mag. (WC)
Image:Metastatic_adenocarcinoma_-_cerebellum_-_intermed_mag.jpg | Bergmann gliosis due to compression by metastasis - intermed mag. (WC)
</gallery>
Image:
*[http://tpx.sagepub.com/content/35/5/676/F5.expansion.html Bergmann gliosis (sagepub.com)].
 
====Reactive change vs. malignancy====
Reactive changes vs. malignancy (mnemonic ''MIMICS''):<ref name=Ref_TPoSP254>{{Ref TPoSP|254}}</ref>
*'''MI'''crovesicular pattern.
*'''M'''itoses.
*'''I'''rregular spacing.
*'''C'''alcifications.
*'''S'''atellitosis, perineuronal.
**Large "crowds" of glial cells associated with nuclei.
 
===Inflammatory===
DDx:
*Autoimmune - [[Multiple sclerosis]].
*Neoplastic - [[Neuropathology tumours#CNS lymphoma|CNS lymphoma]].
*Infectious - [[HSV]].


====Normal cellular constituents in a table====
====Encephalitis====
{| class="wikitable"
see also:
|
* [[Viruses]]
|Key feature
* [[Microorganisms]]
|Other features
 
|Image
=====General=====
|-
DDx:
|Neuron
*Viral encephalitis (Neurotrophic viruses):<ref>{{Cite journal  | last1 = Ludlow | first1 = M. | last2 = Kortekaas | first2 = J. | last3 = Herden | first3 = C. | last4 = Hoffmann | first4 = B. | last5 = Tappe | first5 = D. | last6 = Trebst | first6 = C. | last7 = Griffin | first7 = DE. | last8 = Brindle | first8 = HE. | last9 = Solomon | first9 = T. | title = Neurotropic virus infections as the cause of immediate and delayed neuropathology. | journal = Acta Neuropathol | volume = 131 | issue = 2 | pages = 159-84 | month = Feb | year = 2016 | doi = 10.1007/s00401-015-1511-3 | PMID = 26659576 }}</ref>
| cytoplasm
** Eteroviruses are the most common cause of aseptic meningitis.
| Nissl substance<br> (prominent RER), "sharp" corners <br>in cell membrane
***Coxackie Virus.
| [http://commons.wikimedia.org/wiki/File:Alzheimer_type_II_astrocyte_high_mag_cropped.jpg red neurons (WC)]
***Enteric cytopathic human orphan (ECHO) virus.
|-
** Human Herpesviruses (HSV1, HSV2, VZV, CMV, EBV, Roseola)
|Astrocyte
*** HSV encephalitis has high mortality without acyclovir treatment.
| non-ovoid nucleus
*** Childhood cerebellitis mainly associated with varicella.
| no cytoplasm
*** VZV is the second most common viral meningitis after enterovirus.
| [http://embryology.med.unsw.edu.au/histology/endocrine/pin42he.jpg (unsw.edu)]
** Measles virus(worldwide more than 100.000 deaths annually).
***Is linked to [[acute demyelinating encephalomyelitis]] (ADEM) and Subacute sclerosing encephalitis (SSPE).
** Seasonal influenza A virus (highest patogenic potential: avian influenza H5N1).
** Polio and Non-Polio Enterovirus (mostly children).
***Although massive eradication: Polio still existent in Pakistan, Afghanistan, Nigeria.
** Rabies virus
** Tick-borne encephalitis virus (Europe, Siberia, Russian far-east).
** West-Nile virus (US, Southern europe).
** St. Louis encephalitis virus (US).
** Japanese encephalitis virus (South, south-east asia, high disability rate).
** La Crosse virus (esp. children, midwest & eastern US).
** Borna disease virus (VSBV-1).
** Equine encephalitis viruses (EEEV, VEEV, WEEV, CHIKV).
*Paraneoplastic syndromes.
*Autoimmune antibody-mediated limbic encephalitis (NMDAR).
*Purulent bacterial encephalitis
**Streptococcus, [[Actinomyces]] ....
*Septic metastatic encephalitis
**microabscesses, local astrogliosis, two or more granulocytic infiltrates without relation to vessel.<ref>{{Cite journal  | last1 = Tauber | first1 = SC. | last2 = Bunkowski | first2 = S. | last3 = Brück | first3 = W. | last4 = Nau | first4 = R. | title = Septic metastatic encephalitis: coexistence of brain damage and repair. | journal = Neuropathol Appl Neurobiol | volume = 37 | issue = 7 | pages = 768-76 | month = Dec | year = 2011 | doi = 10.1111/j.1365-2990.2011.01196.x | PMID = 21696418 }}</ref>
*Septic embolic encephalitis
**Embolic endocarditis, Stroke-like lesions.<ref>{{Cite journal  | last1 = Bitsch | first1 = A. | last2 = Nau | first2 = R. | last3 = Hilgers | first3 = RA. | last4 = Verheggen | first4 = R. | last5 = Werner | first5 = G. | last6 = Prange | first6 = HW. | title = Focal neurologic deficits in infective endocarditis and other septic diseases. | journal = Acta Neurol Scand | volume = 94 | issue = 4 | pages = 279-86 | month = Oct | year = 1996 | doi =  | PMID = 8937541 }}</ref>
*Non-purulent bacterial encephalitis
** [[Tuberculosis]]...
 
=====Gross=====
*Frontal and temporal lobe - most common for HSV encephalitis.<ref>{{Ref APBR|416 Q47}}</ref>
 
=====Microscopic=====
Features:<ref name=pmid20051019>{{Cite journal  | last1 = Takei | first1 = H. | last2 = Wilfong | first2 = A. | last3 = Malphrus | first3 = A. | last4 = Yoshor | first4 = D. | last5 = Hunter | first5 = JV. | last6 = Armstrong | first6 = DL. | last7 = Bhattacharjee | first7 = MB. | title = Dual pathology in Rasmussen's encephalitis: a study of seven cases and review of the literature. | journal = Neuropathology | volume = 30 | issue = 4 | pages = 381-91 | month = Aug | year = 2010 | doi = 10.1111/j.1440-1789.2009.01079.x | PMID = 20051019 }}</ref>
*Perivascular inflammation.
*Microglia.
*+/-Neuronophagia.
**Phagocytosis of neurons.<ref>URL: [http://medical-dictionary.thefreedictionary.com/neuronophagia http://medical-dictionary.thefreedictionary.com/neuronophagia]. Accessed on: 11 April 2012.</ref>
*+/-Viral cytopathic changes.
*+/-Perineuronal inflammation.
 
Notes:
*Hemorrhage<ref name=pmid18246335>{{Cite journal  | last1 = Vossough | first1 = A. | last2 = Zimmerman | first2 = RA. | last3 = Bilaniuk | first3 = LT. | last4 = Schwartz | first4 = EM. | title = Imaging findings of neonatal herpes simplex virus type 2 encephalitis. | journal = Neuroradiology | volume = 50 | issue = 4 | pages = 355-66 | month = Apr | year = 2008 | doi = 10.1007/s00234-007-0349-3 | PMID = 18246335 }}</ref> and necrosis - characteristic of HSV encephalitis.
 
Image:
*[http://neuropathology-web.org/chapter5/images5/5-21l.jpg HSV encephalitis (neuropathology-web.org)].<ref>URL: [http://neuropathology-web.org/chapter5/chapter5dViruses.html http://neuropathology-web.org/chapter5/chapter5dViruses.html]. Accessed on: 27 January 2012.</ref>
 
=====IHC=====
IHC stains for:
*Viral etiologies, e.g. [[HSV]], [[CMV]].
*Parasites, e.g. [[toxoplasma]].
*[[Fungi]], e.g. PASD.
 
<gallery>
File:CNS_lymphocytic_encephalitis_frozen_section.jpg | Intraoperative appearance of a lymphocytic encephalitis (WC/jensflorian)
File:CNS_lymphocytic_encephalitis_FFPE_section.jpg | Perivascular inflammation in a lymphocytic encephalitis (WC/jensflorian)
File:HSV_hemorrhagic_encephalitis.jpg | Hemorrhage in HSV encephalitis (WC/jensflorian)
File:HSV_necrotizing_encephalitis.jpg | HSV encephalitis, higher magnification (WC/jensflorian)
File:Cmv_status_verrucosus.jpg | Neonatal brain with migration disturbances due to CMV infection (WC/jensflorian)
File:Cmv_neuronal_inclusions.jpg | Neuronal nuclear inclusions in a neonatal CMV infection (WC/jensflorian)
File:Rabies encephalitis PHIL 3368 lores.jpg | Rabies encephalitis (CDC.gov)
File:Rabies negri bodies brain.jpg | Negri bodies in Purkinje cells (CDC.gov)
</gallery>
 
====Vasculitis====
DDx Cerebral vasculitis / angiitis:
*[[Systemic lupus erythematosus]] (SLE)
*[[Rheumatoid arthritis]].
*Medications and drugs (amphetamine, cocaine and heroin).
*Paraneoplastic(lymphomas, leukemia and lung cancer).
*[[Granulomatosis_with_polyangiitis]]
*[[Giant cell arteritis]]
*[[Takayasu's arteritis]]
*[[Polyarteritis nodosa]]
*Beta-amyloid-related angiitis (ABRA)
 
<gallery>
File:ABRA_HE_40x.jpg | Beta-amyloid related angitis, HE (WC)
File:ABRA_beta-amyloid_40x.jpg |  Beta-amyloid related angiitis, abeta IHC (WC)
File:Giant cell arteritis -- low mag.jpg | Giant cell arteritis, HE (WC)
</gallery>
 
===Architecture===
====Rosettes====
*Rosette = circular/flower-like arrangement of cells.<ref name=pmid16551982>{{cite journal |author=Wippold FJ, Perry A |title=Neuropathology for the neuroradiologist: rosettes and pseudorosettes |journal=AJNR Am J Neuroradiol |volume=27 |issue=3 |pages=488–92 |year=2006 |month=March |pmid=16551982 |doi= |url=}}</ref>
 
*Perivascular pseudorosette = circular/flower-like arrangement of cells with blood vessel at the centre.<ref name=pmid16551982>{{cite journal |author=Wippold FJ, Perry A |title=Neuropathology for the neuroradiologist: rosettes and pseudorosettes |journal=AJNR Am J Neuroradiol |volume=27 |issue=3 |pages=488–92 |year=2006 |month=March |pmid=16551982 |doi= |url=}}</ref>
**[[Ependymoma]].
**[[Medulloblastoma]], PNET.
**[[Central neurocytoma]].
**[[Glioblastoma]]s.
 
*Homer-Wright rosette = (circular) rosette with a small (~100 micrometers ???) meshwork of fibers (neuropil) at the centre.<ref name=pmid16551982>{{cite journal |author=Wippold FJ, Perry A |title=Neuropathology for the neuroradiologist: rosettes and pseudorosettes |journal=AJNR Am J Neuroradiol |volume=27 |issue=3 |pages=488–92 |year=2006 |month=March |pmid=16551982 |doi= |url=}}</ref>
**Medulloblastoma.
***Image: [http://moon.ouhsc.edu/kfung/IACP-OLP/APAQ-Images/N1-TU-01-17.gif Medulloblastoma (ouhsc.edu)].<ref>URL: [http://moon.ouhsc.edu/kfung/IACP-OLP/APAQ-Text/N1-TU-01.htm#17 http://moon.ouhsc.edu/kfung/IACP-OLP/APAQ-Text/N1-TU-01.htm#17]. Accessed on: 3 December 2010.</ref>
**PNET (can be thought of as a supratentorial medulloblastoma) .
**Neuroblastoma
 
*Flexner-Wintersteiner rosette = rosette with empty centre (donut hole).<ref name=pmid16551982/>
**[[Retinoblastoma]]s.
**[[Pineoblastomas]].
**[[Medulloepithelioma]]s.
 
*True ependymal rosette = surrounds a space.<ref name=pmid16551982/>
**[[Ependymoma]].
 
*Pineocytomatous/neurocytic rosette = irregular rosette with a large meshwork of fibers (neuropil) at the centre.<ref name=pmid16551982>{{cite journal |author=Wippold FJ, Perry A |title=Neuropathology for the neuroradiologist: rosettes and pseudorosettes |journal=AJNR Am J Neuroradiol |volume=27 |issue=3 |pages=488–92 |year=2006 |month=March |pmid=16551982 |doi= |url=}}</ref>
**Similar to Homer-Wright rosette.
**[[Pineocytoma]].
**[[Neurocytoma]].
**[[RGNT]] - Rosette forming glioneuronal tumor of the IVth ventricle.
 
*Radial (cartwheel) profiles = neoplastic cells anchoring to stromal vessels, shorter processes than in ependymal pseudorosettes
**[[Astroblastoma]].
**[[Glioblastoma]].
 
*Multilayered rosettes
**[[Ependymomblastoma]]s.
**[[Medulloepithelioma]]s.
 
*Meningeothelial rosettes
**[[Meningioma]] - a rare pattern.<ref>{{Cite journal  | last1 = Liverman | first1 = C. | last2 = Mafra | first2 = M. | last3 = Chuang | first3 = SS. | last4 = Shivane | first4 = A. | last5 = Chakrabarty | first5 = A. | last6 = Highley | first6 = R. | last7 = Hilton | first7 = DA. | last8 = Byrne | first8 = NP. | last9 = Wesseling | first9 = P. | title = A clinicopathologic study of 11 rosette-forming meningiomas: a rare and potentially confusing pattern. | journal = Acta Neuropathol | volume = 130 | issue = 2 | pages = 311-3 | month = Aug | year = 2015 | doi = 10.1007/s00401-015-1456-6 | PMID = 26106026 }}</ref>
 
<gallery>
Image:Neuroblastoma Homer Wright rosettes HE.jpg | Homer-Wright rosettes (WC).
Image:RGNT HE 2.jpg | Neurocytic rosettes (WC).
Image:Ependymoma H&E.jpg | Perivascular pseudorosette (WC).
Image:Ependymoblastoma ETMRjpg.jpg | Multilayered rosettes (WC).
Image:Ependymoblastomatous Rosette.jpg | Ependymoblastous rosettes (WC/Marvin101).
Image:Ependymoma true ependymal rosettes and pseudorosettes.jpg | True ependymal rosettes and pseudorosettes (WC).
Image:Astroblastoma HE Specimen.jpg | Radial (cartwheel) profiles (WC).
</gallery>
 
====Other important histological features====
*Rosenthal fibres = worm-like or corkscrew-like (brightly) eosinophilic bodies; 10-40 micrometers.
**Key feature: variable thickness; helps separate from RBCs.
**Well-seen on trichrome stains.
<gallery>
Image:Rosenthal_HE_40x.jpg | Rosenthal fibres. (WP)
Image:Rosenthal_fibers.jpg | Rosenthal fibres - smear (WC/AFIP)
</gallery>
*Eosinophilic granular bodies = related to Rosenthal fibres; round cytoplasmic hyaline droplets in [[astrocyte]]s.<ref>{{Ref MBNP|11}}</ref>
<gallery>
File:Pilocytic Micro.jpg | Eosinophilic granular bodies in pilocytic astrocytoma smear (WC/AFIP)
File:PXA HE x20.jpg | Eosinophilic granular body in a pleomorphic xanthoastrocytoma (WC/jensflorian)
</gallery>
 
*Pseudopalisading - picket fence-like alignment of cells; long axis of cells perpendicular to interface with other structures/cells.
**Pseudopalisading of tumour cells (around necrotic regions) is seen in [[glioblastoma]].
<gallery>
File:GBM pseudopalisading necrosis.jpg | Pseudopalisading necrosis in a glioblastoma (WC/jensflorian)
</gallery>
 
*Perivascular lymphocytic cuffing - Lymphocytes surrounding vessels.
** Seen in many inflammatory conditions including MS.
** Often seen in [[ganglioglioma]] and [[pleomorphic xanthoastrocytoma]].
** Less common in some gemistocytic [[astrocytoma]].
*** No association with survival. <ref>{{Cite journal  | last1 = Rossi | first1 = ML. | last2 = Jones | first2 = NR. | last3 = Candy | first3 = E. | last4 = Nicoll | first4 = JA. | last5 = Compton | first5 = JS. | last6 = Hughes | first6 = JT. | last7 = Esiri | first7 = MM. | last8 = Moss | first8 = TH. | last9 = Cruz-Sanchez | first9 = FF. | title = The mononuclear cell infiltrate compared with survival in high-grade astrocytomas. | journal = Acta Neuropathol | volume = 78 | issue = 2 | pages = 189-93 | month =  | year = 1989 | doi =  | PMID = 2750489 }}</ref>
<gallery>
File:Ganglioglioma lymphocytic cuffing PAS.jpg | Lymphocytic cuffing in [[ganglioglioma]] (WC/jensflorian)
</gallery>
 
Note:
*Good set of articles: [http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=PureSearch&db=PubMed&details_term=Neuropathology%20for%20the%20neuroradiologist Neuropathology for radiologists (ncbi.nlm.nih.gov)].
 
===Inclusion bodies===
*Negri bodies.
**Cytoplasmic inclusions; classically in Purkinje cells of the cerebellum, pyramidal cells of Ammon's horn.
**[[Rabies]].
<gallery>
Image:Rabies_encephalitis_Negri_bodies_PHIL_3377_lores.jpg | Negri bodies. (WC/CDC)
</gallery>
*Owl eye inclusions.
**Basiopilic neuronal inclusions in enlarged cells, typically seen in CMV encephalitis
<gallery>
Image:CMV encephalitis owl eye inclusions HE stain.jpg | Owl eye inclusions
</gallery>
 
*Lewy bodies.
**Eosinophilic cytoplasmic inclusion - composed mostly of alpha-synuclein.<ref name=pmid15235805>{{cite journal |author=Marui W, Iseki E, Kato M, Akatsu H, Kosaka K |title=Pathological entity of dementia with Lewy bodies and its differentiation from Alzheimer's disease |journal=Acta Neuropathol. |volume=108 |issue=2 |pages=121–8 |year=2004 |month=August |pmid=15235805 |doi=10.1007/s00401-004-0869-4 |url=}}</ref>
<gallery>
Image:Lewy_Koerperchen.JPG | Lewy body. (WC)
</gallery>
====Table of inclusions====
{| class="wikitable sortable"
! Feature
! Appearance
! Associated disease
! Comment
! Image
|-
|-
|Oligodendrocyte
| Grumose bodies<br>[[AKA]] granular bodies
| round small nucleus
| granular and eosinophilic ~50 micrometers
| peri-nuclear clearing
| neurodegenerative disease, neuroaxonal dystrophies, aging
|
| ?Comment
| ?Image
|-
|-
|Microglia
| Cowdry type 1<br>AKA Cowdry type A
| rod-like shape,<br> may have "bent" nucleus
| eosinophilic & round + halo
| rarely seen in normal tissue
| [[herpes simplex virus]]
| [http://missinglink.ucsf.edu/lm/ids_104_cns_injury/Response%20_to_Injury/Microglia.htm (ucsf.edu)],[http://www.pathology.vcu.edu/WirSelfInst/neuro_medStudents/glialpath.html (vcu.edu)]
| can be confused with <br>Lewy body, Marinesco body
| ?Image
|-
| Lewy body
| round cytoplasmic eosinophilic<br> body +/- pale halo
| [[Parkinson disease]], dementia with Lewy bodies
| morphology dependent on <br>location in brain; +ve for alpha-synuclein, <br>alpha-B crystallin, ubiquitin
| [[Image:Lewy_Koerperchen.JPG |thumb|center|150px|]], [http://firstaidteam.com/usmlerximages/v/USMLERxLewy+bodies.gif.html]
|-
| Lafora body
| round
| myoclonic [[epilepsy]]
| look like corpora amylacea; location: dentate nucleus, liver, skeletal muscle, sweat glands
| ?Image
|-
| Lipofuscin
| yellow & granular
| aging
| olive, dendate
| ?Image
|-
| Negri body
| small eosinophic bodies
| rabies
| found in hippocampal neurons and Purkinje cells
| [[Image:Rabies_encephalitis_Negri_bodies_PHIL_3377_lores.jpg|thumb|center|150px|]]
|-
| Hirano body
| concentric calcification/rod-shaped bright eosinophilic; overlap edge of neuron
| Alzheimer disease, Pick disease<ref name=Ref_MBNP5>{{Ref MBNP|5}}</ref>
| actin crystals, may look like capillaries; location: CA1 of hippocampus
| [http://faculty.washington.edu/alexbert/MEDEX/Fall/adhirano.jpg]<ref name=pakmednet>URL: [http://www.pakmed.net/academic/age/alz/alz030.htm http://www.pakmed.net/academic/age/alz/alz030.htm]. Accessed on: 12 November 2010.</ref>
|-
|-
| Neurofibrillary tangles
| flame-shaped cytoplasmic thingy<br>~30 micrometers
| aging, Alzheimer's disease
| seen with silver stain
| [http://www.pakmed.net/academic/age/alz/plaques_tanglesBorder.jpg Schematic]<ref name=pakmednet>URL: [http://www.pakmed.net/academic/age/alz/alz030.htm http://www.pakmed.net/academic/age/alz/alz030.htm]. Accessed on: 12 November 2010.</ref>, [http://faculty.washington.edu/alexbert/MEDEX/Fall/adtangle.jpg]<ref name=alexbert>URL: [http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm]. Accessed on: 13 November 2010.</ref>
|-
| Granulovacuolar degeneration
| cytoplasmic vacuoles 4-5 micrometers
| ageing, [[Alzheimer's disease]], <br>Pick's disease
| main found in Ammon horn<ref name=Ref_MBNP5>{{Ref MBNP|5}}</ref>
| [http://faculty.washington.edu/alexbert/MEDEX/Fall/adgvd.jpg]<ref name=alexbert>URL: [http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm]. Accessed on: 13 November 2010.</ref>
|-
| Pick bodies
| round, homogenous, intracytoplasmic, ~10 micrometers
| [[Pick's disease]]
| pyramidal neurons, dentate <br>granule cells (hippocampus); +ve for tau, tubulin, ubiquitin
| [http://s212.photobucket.com/albums/cc74/cat_at_uw/Osler%20-%20Neuropath/?action=view&current=Picks60x.jpg&mediafilter=images]
|-
| Bunina body
| size of Nissl granules, eosinophilic
| [[amyotrophic lateral sclerosis]] (ALS)
| EM: membrane-bound bodies; ubiquitin +ve
| [http://pathol.umin.ac.jp/gakubu/exam/2006jpg/19.jpg]
|-
<!-- | Feature
| ?Appearance
| ?Associated disease
| ?Comment
| ?Image
|- -->
|}
|}


====Neurons====
Image collection: [http://s212.photobucket.com/albums/cc74/cat_at_uw/Osler%20-%20Neuropath/?mediafilter=images Inclusion bodies (photobucket.com)].
There are many types of 'em.  Broadly, they can be classified as:
 
#Pyramidal - have a pyramidal shape.
==Immunohistochemistry==
##Dentrites go to molecular layer.
{{Main|Immunohistochemistry}}
##Axons go to outside of cortex.
===General===
#Non-pyramidal.
*S-100.
**Sensitive... but non-specific, e.g. also stains [[melanoma]].
 
===Glial===
*GFAP (glial fibrillary acidic protein) - should stain perikaryon.
 
====Glial tumours====
Standard work-up:
*GFAP.
*MAP2C. <ref>{{Cite journal  | last1 = Blümcke | first1 = I. | last2 = Müller | first2 = S. | last3 = Buslei | first3 = R. | last4 = Riederer | first4 = BM. | last5 = Wiestler | first5 = OD. | title = Microtubule-associated protein-2 immunoreactivity: a useful tool in the differential diagnosis of low-grade neuroepithelial tumors. | journal = Acta Neuropathol | volume = 108 | issue = 2 | pages = 89-96 | month = Aug | year = 2004 | doi = 10.1007/s00401-004-0873-8 | PMID = 15146346 }}</ref>
*Ki-67 (MIB-1).
Useful additional markers:
*IDH1(R132H) in Astrocytic/Oligodendroglial tumors. <ref>{{Cite journal | last1 = Paulus | first1 = W. | title = GFAP, Ki67 and IDH1: perhaps the golden triad of glioma immunohistochemistry. | journal = Acta Neuropathol | volume = 118 | issue = 5 | pages = 603-4 | month = Nov | year = 2009 | doi = 10.1007/s00401-009-0600-6 | PMID = 19847448 }}</ref>
*ATRX in mixed gliomas. <ref>{{Cite journal  | last1 = Reuss | first1 = DE. | last2 = Sahm | first2 = F. | last3 = Schrimpf | first3 = D. | last4 = Wiestler | first4 = B. | last5 = Capper | first5 = D. | last6 = Koelsche | first6 = C. | last7 = Schweizer | first7 = L. | last8 = Korshunov | first8 = A. | last9 = Jones | first9 = DT. | title = ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma. | journal = Acta Neuropathol | volume = 129 | issue = 1 | pages = 133-46 | month = Jan | year = 2015 | doi = 10.1007/s00401-014-1370-3 | PMID = 25427834 }}</ref>
*EMA in Ependymal tumors. <ref>{{Cite journal  | last1 = Hasselblatt | first1 = M. | last2 = Paulus | first2 = W. | title = Sensitivity and specificity of epithelial membrane antigen staining patterns in ependymomas. | journal = Acta Neuropathol | volume = 106 | issue = 4 | pages = 385-8 | month = Oct | year = 2003 | doi = 10.1007/s00401-003-0752-8 | PMID = 12898159 }}</ref>
*OLIG-2 usually -ve in Ependymomas. <ref>{{Cite journal  | last1 = Ishizawa | first1 = K. | last2 = Komori | first2 = T. | last3 = Shimada | first3 = S. | last4 = Hirose | first4 = T. | title = Olig2 and CD99 are useful negative markers for the diagnosis of brain tumors. | journal = Clin Neuropathol | volume = 27 | issue = 3 | pages = 118-28 | month =  | year =  | doi =  | PMID = 18552083 }}</ref><ref>{{Cite journal  | last1 = Otero | first1 = JJ. | last2 = Rowitch | first2 = D. | last3 = Vandenberg | first3 = S. | title = OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms. | journal = J Neurooncol | volume = 104 | issue = 2 | pages = 423-38 | month = Sep | year = 2011 | doi = 10.1007/s11060-010-0509-x | PMID = 21193945 }}</ref>
===Neuronal===
*Synaptophysin.
*Chromogranin.
 
===Carcinoma vs. glial tumours===
*AE1/AE3 often +ve in glial tumours (e.g. astrocytomas, oligodendrogliomas); CAM5.2 is usu. -ve in glial tumours.<ref name=Ref_PSNP_12>{{Ref PSNP|12}}</ref>


Motor neurons:
===Others===
*Coarse Nissl substance - '''key feature'''.
*APP (amyloid precursor protein) - detects axonal swellings.
**Nissl described as having a ''tigroid appearance''.<ref>URL: [http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1 http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1]. Accessed on: 5 July 2010.</ref>
*NF (neurofilament) - detects axonal swellings.
*Polygonal shape.
*Send dendrites in all directions.


Image: [http://www.stonybrookmedicalcenter.org/sbumcfiles/images/238-002.jpg Motor neuron (stonybrookmedicalcenter.org)].
=Brain tumours=
{{main|Neuropathology tumours}}
Tumours are a big part of neuropathology. The most common brain tumour (in adults) is a metastasis. The most common primary tumours originating in the brain (in adults) are [[glioma]]s. More than 50% of these are classified as [[glioblastoma]] which has a horrible prognosis.


===Histology - where===
=Non-tumour=
====Subependyma====
==Vascular disorders==
Features:<ref>Half-day. 28 June 2010.</ref>
===Cerebral hemorrhage===
*Ependyma (simple ciliated cuboidal epithelium).
:See: ''[[Intracranial hematoma]]'' for intracranial bleeds
*Subependymal plate - connective tissue with blood vessels.


====Pons====
Includes discussion of:
Features:
*[[Epidural hematoma]].
*Looks like bacon.<ref>Half-day. 28 June 2010.</ref>
*[[Subdural hematoma]].  
*Image: [http://www.stonybrookmedicalcenter.org/sbumcfiles/images/243-scout.jpg Pons (stonybrookmedicalcenter.org)].
*[[Subarachnoid hematoma]].
*[[Intracerebral hematoma]]s.


====Caudate====
===Duret hematoma===
Features:
*[[AKA]] Duret hemorrhage.
*Neurons with adjacent ependymal lining.<ref>URL: [http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1 http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1]. Accessed on: 2 July 2010.</ref>
====General====
**The caudate forms lateral wall of lateral ventricle.
*Bleed in the upper brainstem (midbrain and pons).
**Thought to be due to transtentorial herniation secondary to supratentorial mass effect (e.g. supratentorial tumour, [[intracranial hemorrhage]]).<ref name=pmid11819006>{{Cite journal  | last1 = Parizel | first1 = PM. | last2 = Makkat | first2 = S. | last3 = Jorens | first3 = PG. | last4 = Ozsarlak | first4 = O. | last5 = Cras | first5 = P. | last6 = Van Goethem | first6 = JW. | last7 = van den Hauwe | first7 = L. | last8 = Verlooy | first8 = J. | last9 = De Schepper | first9 = AM. | title = Brainstem hemorrhage in descending transtentorial herniation (Duret hemorrhage). | journal = Intensive Care Med | volume = 28 | issue = 1 | pages = 85-8 | month = Jan | year = 2002 | doi = 10.1007/s00134-001-1160-y | PMID = 11819006 }}</ref>
*Often fatal.<ref name=pmid11098635>{{Cite journal  | last1 = Fujimoto | first1 = Y. | last2 = Aguiar | first2 = PH. | last3 = Freitas | first3 = AB. | last4 = de Andrade | first4 = AF. | last5 = Marino Júnior | first5 = R. | title = Recovery from Duret hemorrhage: a rare complication after craniotomy--case report. | journal = Neurol Med Chir (Tokyo) | volume = 40 | issue = 10 | pages = 508-10 | month = Oct | year = 2000 | doi =  | PMID = 11098635 }}</ref>
====Gross====
*Extravasated blood in midbrain and pons - usu. ventral (anterior) and paramedian (adjacent to the midline).<ref name=pmid11819006/>


====Putamen====
Image:
Features:
*[http://library.med.utah.edu/WebPath/jpeg5/CNS037.jpg Duret hemorrhage (med.utah.edu)].<ref>URL: [http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html http://library.med.utah.edu/WebPath/EXAM/IMGQUIZ/npfrm.html]. Accessed on: 4 December 2011.</ref>
*Histologically identical to the ''caudate'' - but not adjacent to a ventricle, i.e. an ependymal lining.
*Striatopallidal fibers [[AKA]] ''pencils of Wilson'' - bundles of blue fibres (on H&E LFB).
**Image: [http://frontalcortex.com/?page=oll&topic=24&qid=760 Pencils of Wilson (frontalcortex.com)].


====Globus pallidus====
====Microscopic====
Features:
Features:
*Histologically distinct from caudate and putamen.
*RBC extravasation.
*+/-Hemosiderin-laden macrophages.
*+/-Ischemic neurons.


====Hippocampus====
===Cerebral amyloid angiopathy===
Hippocampal formation:<ref>URL: [http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1 http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1]. Accessed on: 2 July 2010.</ref>
====General====
#Dentate gyrus.
*Abbreviated ''CAA''.
#*"Dense" thin layer of nuclei.
*Disease of the old.
#*Quasi "U-shaped"; "open" (top) portion of "U" is superolateral.
*Strong association with ''[[lobar haemorrhage]]'' (bleeds of the cerebellar cortex and cerebral cortex).<ref name=pmid16982664>{{cite journal |author=Thanvi B, Robinson T |title=Sporadic cerebral amyloid angiopathy--an important cause of cerebral haemorrhage in older people |journal=Age Ageing |volume=35 |issue=6 |pages=565–71 |year=2006 |month=November |pmid=16982664 |doi=10.1093/ageing/afl108 |url=}}</ref>
#*Image: [http://www.stonybrookmedicalcenter.org/sbumcfiles/images/225-001.jpg Dentate gyrus (stonybrookmedicalcenter.org)].
#Hippocampus proper ([[AKA]] ''Ammon's horn'') - this is subdivided:
#*CA3 - superior.
#*CA1 - inferior (next to subiculum).
#*CA2 - in between CA3 and CA1, lateral.
#*CA4 - medial (closest to dentate gyrus; CA4 sits in "open" part of "U").
#Subicular complex.


Images:  
Etiology:
*[http://en.wikipedia.org/wiki/File:Brainmaps-macaque-hippocampus.jpg Hippocampus - frontal section (WP)].
*[[Amyloid]] deposition in the basal lamina of smooth muscle (in the cerebellar cortex and cerebral cortex).
*[http://commons.wikimedia.org/wiki/File:Hippocampus_%28brain%29.jpg Hippocampus - good schematic (WC)].
*[http://www.ajnr.org/cgi/content-nw/full/28/5/958/F1 Hippocampus (ajnr.org)].
*[http://edoc.hu-berlin.de/dissertationen/schubert-stephan-nicolas-2003-09-26/HTML/schubert_html_21d219b1.png Hippocampus and subiculum (hu-berlin.de)].
*[http://spinwarp.ucsd.edu/NeuroWeb/Text/br-800epi/br-800epi1.gif Hippocampus - crappy schematic (ucsd.edu)].


Important note:
====Gross====
*CA1 - weak link, dies in ischemia, affected by hypoglycemia.
*Bleeds typically superficial (cortex and subcortical white matter) and in the frontal lobe or parietal lobe.<ref name=pmid17297004>{{Cite journal  | last1 = Haacke | first1 = EM. | last2 = DelProposto | first2 = ZS. | last3 = Chaturvedi | first3 = S. | last4 = Sehgal | first4 = V. | last5 = Tenzer | first5 = M. | last6 = Neelavalli | first6 = J. | last7 = Kido | first7 = D. | title = Imaging cerebral amyloid angiopathy with susceptibility-weighted imaging. | journal = AJNR Am J Neuroradiol | volume = 28 | issue = 2 | pages = 316-7 | month = Feb | year = 2007 | doi =  | PMID = 17297004 | URL = http://www.ajnr.org/content/28/2/316.long }}</ref>
*CA2 - resistant to ischemia.


DDx of ischemia-like changes in the hippocampus:
====Microscopic====
*Toxins.
Features:
*Amorphous, acellular eosinophilic material within walls of small arteries.
**This is a high power diagnosis with congo red staining.


====Cerebellum====
Notes:
Main components:
*Amyloidosis is seen in all individuals with [[Alzheimer's disease]]; the amount of amyloid is what differs -- in CAA it is lots and lots.
*Cortex (superficial) - branches (Christmas tree-like).
*The white matter is typically spared by CAA.<ref name=pmid19225408>{{Cite journal  | last1 = Schröder | first1 = R. | last2 = Deckert | first2 = M. | last3 = Linke | first3 = RP. | title = Novel isolated cerebral ALlambda amyloid angiopathy with widespread subcortical distribution and leukoencephalopathy due to atypical monoclonal plasma cell proliferation, and terminal systemic gammopathy. | journal = J Neuropathol Exp Neurol | volume = 68 | issue = 3 | pages = 286-99 | month = Mar | year = 2009 | doi = 10.1097/NEN.0b013e31819a87f9 | PMID = 19225408 }}
*Dentate nucleus (deep) - looks like the bite impression of a molar.
</ref>
**Image: [http://www.stonybrookmedicalcenter.org/sbumcfiles/images/227-scout.jpg Cerebellum, cortex & dendate nucleus - low power (stonybrookmedicalcenter.org)].


Cerebellar cortex:
====Images====
*Layers (superficial to deep) - mnemonic ''MPG'':<ref>URL: [http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1 http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1]. Accessed on: 2 July 2010.</ref>
<gallery>
*#Molecular layer -- "very pink" on H&E.
Image:Cerebral_amyloid_angiopathy_-_very_high_mag.jpg |CAA - congo red - very high mag. (WC)
*#*Inhibitory interneurons: stellate cells, basket cells.
Image:Cerebral_amyloid_angiopathy_-_low_mag.jpg |CAA - congo red - low mag. (WC)
*#Purkinje cell layer.
Image:Cerebral_amyloid_angiopathy_-2b-_amyloid_beta_-_high_mag.jpg |CAA - beta-amyloid - high mag. (WC)
*#*One cell layer thick - hueuege cells.
</gallery>
*#Granule cell layer -- "very blue" on H&E.  
====Stains====
*#*Granule cells (many), interneurons (Golgi cells --few in number). (???)
*[[Congo red]].
*Images:
**[http://www.stonybrookmedicalcenter.org/sbumcfiles/images/227_001.jpg Cerebellar cortex - micrograph (stonybrookmedicalcenter.org)].
**[http://upload.wikimedia.org/wikipedia/commons/7/7c/Gray706.png Cerebellar cortex - schematic (Gray's Anatomy - WC)].


====Cerebral cortex====
====IHC====
Layers (superficial to deep):
*Abeta-amyloid (AKA beta-amyloid).
#Molecular layer.
#*Empty appearing.
#Outer granular layer.
#Outer pyramidal layer.
#Inner granular layer.
#*Not prominent in frontal cortex.
#*Where the thalamic axons end.
#Inner pyramidal layer.
#*Location of ''Betz neurons'' - large motor neurons of cerebral cortex.
#Polymorphic layer.


Images:
===Cerebral amyloid angiopathy associated with inflammation (I-CAA)===
*[http://commons.wikimedia.org/wiki/File:Cajal_cortex_drawings.png Cajal drawings - different areas (WC)].
* Cognitive decline.
*[http://www.ruf.rice.edu/~lngbrain/cglidden/Lab8_fig1.gif Different stains (rice.edu)].
* Microbleedings in MRI.  
*[http://williamcalvin.com/bk7/img/bk7p31.jpg (williamcalvin.com)].
* Responsive to steroids.
*[http://www.benbest.com/science/anatmind/anatmd5.html (benbest.com)].
* Abeta deposits in vessels.
* Perivascular lymphocytic infiltrate (but no vasculitis!).
* Giant cells may be present.


==Histopathology==
===Vascular malformations===
*Reactive astrocytes.
{{Main|Vascular malformations}}
**Eosinophilic cytoplasm.
Types:<ref name=pmid17076525>{{cite journal |author=Prayson RA, Kleinschmidt-DeMasters BK |title=An algorithmic approach to the brain biopsy--part II |journal=Arch. Pathol. Lab. Med. |volume=130 |issue=11 |pages=1639–48 |year=2006 |month=November |pmid=17076525 |doi= |url=}}</ref>
**Peripheral nucleus.
*[[Vascular_malformations#Arteriovenous_malformation|Arteriovenous malformation]].
**Well-defined cell border.
*Varix.
**Many branching processes.
*Venous angioma.
*[[Vascular_malformations#Cavernous_hemangioma|Cavernous hemangioma]]  (Cavernoma).
*Capillary teleangiectasia.
Also see: ''[[Sturge-Weber syndrome]]''.


Alzheimer type II astrocytes:<ref>URL: [http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html]. Accessed on: 2 July 2010.</ref>
===Atherosclerosis===
*Large cleared nuclei.
{{Main|Vascular_disease#Atherosclerosis}}
*Indistinct cytoplasm.
*Intracranial atherosclerosis most common at circle of Willis.
*Images:
*Macroscopic yellow discoloration.
**[http://commons.wikimedia.org/wiki/File:Alzheimer_type_II_astrocyte_high_mag.jpg Alzheimer type II astrocytes (WC)].
*Luminal stenosis and eccentric intimal thickening.
**[http://neuroquiz.com/?page=image&topic=1&qid=2714 Alzheimer type II astrocytes (neuroquiz.com)].
<gallery>
**[http://www.neuropathologyweb.org/chapter10/images10/10-AlzIIl.jpg Alzheimer type II astrocytes (neuropathologyweb.org)] .
File:Carotid Plaque (121061911).jpg|Plaque of the carotid bifurcation (Ed Uthman).
</gallery>


*Axonal swellings
===Other large arterial diseases===
**Image: [http://www.neuropathologyweb.org/chapter3/images3/3-pvlaxonsweling.jpg Axonal swelling] - neuropathologyweb.org.
*[[Vascular_disease#Fibromuscular_dysplasia|Fibromuscular dysplasia]].
*Moyamoya disease.
**Progressive stenosis of basal intracranial arteries and abnormal vascularization.
*[[Aortic dissection|Arterial dissection]].
*[[Giant cell arteritis]].
*[[Takayasu's arteritis]].
*[[Antiphospholipid antibody syndrome|Antiphospholipid antibody]] mediated thrombosis.


===Architecture===
===Microangiopathy===
*Rosette = circular/flower-like arrangement of cells<ref name=pmid16551982>PMID 16551982</ref>
*Defined as Small vessel disease (<300µm in transverse section).
*Pseudorosette = circular/flower-like arrangement of cells with blood vessel at the centre<ref name=pmid16551982>PMID 16551982</ref>
*Includes atherosclerosis and cerebral amyloid angiopathy.
*Rosenthal fibres = worm-like or corkscrew-like eosinophilic bodies.
Other causes:
**Image: [http://en.wikipedia.org/wiki/File:Rosenthal_HE_40x.jpg Rosenthal fibres] - wikipedia.org.
*Primary angitis of the CNS (PACNS).
*Pseudopallisading
*[[Polyarteritis nodosa]].
*[[Granulomatosis with polyangiitis]] (Wegener's granulomatosis).
*[[Lymphomatoid granulomatosis]].
*Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (commonly abbreviated ''CADASIL'').
{{Main|Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy}}


Notes: Good set of articles - <ref>http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=PureSearch&db=PubMed&details_term=Neuropathology%20for%20the%20neuroradiologist</ref>
===Hypoxic-ischemic encephalopathy===
*Abbreviated ''HIE''.
{{Main|Hypoxic-ischemic encephalopathy}}
**Hypoxia: reduction in oxygen supply or utilization.
**Ischemia: reduction in blood supply.


==Ring enhancing lesions==
===Cerebrovascular accident===
In HIV/AIDS patients... mass on CT if infection:
*Abbreviated ''CVA''.  
*Toxoplasmosis - most common.<ref>MUN. Feb 3, 2009.</ref>
*[[AKA]] ''stroke''.
{{Main|Cerebrovascular accident}}
*Stroke includes:
**Infarction (ischemia in defined vascular distribution persisting for at least 24hrs).
**Intracrebral hemorrhage (focal blood accumulation in the brain parenchyma).
**Subarachnoid hemorrhage (SAH).
**Cerebral venous thrombosis (CVT).  


Ring enhancing lesion (DDx) - mnemonic ''MAGICAL DR'':<ref>TN2005 NS7.</ref>
*Metstasis.
*Abscess.
*Glioblastoma.
*Infarct.
*Contusion.
*AIDS-related.
*Lymphoma + HIV assoc. disease (toxoplasma).
*Demyelination (e.g. multiple sclerosis).
*Resolving hematoma.


==Alcohol & CNS==
==Alcohol & CNS==
Pathology:<ref>http://www.journals.elsevierhealth.com/periodicals/ycdip/article/S0968-6053(07)00035-X/abstract</ref>
===Clinical===
*Morel's laminar sclerosis
*central pontine myelinolysis
*Wernicke's encephalopathy  
*Wernicke's encephalopathy  
**Mnemonic ''WACO'':
**Mnemonic ''WACO'':
Line 228: Line 664:
***Ocular Sx (CN IV palsy).
***Ocular Sx (CN IV palsy).
**Cause: thiamine deficiency.
**Cause: thiamine deficiency.
===Pathology===
Features:<ref>http://www.journals.elsevierhealth.com/periodicals/ycdip/article/S0968-6053(07)00035-X/abstract</ref>
*Morel's laminar sclerosis = spongy degeneration and gliosis of the cerebral cortex<ref>URL: [http://content.karger.com/ProdukteDB/produkte.asp?Doi=114939 http://content.karger.com/ProdukteDB/produkte.asp?Doi=114939]. Accessed on: 22 September 2010.</ref> usu. prominent in the third layer of the cortex (outer pyramidal layer) and especially in the lateral-frontal cortex.<ref name=pmid15760886>{{cite journal |author=Johkura K, Naito M, Naka T |title=Cortical involvement in Marchiafava-Bignami disease |journal=AJNR Am J Neuroradiol |volume=26 |issue=3 |pages=670–3 |year=2005 |month=March |pmid=15760886 |doi= |url=http://www.ajnr.org/cgi/content/full/26/3/670}}</ref>
*Central pontine myelinolysis (CPM).<ref name=pmid21085565>{{cite journal |author=Campbell MC |title=Hyponatremia and central pontine myelinolysis as a result of beer potomania: a case report |journal=Prim Care Companion J Clin Psychiatry |volume=12 |issue=4 |pages= |year=2010 |pmid=21085565 |pmc=2983455 |doi=10.4088/PCC.09l00936ecr |url=}}</ref>
**Just what it sound like - myelin loss in the central pons.
**Classically associated with rapid correction of hyponatremia.<ref>{{cite journal |author=Bernsen HJ, Prick MJ |title=Improvement of central pontine myelinolysis as demonstrated by repeated magnetic resonance imaging in a patient without evidence of hyponatremia |journal=Acta Neurol Belg |volume=99 |issue=3 |pages=189–93 |year=1999 |month=September |pmid=10544728 |doi= |url=}}</ref>
*Mammillary body shrinkage.<ref name=pmid8947329>{{cite journal |author=Shear PK, Sullivan EV, Lane B, Pfefferbaum A |title=Mammillary body and cerebellar shrinkage in chronic alcoholics with and without amnesia |journal=Alcohol. Clin. Exp. Res. |volume=20 |issue=8 |pages=1489-95 |year=1996 |month=November |pmid=8947329 |doi= |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0145-6008&date=1996&volume=20&issue=8&spage=1489}}</ref>
*Mammillary body shrinkage.<ref name=pmid8947329>{{cite journal |author=Shear PK, Sullivan EV, Lane B, Pfefferbaum A |title=Mammillary body and cerebellar shrinkage in chronic alcoholics with and without amnesia |journal=Alcohol. Clin. Exp. Res. |volume=20 |issue=8 |pages=1489-95 |year=1996 |month=November |pmid=8947329 |doi= |url=http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0145-6008&date=1996&volume=20&issue=8&spage=1489}}</ref>
*Anterior cerebellar vermis atrophy; weak finding - as also age-related.<ref name=pmid3478969>{{cite journal |author=Torvik A |title=Brain lesions in alcoholics: neuropathological observations |journal=Acta Med. Scand. Suppl. |volume=717 |issue= |pages=47–54 |year=1987 |pmid=3478969 |doi= |url=}}</ref>
**Vermis atrophy is also seen in schizophrenia.<ref name=pmid1938163>{{cite journal |author=Sandyk R, Kay SR, Merriam AE |title=Atrophy of the cerebellar vermis: relevance to the symptoms of schizophrenia |journal=Int. J. Neurosci. |volume=57 |issue=3-4 |pages=205–12 |year=1991 |month=April |pmid=1938163 |doi= |url=}}</ref>
====Marchiafava-Bignami Disease====
*Rare.
*Demyelination of the corpus callosum.<ref name=pmid15760886>{{cite journal |author=Johkura K, Naito M, Naka T |title=Cortical involvement in Marchiafava-Bignami disease |journal=AJNR Am J Neuroradiol |volume=26 |issue=3 |pages=670–3 |year=2005 |month=March |pmid=15760886 |doi= |url=http://www.ajnr.org/cgi/content/full/26/3/670}}</ref>
====Wernicke's encephalopathy====
General:
*Due to thiamine deficiency.
**Malnourishment often accompanies [[alcoholism]].
Features:<ref name=pmid3929155>{{Cite journal  | last1 = Torvik | first1 = A. | title = Two types of brain lesions in Wernicke's encephalopathy. | journal = Neuropathol Appl Neurobiol | volume = 11 | issue = 3 | pages = 179-90 | month =  | year =  | doi =  | PMID = 3929155 }}</ref>
*Neurons of mammillary bodies preserved - '''key'''.
*Loss of myelin.
*Hemorrhage.
*Edema.
*Reactive blood vessels.
Note:
*The thalamus and inferior olives show neuronal loss.<ref name=pmid3929155/>
====Common non-specific findings====
*[[Intracranial haemorrhage]] - due to trauma.


==Non-tumour==
==Meningitis==
==Acute disseminated encephalomyelitis==
===General===
===General===
*Thought to be autoimmune.
*Definition: inflammation of the meninges (pia mater, arachnoid membranes, dura mater).  
*May mimic multiple sclerosis.
 
*Abbreviated "ADEM".
Classic clinical presentation:
*Neck stiffness.
*Fever.
*+/-Headache.
*+/-Decreased level of consciousness.
 
CSF findings:
{| class="wikitable sortable"
! Type
! Glucose
! Protein
! Cells
! Cytopathology
|-
| Bacterial, acute
| low
| high
| neutrophils
| [[File:Purulent_CSF.jpg|100px|center|]][[CSF_cytopathology#Acute_bacterial_meningitis|Cytophathology]]
|-
| Viral
| normal
| slight elevation
| lymphocytes
| [[CSF_cytopathology#Viral_meningitis|Cytophathology]]
|}
 
 
 
====Etiology====
*Infectious.
**Bacterial.
**Viral.
**Parasitic
*Autoimmune.
*Toxic.
*Aseptic - see ''[[Mollaret's meningitis]]''.
 
Bacterial meningitis - most probably cause by age:<ref>{{Ref PCPBoD8|666-7}}</ref>
{| class="wikitable sortable"  
! Age
! Organism
|-
| Neonate
| ''Escherichia coli'', ''Group B Streptococcus''
|-
| Infants, children
| ''Streptococcus pneumoniae''
|-
| Adolescents, young adults
| ''Neisseria meningitidis''
|-
| Elderly
| ''Streptococcus pneumoniae'', ''Listeria monocytogenes''
|}
 
===Gross===
Features:
*+/-Clouded appearance of the meninges.
*+/-Pus.
*+/-Petechiae.
*+/-Cerebral edema.


===Diagnosis===
====Image====
*Need to r/o infection (with lumbar puncture).
<gallery>
*No old plaques on imaging (MRI).
Image:Streptococcus_pneumoniae_meningitis,_gross_pathology_33_lores.jpg | Streptococcus Meningitis. (WC/Dr. Edwin P. Ewing, Jr.)
File:Haemophilus influenzae meningitis 5003 lores.jpg | Hemophilus influenza Meningitis. (WC/CDC)
File:Pneumococcal meningitis.jpg | Pneumococcus Meningitis. (WC/Dr. Yale Rosen)
File:Meningitis-MRI.JPG | Bacterial Meningitis MRI (WC/MBq)
</gallery>


===Microscopic===
===Microscopic===
Features:
Features:
*Spares subcortical fibres (???)
*Inflammation of the meninges:
**+/-[[Neutrophil]]s.
**+/-Lymphocytes.
**+/-[[Plasma cell]]s.
*+/-Microorganisms (infectious meningitis):
**Bacteria.
**[[Fungi]], e.g. [[aspergillosis]] (may be intravascular).


===Tx===
Main DDx:
*Steroids.
*[[Lymphoma]].
*Plasmapheresis.


===DDx===
====Image====
*Multiple sclerosis.
<gallery>
Image:Meningitis_Histopathology.jpg | Bacterial meningitis. (WC/Marvin101)
</gallery>


==Cysts==
==Cerebral abscess==
===General===
===General===
*All are "benign", but some may be fatal due to spatial constraints.
*May mimic malignancy clinically.
 
===Microscopic===
Features:
*Sheets of neutrophils surrounded by fibrosing brain.
**Fibrosing brain: pale (lighter pink than normal brain tissue), dense.
 
Images:
*[http://pathology.class.kmu.edu.tw/ch01/4-1.jpg Cerebral abscess - very low mag. (kmu.edu.tw)].<ref>URL: [http://pathology.class.kmu.edu.tw/ch01/Slide4.htm http://pathology.class.kmu.edu.tw/ch01/Slide4.htm]. Accessed on: 1 January 2012.</ref>
*[http://pathology.class.kmu.edu.tw/ch01/4-5.jpg Cerebral abscess - low mag. (kmu.edu.tw)].
 
==Neurodegenerative diseases==
{{Main|Neurodegenerative diseases}}
This is a hueueuge topic.  It is covered in its own article and includes a general discussion of dementia.
 
==Malformation of cortical development(MCD) ==
===Lissencephaly===
* Greek: ‘lissos': smooth and ‘enkephalos': brain.
* Absent (agyria) or decreased (pachygyria) convolutions.
* Cortical thickening
* Smooth cerebral surface
* Subtypes with different layering: 2-layered, 3-layered, and 4-layered forms.
* Heterotopic neurons in a pattern suggestive of laminar organization.
* 14 LIS mutations account for 90% of all cases.<ref name="pmid27781032">{{cite journal |authors=Parrini E, Conti V, Dobyns WB, Guerrini R |title=Genetic Basis of Brain Malformations |journal=Mol Syndromol |volume=7 |issue=4 |pages=220–233 |date=September 2016 |pmid=27781032 |pmc=5073505 |doi=10.1159/000448639 |url=}}</ref>
 
===Polymicrogyria===
* Abnormal cortical lamination.
* Abnormally small and partly fused gyri.
* Can be unilateral, bilateral and symmetrical.
* Intellectual disability.
* Sometimes severe encephalopathy.
* Pharmacoresistant epilepsy
* Cortical lamination can be unlayered or four-layered.
** Unlayered:  Unorganized radial distribution of neurons.
** Four-layered:  Molecular layer, outer neuronal layer, nerve fiber layer, and inner neuronal layer.
* 1q trisomy in unilateral cases.<ref name="pmid32979071">{{cite journal |authors=Kobow K, Jabari S, Pieper T, Kudernatsch M, Polster T, Woermann FG, Kalbhenn T, Hamer H, Rössler K, Mühlebner A, Spliet WGM, Feucht M, Hou Y, Stichel D, Korshunov A, Sahm F, Coras R, Blümcke I, von Deimling A |title=Mosaic trisomy of chromosome 1q in human brain tissue associates with unilateral polymicrogyria, very early-onset focal epilepsy, and severe developmental delay |journal=Acta Neuropathol |volume=140 |issue=6 |pages=881–891 |date=December 2020 |pmid=32979071 |doi=10.1007/s00401-020-02228-5 |url=}}</ref>
 
==Epilepsy==
{{Main|Epilepsy}}
===Focal cortical dysplasia (FCD)===
*Localized malformations of the cortex.
*Frequently associated with epilepsy in children.
*Includes cortical dyslamination, cytoarchitectural changes and white matter abnormalities.
*Current consensus: ILAE classification scheme 2011 <ref>{{Cite journal  | last1 = Blümcke | first1 = I. | last2 = Aronica | first2 = E. | last3 = Miyata | first3 = H. | last4 = Sarnat | first4 = HB. | last5 = Thom | first5 = M. | last6 = Roessler | first6 = K. | last7 = Rydenhag | first7 = B. | last8 = Jehi | first8 = L. | last9 = Krsek | first9 = P. | title = International recommendation for a comprehensive neuropathologic workup of epilepsy surgery brain tissue: A consensus Task Force report from the ILAE Commission on Diagnostic Methods. | journal = Epilepsia | volume = 57 | issue = 3 | pages = 348-58 | month = Mar | year = 2016 | doi = 10.1111/epi.13319 | PMID = 26839983 }}
</ref>(based on previous classification by Palmini 2004):
 
 
*Type I FCD (focal)
**Ia: Abnormal radial cortical lamination.
**Ib: Abnormal tangential cortical lamination.
**Ic: Abnormal radial and tangential cortical lamination.
 
 
*Type II FCD (focal)
**IIa: Presence of dysmorphic neurons.
**IIb: Presence of dysmorphic neurons and balloon cells.


===List of cysts===
*Colloid cyst.<ref>MUN. 11 Mar 2009.</ref>
**Columnar epithelium.
*Arachnoid cyst - considered precursor of meningioma.
**Psammoma bodies.
**Clumps of cells.
**Whorled pattern.
*Dermoid cyst.
**Skin + adnexal structures.
**... think of ovarian dermoid.
*Epidermoid.
*Choriod cyst.
**?


*Neuroenteric cyst.
*Type III FCD (associated with other lesion)
*Epithelial cyst.
**IIIa: FCD associated with [[Epilepsy#Hippocampal_sclerosis|hippocampal sclerosis]].
**IIIb: FCD adjacent to a brain tumor.
**IIIc: FCD adjacent to vascular malformation.
**IIIc: FCD associated with previous injury (trauma, inflammation...).


==Dementia==
*Alzheimer's dementia.
*Vascular.
**multi-infarct dementia.
*Parkinson's associated dementia.
*Lewy body dementia.
*Alcohol-related dementia.
*Fronto-temporal dementia (Pick disease).
*Multisystem atrophy.


Mnemonic ''VITAMIN D VEST'':<ref>TN06 PS19</ref>
<gallery>
*Vitamin deficiency (B12, folate, thiamine).
File:FCDIIa dysmorphic neurons HE.jpg|Dysmorphic neurons in FCD (HE)
*Infection (HIV).
File:FCDIIa neuronal heterotopia neun.jpg|Heterotopic neurons (NeuN)
*Trauma.
</gallery>
*Anoxia.
*Metabolic (Diabetes).
*Intracranial tumour.
*Normal pressure hydrocephalus.
*Degenerative (Alzheimer's, Huntington's, CJD).
*Vascular.
*Endocrine.
*Space occupying lesion (chronic subdural hematoma).
*Toxins (alcohol).


===Lewy body dementia===
===Hamartia===
*Parkinsonian features.
* Small collection of ectopic glioneuronal cells.
*Hallucinations (visual).
**Morpholology resembling oligodendroglial-like cells. <ref>{{Cite journal  | last1 = Kasper | first1 = BS. | last2 = Stefan | first2 = H. | last3 = Buchfelder | first3 = M. | last4 = Paulus | first4 = W. | title = Temporal lobe microdysgenesis in epilepsy versus control brains. | journal = J Neuropathol Exp Neurol | volume = 58 | issue = 1 | pages = 22-8 | month = Jan | year = 1999 | doi =  | PMID = 10068310 }}</ref>
*Progressive cog. decline with fluctuations.
* Mostly amygdala, less common in hippocampus or temporal lobe.
* Can coexist with focal cortical dysplasia.


===Multiple system atrophy===
==Demyelination==
*Alpha-synuclein-rich glial cytoplasmic inclusions - finding at autopsy.<ref name=pmid18825660>{{Cite journal  | last1 = Wenning | first1 = GK. | last2 = Stefanova | first2 = N. | last3 = Jellinger | first3 = KA. | last4 = Poewe | first4 = W. | last5 = Schlossmacher | first5 = MG. | title = Multiple system atrophy: a primary oligodendrogliopathy. | journal = Ann Neurol | volume = 64 | issue = 3 | pages = 239-46 | month = Sep | year = 2008 | doi = 10.1002/ana.21465 | PMID = 18825660 }}
</ref>
**Alpha-synuclein is implicated in a number of neurodegenerative diseases.<ref name=pmid18855701>{{Cite journal  | last1 = Uversky | first1 = VN. | title = Alpha-synuclein misfolding and neurodegenerative diseases. | journal = Curr Protein Pept Sci | volume = 9 | issue = 5 | pages = 507-40 | month = Oct | year = 2008 | doi =  | PMID = 18855701 }}</ref>


==Brain tumours==
===Multiple sclerosis===
{{main|Neuropathology tumours}}
*Abbreviated ''MS''.
Tumours are a big part of neuropathology. 
{{Main|Multiple sclerosis}}


==Paediatric pathology==
===Osmotic demyelination syndrome===
===Joubert syndrome===
{{Main|Osmotic demyelination syndrome}}
*Malformation of the cerebellar vermis.<ref name=ninds_joubert>[http://www.ninds.nih.gov/disorders/joubert/joubert.htm http://www.ninds.nih.gov/disorders/joubert/joubert.htm]</ref>
*Previously known as ''central pontine myelinolysis'' (abbreviated ''CPM'').


===Epidemiology===
===Acute disseminated encephalomyelitis===
*Autosomal recessive - mutation in a number of genes including NPHP1, AHI1, and CEP290.<ref name=ninds_joubert/>
*Abbreviated ''ADEM''.
{{Main|Acute disseminated encephalomyelitis}}


==Histiocytoses==
===Neuromyelitis optica===
*Abbreviated ''NMO''.


Features of histiocytoses:<ref>Sternberg Surg. Path. P.479.</ref>  
General:
{| class="wikitable" border="1"
*Rare autoimmune disease - once considered a variant of [[multiple sclerosis]].
|-
**Autoantibodies directed at aquaporin-4.<ref name=pmid22087205>{{Cite journal  | last1 = Kim | first1 = W. | last2 = Kim | first2 = SH. | last3 = Kim | first3 = HJ. | title = New insights into neuromyelitis optica. | journal = J Clin Neurol | volume = 7 | issue = 3 | pages = 115-27 | month = Sep | year = 2011 | doi = 10.3988/jcn.2011.7.3.115 | PMID = 22087205 }}</ref>
! 
!  Histologic features
!  EM features
!  CD68
!  S-100
!  CD1a
|-
| Macrophage
| epithelioid cells, giant cells
| -
| +
| -
| -
|-
| Erdheim-Chester disease
| Touton giant cells
| -
|  +
|  +/-
| -
|-
|  [[Rosai-Dorfman disease|Rosai-Dorfman]]
|  Emperipolesis
|  -
|  +
|  +
|  -
|-
|  Langerhans-histiocytosis
|  Reniform nuclei,<br>eosinophilic cytoplasm
|  Birbeck granules
|  +
|  +
|  +
|}


==Stroke==
Diagnosis:
===Gross===
*NMO-IgG.
*Soft/mushy brain.
*Older infarcts.
**A "roof" is present - a thin submeningeal layer is preserved by the CSF.<ref>MUN. 16 December 2009.</ref>
***"Roof" is absent in trauma.
**Cavity - in older infarcts.
***''Multiple sclerosis'' does not cavitate.


==Hypoxic-ischemic encephalopathy==
Clinical - preferentially:
===General===
*Eye (optic neuritis).
*Often due to ''cardiac arrest'', i.e. global ischemia.
*Spinal cord (myelitis).


===Microscopic===
Microscopic:
Features:
*Inflammation - lymphocytes, macrophages.
*Hippocampal ischemic changes:
*Reactive astrocytes.
**Loss of neurons in CA1, CA3 and CA4 +/- "cavitation".
***Neuronal loss: No blue (nuclei) where there should be some.
***Cavitation: bubbles/clear spaces where there should be none.
**CA2 neurons preserved.


*"Anoxic neurons".<ref>URL: [http://www.neuropathologyweb.org/chapter2/chapter2aHIE.html http://www.neuropathologyweb.org/chapter2/chapter2aHIE.html]. Accessed on: 12 July 2010.</ref>
Images:
**Shrunken neurons with intensely eosinophilic cytoplasm and pyknotic (shrunken) nuclei.
*[http://path.upmc.edu/cases/case637.html Neuromyelitis optica - several images (upmc.edu)].
**Images:  
***[http://www.neuropathologyweb.org/chapter2/images2/2-1HIE.jpg Anoxic neurons (neuropathologyweb.org)].
***[http://commons.wikimedia.org/wiki/File:Alzheimer_type_II_astrocyte_high_mag_cropped.jpg Anoxic neurons (???) (WC)].


==Multiple sclerosis==
IHC:
===General===
*Mixed lymphocyte population with CD3 > CD20.
*A bread 'n butter disease of neurology in Canada.
*Aquaporin-4 loss.


===Radiologic/Gross===
===Progressive multifocal leukoencephalopathy===
Features:<ref>URL: [http://library.med.utah.edu/kw/ms/path.html http://library.med.utah.edu/kw/ms/path.html]. Accessed on: 12 July 2010.</ref>
*Abbreviated ''PML''.
*White matter lesions.
{{Main|Progressive multifocal leukoencephalopathy}}
**Cerebrum (classically): periventricular distribution.
**Optic nerves (optic neuritis) - classic presentation.


===Microscopic===
Features:<ref>URL: [http://library.med.utah.edu/kw/ms/path.html http://library.med.utah.edu/kw/ms/path.html]. Accessed on: 12 July 2010.</ref>
*Perivascular inflammation.
*Demyelination.
**Subcortical myelinated fibers are often spared.


Classification of MS lesions:
*Early active.
*Inactive.
*Early remyelinating.
*Late remyelinating.


==Weird stuff==
=Cysts=
==Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)==
===General===
===General===
*Autosomal dominant disorder - the name implies.<ref name=pmid19174371>{{Cite journal  | last1 = Tikka | first1 = S. | last2 = Mykkänen | first2 = K. | last3 = Ruchoux | first3 = MM. | last4 = Bergholm | first4 = R. | last5 = Junna | first5 = M. | last6 = Pöyhönen | first6 = M. | last7 = Yki-Järvinen | first7 = H. | last8 = Joutel | first8 = A. | last9 = Viitanen | first9 = M. | title = Congruence between NOTCH3 mutations and GOM in 131 CADASIL patients. | journal = Brain | volume = 132 | issue = Pt 4 | pages = 933-9 | month = Apr | year = 2009 | doi = 10.1093/brain/awn364 | PMID = 19174371 }}
*All are "benign", but some may be fatal due to spatial constraints.
</ref>
*Cases strokes in 40-50 year-old.
*Characteristic MRI findings - present in asymptomatic individuals with mutation.


===Etiology===
===List of cysts===
*Mutation of ''Notch 3'' gene.<ref name=pmid15537516>{{Cite journal  | last1 = Kalaria | first1 = RN. | last2 = Viitanen | first2 = M. | last3 = Kalimo | first3 = H. | last4 = Dichgans | first4 = M. | last5 = Tabira | first5 = T. | title = The pathogenesis of CADASIL: an update. | journal = J Neurol Sci | volume = 226 | issue = 1-2 | pages = 35-9 | month = Nov | year = 2004 | doi = 10.1016/j.jns.2004.09.008 | PMID = 15537516 }}</ref>
*[[Colloid cyst]].
**Columnar epithelium.
*Arachnoid cyst - considered precursor of [[meningioma]].
**[[Psammoma bodies]].
**Clumps of cells.
**Whorled pattern.
*[[Dermoid cyst]].
**Skin + adnexal structures.
**... think of ovarian dermoid.
*Epidermoid cyst.
*Choroid plexus cyst.
*Neuroenteric cyst.
**Foregut cyst with connection to dura.<ref>URL: [http://bhj.org/journal/2003_4502_april/neurentericcyst_373.htm http://bhj.org/journal/2003_4502_april/neurentericcyst_373.htm]. Accessed on: 19 December 2011.</ref>
***Gastrointestinal tract epithelium.
***Usually seen with vertebral anomalies.
*Epithelial cyst.
*Cyst with a mural nodule tumor of the brain.
**Commonly seen in: <ref>{{Cite journal  | last1 = Raz | first1 = E. | last2 = Zagzag | first2 = D. | last3 = Saba | first3 = L. | last4 = Mannelli | first4 = L. | last5 = Di Paolo | first5 = PL. | last6 = D'Ambrosio | first6 = F. | last7 = Knopp | first7 = E. | title = Cyst with a mural nodule tumor of the brain. | journal = Cancer Imaging | volume = 12 | issue = | pages = 237-44 | month = Aug | year = 2012 | doi = 10.1102/1470-7330.2012.0028 | PMID = 22935908 }}</ref>
**[[Hemangioblastoma]]
**[[Craniopharyngioma]]
**[[Ganglioglioma]]
*Others.


===Diagnosis===
==Colloid cyst==
*Proven ''Notch 3'' mutation.
===General===
*Can be diagnosed on a skin biopsy.
Classic presentation:<ref name=pmid15228889>{{Cite journal  | last1 = Spears | first1 = RC. | title = Colloid cyst headache. | journal = Curr Pain Headache Rep | volume = 8 | issue = 4 | pages = 297-300 | month = Aug | year = 2004 | doi = | PMID = 15228889 }}</ref>
*IHC for ''Notch 3'' -- +ve staining in Notch 3 mutants.
*Headache - may be relieved by lying down.
*Can cause [[sudden natural death]].<ref name=pmid14716130>{{Cite journal  | last1 = Kava | first1 = MP. | last2 = Tullu | first2 = MS. | last3 = Deshmukh | first3 = CT. | last4 = Shenoy | first4 = A. | title = Colloid cyst of the third ventricle: a cause of sudden death in a child. | journal = Indian J Cancer | volume = 40 | issue = 1 | pages = 31-3 | month =  | year =  | doi =  | PMID = 14716130 }}</ref>


===Histology===
===Gross===
Features:
*Fluid filled cyst - classically in the third ventricle.
*Subcortical infarcts.
**Patches of (non-myelinated) tissue within the white matter deep to the cortex with abundant macrophages.


Note:
====Images====
*No cortical involvement -- this is unlike ''multiple sclerosis''.
<gallery>
Image:Human brain showning a colloid cyst in the third ventricle.jpg| Colloid cyst at autopsy. (Shaktawat ''et al.''<ref name=pmid16867192>{{Cite journal  | last1 = Shaktawat | first1 = SS. | last2 = Salman | first2 = WD. | last3 = Twaij | first3 = Z. | last4 = Al-Dawoud | first4 = A. | title = Unexpected death after headache due to a colloid cyst of the third ventricle. | journal = World J Surg Oncol | volume = 4 | issue =  | pages = 47 | month =  | year = 2006 | doi = 10.1186/1477-7819-4-47 | PMID = 16867192 }}</ref>)
</gallery>
www:
*[http://www.ajnr.org/content/21/8/1470/F3.expansion.html Colloid cyst of third ventricle (ajnr.org)].<ref name=pmid11003281/>


DDx:
===Microscopic===
*Amyloidosis.
Features:<ref name=pmid11003281>{{Cite journal  | last1 = Armao | first1 = D. | last2 = Castillo | first2 = M. | last3 = Chen | first3 = H. | last4 = Kwock | first4 = L. | title = Colloid cyst of the third ventricle: imaging-pathologic correlation. | journal = AJNR Am J Neuroradiol | volume = 21 | issue = 8 | pages = 1470-7 | month = Sep | year = 2000 | doi =  | PMID = 11003281 }}</ref>
*Binswanger's disease - multi-infarct dementia affecting subcortical white matter.
*Simple epithelium with ciliated cells and goblet cells.
**Often diagnosed as ''Alzheimer's disease'' in the past.


===Electron microscopy===
====Images====
*Granular osmiophilic material (GOM).
<gallery>
Image:Colloid_Cyst_HE_40x.jpg | Colloid cyst. (WC)
</gallery>
www:
*[http://www.ajnr.org/content/21/8/1470/F4.expansion.html Colloid cyst (ajnr.org)].<ref name=pmid11003281/>


==Binswanger's disease==
=Paediatric pathology=
==Kernicterus==
===General===
===General===
*Multi-infarct dementia affecting subcortical white matter.
*Due to hyperbilirubinemia.<ref name=pmid7063283>{{Cite journal  | last1 = Turkel | first1 = SB. | last2 = Miller | first2 = CA. | last3 = Guttenberg | first3 = ME. | last4 = Moynes | first4 = DR. | last5 = Godgman | first5 = JE. | title = A clinical pathologic reappraisal of kernicterus. | journal = Pediatrics | volume = 69 | issue = 3 | pages = 267-72 | month = Mar | year = 1982 | doi =  | PMID = 7063283 }}</ref>
*Waste-basket diagnosis; diagnosed if CADASIL and amyloidosis have been excluded.
 
*Diagnosis has been controversial -- most with this entity (in the past) were diagnosed with ''Alzheimer's disease''.
===Gross===
*Yellow staining:<ref name=npw>URL: [http://neuropathology-web.org/chapter3/chapter3eBilirubinencephalopathy.html http://neuropathology-web.org/chapter3/chapter3eBilirubinencephalopathy.html]. Accessed on: 30 May 2012.</ref>
**Basal ganglia.<ref name=pmid10920171>{{Cite journal  | last1 = Hansen | first1 = TW. | last2 = Hervieux | first2 = JF. | last3 = Orth | first3 = J. | last4 = Schmorl | first4 = CG. | last5 = Baumes | first5 = JB. | title = Pioneers in the scientific study of neonatal jaundice and kernicterus. | journal = Pediatrics | volume = 106 | issue = 2 | pages = E15 | month = Aug | year = 2000 | doi =  | PMID = 10920171 }}</ref>
**Hippocampus.<ref name=pmid15091133>{{Cite journal  | last1 = Paksoy | first1 = Y. | last2 = Koç | first2 = H. | last3 = Genç | first3 = BO. | title = Bilateral mesial temporal sclerosis and kernicterus. | journal = J Comput Assist Tomogr | volume = 28 | issue = 2 | pages = 269-72 | month =  | year =  | doi =  | PMID = 15091133 }}</ref>
**Subthalamic nucleus.
 
Note:
*May not be specific.<ref name=pmid7063283/>
 
Image:
*[http://www.flickr.com/photos/neonatal-box/6275988844/ Kernicterus (flickr.com)].


===Microscopic===
===Microscopic===
Features:
Features - similar to [[HIE]]:<ref name=npw/>
*Subcortical lesions that replace the myelin consisting of macrophages.
*+/-Red neurons.
*+/-Gliosis.
 
==Joubert syndrome==
*Malformation of the cerebellar vermis.<ref name=ninds_joubert>[http://www.ninds.nih.gov/disorders/joubert/joubert.htm http://www.ninds.nih.gov/disorders/joubert/joubert.htm]</ref>
 
===Epidemiology===
*Autosomal recessive - mutation in a number of genes including NPHP1, AHI1, and CEP290.<ref name=ninds_joubert/>


==See also==
=See also=
*[[Brain tumours]].
*[[Brain tumours]].
*[[Pituitary gland]].
*[[Pituitary gland]].
*[[Histiocytoses]].
*[[Intracranial hematomas]].
*[[Spine]].


==References==
=References=
{{reflist|2}}
{{reflist|2}}


==External links==
=External links=
*[http://www.neuropathologyweb.org/ Neuropathology (neuropathologyweb.org)].
*[http://www.neuropathologyweb.org/ Neuropathology (neuropathologyweb.org)].
**[http://www.neuropathologyweb.org/test6/6test.html Quiz (neuropathologyweb.org)].
*[http://blog.lib.umn.edu/santa013/neuropathology/ Neuropathology cases (lib.umn.edu)].
*[http://blog.lib.umn.edu/santa013/neuropathology/ Neuropathology cases (lib.umn.edu)].
*[http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1 Neuropathology micrographs - identifying the site (stonybrookmedicalcenter.org)].
*[http://www.stonybrookmedicalcenter.org/pathology/neuropathology/chapter1 Neuropathology micrographs - identifying the site (stonybrookmedicalcenter.org)].
*[http://moon.ouhsc.edu/kfung/jty1/neurotest/AAQuestion-41-60.htm Neurocytopathology quiz (ouhsc.edu)].
*[http://wiki.cns.org/wiki/index.php/Main_Page WikiCNS (wiki.cns.org)].


[[Category:Neuropathology]]
[[Category:Neuropathology]]

Latest revision as of 17:17, 25 March 2021

Gross image showing changes of a stroke. (WC/Marvin 101)

This article is an introduction to neuropathology. There are separate articles for brain tumours, the pituitary gland, the spine, the eye, muscle pathologies, neurohistology and neuroanatomy.

Neuropathology is the bane of many anatomical pathologists in teaching hospitals... 'cause they have to fill in for the neuropathologist when he or she is on vacation.

Neuroanatomy

Main article: Neuroanatomy

This is a large topic. It covered in a separate article, that also covers grossing.

Neuroradiology

Key factors to consider in evaluation:

  1. Location.
  2. Number of lesions - single versus multiple.
  3. Cystic versus solid lesion.
  4. Enhancement.

Lesion location

In neuroradiology and neuropathology, real estate is crucial. Lesion location can often narrow your differential.

Cortical lesions (gray matter):

Cortical-subcortical junction:

Subcortical lesions (white matter):

Deep gray matter lesions (e.g. basal ganglia):

Cerebellar lesions:

Intraventricular lesions:

Suprasellar (above the pituitary):

Number of lesions

If single lesion = think primary, neoplastic If multiple lesions = think metastatic, neoplastic or infectious NB: glioblastoma can be multifocal (and the foci can be quite far apart)

Cystic vs. solid lesions

Some tumours are classically cystic with a small solid component (so-called cyst with a mural nodule) -- e.g. pilocytic astrocytoma, ganglioglioma, hemangioblastoma

Enhancing vs. non-enhancing:

  • In adults, enhancing generally = high grade.
  • In pediatrics, it often depends on the pattern.

Two main patterns to be mindful of -- ring enhancing lesions, and cystic lesions with a mural nodule.

Ring enhancing lesions

In HIV/AIDS patients... mass on CT if infection:

Ring enhancing lesion (DDx) - mnemonic MAGICAL DR:[2]

Cyst with enhancing mural nodule

  • hemangioblastoma (#1 in adults)
  • pilocytic astrocytoma (#1 in peds)
  • pleomorphic xanthoastrocytoma
  • ganglioglioma

Grossing

This is covered in the neuroanatomy article.

Gross pathology

The gross usually useless for arriving at a definitive diagnosis.

Exceptions:[3]

Normal histology

Main article: Neurohistology

This is a big topic. It is covered in a separate article called neurohistology.

Histopathology

Neuronal changes

Anoxic neurons

  • AKA red neurons.

Features:

  • Intensely red cytoplasm.
  • Pyknosis = nuclear shrinkage + darker staining.
Images

  • Anoxic neurons (WC)

  • Neurons in an acute stroke. (WC)

www:

Central chromatolysis

Features:[6]

  • Central clearing.
    • Nucleus and Nissl substance are pushed to cell periphery.

DDx:

Images

  • Central chromatolysis - intermed. mag. (WC)

  • Central chromatolysis - NF stain - very high mag. (WC)

Axonal swellings

H&E:

  • Eosinophilic (light pink) - ground glass-like appearance.
  • Shape:
    • Round if sectioned perpendicular to axis of axon.
      • Bound by cell membrane.
      • Large ~ typically 2-4x RBC diameter.
    • Sausage-shaped if cut in along axis.

Images:

IHC
  • APP.

Image:

Glial changes

Astrocyte changes

Reactive astrocytes:

  • Approximately equally-spaced; distance between neighbouring astrocytes is ~2x (or more) the cell size.
  • Well-defined cell border.
  • Eosinophilic cytoplasm with many branching processes.
    • Classically described as "funnel-shaped" in benign astrocytes.[11]
  • Peripheral nucleus.

  • Reactive astrocytes - high mag. (WC)

Alzheimer type II astrocyte:[12]

  • Alzheimer type II astrocytes. (WC)

Creutzfeldt cell:[14]

  • Astrocyte that mimics a mitoses; has moderate (identifiable) cytoplasm.
  • Finding associated with demyelinating disease.
  • Image: Crutzfeldt cell (upmc.edu).[15]

Gemistocytic astrocytes:[16]

  • Distinct eosinophilic cytoplasm - with ground-glass appearance.

Tufted astrocytes:[17]

  • Cellular processes loaded with tau protein (as may be seen with tau IHC or Gallyas silver stain); Parisian-star-like appearance with special stain.
  • +/-Multinucleated.
  • A classic feature of progressive supranuclear palsy.

Other glial

Bergmann gliosis (in the cerebellum):[14]

  • Thin layer of cells (2-3 cells) with open nuclei that are larger than granular cell layer nuclei; seen with Purkinje cell loss.

  • Bergmann gliosis - intermed. mag. (WC)

  • Bergmann gliosis - high mag. (WC)

  • Bergmann gliosis due to compression by metastasis - intermed mag. (WC)

Image:

Reactive change vs. malignancy

Reactive changes vs. malignancy (mnemonic MIMICS):[18]

  • MIcrovesicular pattern.
  • Mitoses.
  • Irregular spacing.
  • Calcifications.
  • Satellitosis, perineuronal.
    • Large "crowds" of glial cells associated with nuclei.

Inflammatory

DDx:

Encephalitis

see also:

General

DDx:

  • Viral encephalitis (Neurotrophic viruses):[19]
    • Eteroviruses are the most common cause of aseptic meningitis.
      • Coxackie Virus.
      • Enteric cytopathic human orphan (ECHO) virus.
    • Human Herpesviruses (HSV1, HSV2, VZV, CMV, EBV, Roseola)
      • HSV encephalitis has high mortality without acyclovir treatment.
      • Childhood cerebellitis mainly associated with varicella.
      • VZV is the second most common viral meningitis after enterovirus.
    • Measles virus(worldwide more than 100.000 deaths annually).
    • Seasonal influenza A virus (highest patogenic potential: avian influenza H5N1).
    • Polio and Non-Polio Enterovirus (mostly children).
      • Although massive eradication: Polio still existent in Pakistan, Afghanistan, Nigeria.
    • Rabies virus
    • Tick-borne encephalitis virus (Europe, Siberia, Russian far-east).
    • West-Nile virus (US, Southern europe).
    • St. Louis encephalitis virus (US).
    • Japanese encephalitis virus (South, south-east asia, high disability rate).
    • La Crosse virus (esp. children, midwest & eastern US).
    • Borna disease virus (VSBV-1).
    • Equine encephalitis viruses (EEEV, VEEV, WEEV, CHIKV).
  • Paraneoplastic syndromes.
  • Autoimmune antibody-mediated limbic encephalitis (NMDAR).
  • Purulent bacterial encephalitis
  • Septic metastatic encephalitis
    • microabscesses, local astrogliosis, two or more granulocytic infiltrates without relation to vessel.[20]
  • Septic embolic encephalitis
    • Embolic endocarditis, Stroke-like lesions.[21]
  • Non-purulent bacterial encephalitis
Gross
  • Frontal and temporal lobe - most common for HSV encephalitis.[22]
Microscopic

Features:[23]

  • Perivascular inflammation.
  • Microglia.
  • +/-Neuronophagia.
    • Phagocytosis of neurons.[24]
  • +/-Viral cytopathic changes.
  • +/-Perineuronal inflammation.

Notes:

  • Hemorrhage[25] and necrosis - characteristic of HSV encephalitis.

Image:

IHC

IHC stains for:

  • Intraoperative appearance of a lymphocytic encephalitis (WC/jensflorian)

  • Perivascular inflammation in a lymphocytic encephalitis (WC/jensflorian)

  • Hemorrhage in HSV encephalitis (WC/jensflorian)

  • HSV encephalitis, higher magnification (WC/jensflorian)

  • Neonatal brain with migration disturbances due to CMV infection (WC/jensflorian)

  • Neuronal nuclear inclusions in a neonatal CMV infection (WC/jensflorian)

  • Rabies encephalitis (CDC.gov)

  • Negri bodies in Purkinje cells (CDC.gov)

Vasculitis

DDx Cerebral vasculitis / angiitis:

  • Beta-amyloid related angitis, HE (WC)

  • Beta-amyloid related angiitis, abeta IHC (WC)

  • Giant cell arteritis, HE (WC)

Architecture

Rosettes

  • Rosette = circular/flower-like arrangement of cells.[27]
  • Homer-Wright rosette = (circular) rosette with a small (~100 micrometers ???) meshwork of fibers (neuropil) at the centre.[27]
  • Pineocytomatous/neurocytic rosette = irregular rosette with a large meshwork of fibers (neuropil) at the centre.[27]
  • Radial (cartwheel) profiles = neoplastic cells anchoring to stromal vessels, shorter processes than in ependymal pseudorosettes

  • Homer-Wright rosettes (WC).

  • Neurocytic rosettes (WC).

  • Perivascular pseudorosette (WC).

  • Multilayered rosettes (WC).

  • Ependymoblastous rosettes (WC/Marvin101).

  • True ependymal rosettes and pseudorosettes (WC).

  • Radial (cartwheel) profiles (WC).

Other important histological features

  • Rosenthal fibres = worm-like or corkscrew-like (brightly) eosinophilic bodies; 10-40 micrometers.
    • Key feature: variable thickness; helps separate from RBCs.
    • Well-seen on trichrome stains.

  • Rosenthal fibres. (WP)

  • Rosenthal fibres - smear (WC/AFIP)

  • Eosinophilic granular bodies = related to Rosenthal fibres; round cytoplasmic hyaline droplets in astrocytes.[30]

  • Eosinophilic granular bodies in pilocytic astrocytoma smear (WC/AFIP)

  • Eosinophilic granular body in a pleomorphic xanthoastrocytoma (WC/jensflorian)

  • Pseudopalisading - picket fence-like alignment of cells; long axis of cells perpendicular to interface with other structures/cells.
    • Pseudopalisading of tumour cells (around necrotic regions) is seen in glioblastoma.

  • Pseudopalisading necrosis in a glioblastoma (WC/jensflorian)

Note:

Inclusion bodies

  • Negri bodies.
    • Cytoplasmic inclusions; classically in Purkinje cells of the cerebellum, pyramidal cells of Ammon's horn.
    • Rabies.

  • Negri bodies. (WC/CDC)

  • Owl eye inclusions.
    • Basiopilic neuronal inclusions in enlarged cells, typically seen in CMV encephalitis

  • Owl eye inclusions

  • Lewy bodies.
    • Eosinophilic cytoplasmic inclusion - composed mostly of alpha-synuclein.[32]

  • Lewy body. (WC)

Table of inclusions

Feature Appearance Associated disease Comment Image
Grumose bodies
AKA granular bodies 		granular and eosinophilic ~50 micrometers neurodegenerative disease, neuroaxonal dystrophies, aging ?Comment ?Image
Cowdry type 1
AKA Cowdry type A 		eosinophilic & round + halo herpes simplex virus can be confused with
Lewy body, Marinesco body 		?Image
Lewy body round cytoplasmic eosinophilic
body +/- pale halo 		Parkinson disease, dementia with Lewy bodies morphology dependent on
location in brain; +ve for alpha-synuclein,
alpha-B crystallin, ubiquitin
Lewy Koerperchen.JPG
, [1]
Lafora body round myoclonic epilepsy look like corpora amylacea; location: dentate nucleus, liver, skeletal muscle, sweat glands ?Image
Lipofuscin yellow & granular aging olive, dendate ?Image
Negri body small eosinophic bodies rabies found in hippocampal neurons and Purkinje cells
Rabies encephalitis Negri bodies PHIL 3377 lores.jpg
Hirano body concentric calcification/rod-shaped bright eosinophilic; overlap edge of neuron Alzheimer disease, Pick disease[33] actin crystals, may look like capillaries; location: CA1 of hippocampus [2][34]
Neurofibrillary tangles flame-shaped cytoplasmic thingy
~30 micrometers 		aging, Alzheimer's disease seen with silver stain Schematic[34], [3][35]
Granulovacuolar degeneration cytoplasmic vacuoles 4-5 micrometers ageing, Alzheimer's disease,
Pick's disease 		main found in Ammon horn[33] [4][35]
Pick bodies round, homogenous, intracytoplasmic, ~10 micrometers Pick's disease pyramidal neurons, dentate
granule cells (hippocampus); +ve for tau, tubulin, ubiquitin 		[5]
Bunina body size of Nissl granules, eosinophilic amyotrophic lateral sclerosis (ALS) EM: membrane-bound bodies; ubiquitin +ve [6]

Image collection: Inclusion bodies (photobucket.com).

Immunohistochemistry

Main article: Immunohistochemistry

General

  • S-100.
    • Sensitive... but non-specific, e.g. also stains melanoma.

Glial

  • GFAP (glial fibrillary acidic protein) - should stain perikaryon.

Glial tumours

Standard work-up:

  • GFAP.
  • MAP2C. [36]
  • Ki-67 (MIB-1).

Useful additional markers:

  • IDH1(R132H) in Astrocytic/Oligodendroglial tumors. [37]
  • ATRX in mixed gliomas. [38]
  • EMA in Ependymal tumors. [39]
  • OLIG-2 usually -ve in Ependymomas. [40][41]

Neuronal

  • Synaptophysin.
  • Chromogranin.

Carcinoma vs. glial tumours

  • AE1/AE3 often +ve in glial tumours (e.g. astrocytomas, oligodendrogliomas); CAM5.2 is usu. -ve in glial tumours.[42]

Others

  • APP (amyloid precursor protein) - detects axonal swellings.
  • NF (neurofilament) - detects axonal swellings.

Brain tumours

Main article: Neuropathology tumours

Tumours are a big part of neuropathology. The most common brain tumour (in adults) is a metastasis. The most common primary tumours originating in the brain (in adults) are gliomas. More than 50% of these are classified as glioblastoma which has a horrible prognosis.

Non-tumour

Vascular disorders

Cerebral hemorrhage

See: Intracranial hematoma for intracranial bleeds

Includes discussion of:

Duret hematoma

  • AKA Duret hemorrhage.

General

  • Bleed in the upper brainstem (midbrain and pons).
    • Thought to be due to transtentorial herniation secondary to supratentorial mass effect (e.g. supratentorial tumour, intracranial hemorrhage).[43]
  • Often fatal.[44]

Gross

  • Extravasated blood in midbrain and pons - usu. ventral (anterior) and paramedian (adjacent to the midline).[43]

Image:

Microscopic

Features:

  • RBC extravasation.
  • +/-Hemosiderin-laden macrophages.
  • +/-Ischemic neurons.

Cerebral amyloid angiopathy

General

  • Abbreviated CAA.
  • Disease of the old.
  • Strong association with lobar haemorrhage (bleeds of the cerebellar cortex and cerebral cortex).[46]

Etiology:

  • Amyloid deposition in the basal lamina of smooth muscle (in the cerebellar cortex and cerebral cortex).

Gross

  • Bleeds typically superficial (cortex and subcortical white matter) and in the frontal lobe or parietal lobe.[47]

Microscopic

Features:

  • Amorphous, acellular eosinophilic material within walls of small arteries.
    • This is a high power diagnosis with congo red staining.

Notes:

  • Amyloidosis is seen in all individuals with Alzheimer's disease; the amount of amyloid is what differs -- in CAA it is lots and lots.
  • The white matter is typically spared by CAA.[48]

Images

  • CAA - congo red - very high mag. (WC)

  • CAA - congo red - low mag. (WC)

  • CAA - beta-amyloid - high mag. (WC)

Stains

IHC

  • Abeta-amyloid (AKA beta-amyloid).

Cerebral amyloid angiopathy associated with inflammation (I-CAA)

  • Cognitive decline.
  • Microbleedings in MRI.
  • Responsive to steroids.
  • Abeta deposits in vessels.
  • Perivascular lymphocytic infiltrate (but no vasculitis!).
  • Giant cells may be present.

Vascular malformations

Main article: Vascular malformations

Types:[49]

Also see: Sturge-Weber syndrome.

Atherosclerosis

Main article: Vascular_disease#Atherosclerosis
  • Intracranial atherosclerosis most common at circle of Willis.
  • Macroscopic yellow discoloration.
  • Luminal stenosis and eccentric intimal thickening.

  • Plaque of the carotid bifurcation (Ed Uthman).

Other large arterial diseases

Microangiopathy

  • Defined as Small vessel disease (<300µm in transverse section).
  • Includes atherosclerosis and cerebral amyloid angiopathy.

Other causes:

Main article: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy

Hypoxic-ischemic encephalopathy

  • Abbreviated HIE.
Main article: Hypoxic-ischemic encephalopathy
    • Hypoxia: reduction in oxygen supply or utilization.
    • Ischemia: reduction in blood supply.

Cerebrovascular accident

  • Abbreviated CVA.
  • AKA stroke.
Main article: Cerebrovascular accident
  • Stroke includes:
    • Infarction (ischemia in defined vascular distribution persisting for at least 24hrs).
    • Intracrebral hemorrhage (focal blood accumulation in the brain parenchyma).
    • Subarachnoid hemorrhage (SAH).
    • Cerebral venous thrombosis (CVT).


Alcohol & CNS

Clinical

  • Wernicke's encephalopathy
    • Mnemonic WACO:
      • Wernicke's.
      • Ataxia.
      • Confusion, confabulation -- Korsakoff.
      • Ocular Sx (CN IV palsy).
    • Cause: thiamine deficiency.

Pathology

Features:[50]

  • Morel's laminar sclerosis = spongy degeneration and gliosis of the cerebral cortex[51] usu. prominent in the third layer of the cortex (outer pyramidal layer) and especially in the lateral-frontal cortex.[52]
  • Central pontine myelinolysis (CPM).[53]
    • Just what it sound like - myelin loss in the central pons.
    • Classically associated with rapid correction of hyponatremia.[54]
  • Mammillary body shrinkage.[55]
  • Anterior cerebellar vermis atrophy; weak finding - as also age-related.[56]
    • Vermis atrophy is also seen in schizophrenia.[57]

Marchiafava-Bignami Disease

  • Rare.
  • Demyelination of the corpus callosum.[52]

Wernicke's encephalopathy

General:

  • Due to thiamine deficiency.

Features:[58]

  • Neurons of mammillary bodies preserved - key.
  • Loss of myelin.
  • Hemorrhage.
  • Edema.
  • Reactive blood vessels.

Note:

  • The thalamus and inferior olives show neuronal loss.[58]

Common non-specific findings

Meningitis

General

  • Definition: inflammation of the meninges (pia mater, arachnoid membranes, dura mater).

Classic clinical presentation:

  • Neck stiffness.
  • Fever.
  • +/-Headache.
  • +/-Decreased level of consciousness.

CSF findings:

Type Glucose Protein Cells Cytopathology
Bacterial, acute low high neutrophils
Purulent CSF.jpg
Cytophathology
Viral normal slight elevation lymphocytes Cytophathology


Etiology

Bacterial meningitis - most probably cause by age:[59]

Age Organism
Neonate Escherichia coli, Group B Streptococcus
Infants, children Streptococcus pneumoniae
Adolescents, young adults Neisseria meningitidis
Elderly Streptococcus pneumoniae, Listeria monocytogenes

Gross

Features:

  • +/-Clouded appearance of the meninges.
  • +/-Pus.
  • +/-Petechiae.
  • +/-Cerebral edema.

Image

  • Streptococcus Meningitis. (WC/Dr. Edwin P. Ewing, Jr.)

  • Hemophilus influenza Meningitis. (WC/CDC)

  • Pneumococcus Meningitis. (WC/Dr. Yale Rosen)

  • Bacterial Meningitis MRI (WC/MBq)

Microscopic

Features:

Main DDx:

Image

  • Bacterial meningitis. (WC/Marvin101)

Cerebral abscess

General

  • May mimic malignancy clinically.

Microscopic

Features:

  • Sheets of neutrophils surrounded by fibrosing brain.
    • Fibrosing brain: pale (lighter pink than normal brain tissue), dense.

Images:

Neurodegenerative diseases

Main article: Neurodegenerative diseases

This is a hueueuge topic. It is covered in its own article and includes a general discussion of dementia.

Malformation of cortical development(MCD)

Lissencephaly

  • Greek: ‘lissos': smooth and ‘enkephalos': brain.
  • Absent (agyria) or decreased (pachygyria) convolutions.
  • Cortical thickening
  • Smooth cerebral surface
  • Subtypes with different layering: 2-layered, 3-layered, and 4-layered forms.
  • Heterotopic neurons in a pattern suggestive of laminar organization.
  • 14 LIS mutations account for 90% of all cases.[61]

Polymicrogyria

  • Abnormal cortical lamination.
  • Abnormally small and partly fused gyri.
  • Can be unilateral, bilateral and symmetrical.
  • Intellectual disability.
  • Sometimes severe encephalopathy.
  • Pharmacoresistant epilepsy
  • Cortical lamination can be unlayered or four-layered.
    • Unlayered: Unorganized radial distribution of neurons.
    • Four-layered: Molecular layer, outer neuronal layer, nerve fiber layer, and inner neuronal layer.
  • 1q trisomy in unilateral cases.[62]

Epilepsy

Main article: Epilepsy

Focal cortical dysplasia (FCD)

  • Localized malformations of the cortex.
  • Frequently associated with epilepsy in children.
  • Includes cortical dyslamination, cytoarchitectural changes and white matter abnormalities.
  • Current consensus: ILAE classification scheme 2011 [63](based on previous classification by Palmini 2004):


  • Type I FCD (focal)
    • Ia: Abnormal radial cortical lamination.
    • Ib: Abnormal tangential cortical lamination.
    • Ic: Abnormal radial and tangential cortical lamination.


  • Type II FCD (focal)
    • IIa: Presence of dysmorphic neurons.
    • IIb: Presence of dysmorphic neurons and balloon cells.


  • Type III FCD (associated with other lesion)
    • IIIa: FCD associated with hippocampal sclerosis.
    • IIIb: FCD adjacent to a brain tumor.
    • IIIc: FCD adjacent to vascular malformation.
    • IIIc: FCD associated with previous injury (trauma, inflammation...).


  • Dysmorphic neurons in FCD (HE)

  • Heterotopic neurons (NeuN)

Hamartia

  • Small collection of ectopic glioneuronal cells.
    • Morpholology resembling oligodendroglial-like cells. [64]
  • Mostly amygdala, less common in hippocampus or temporal lobe.
  • Can coexist with focal cortical dysplasia.

Demyelination

Multiple sclerosis

  • Abbreviated MS.
Main article: Multiple sclerosis

Osmotic demyelination syndrome

Main article: Osmotic demyelination syndrome
  • Previously known as central pontine myelinolysis (abbreviated CPM).

Acute disseminated encephalomyelitis

  • Abbreviated ADEM.
Main article: Acute disseminated encephalomyelitis

Neuromyelitis optica

  • Abbreviated NMO.

General:

  • Rare autoimmune disease - once considered a variant of multiple sclerosis.
    • Autoantibodies directed at aquaporin-4.[65]

Diagnosis:

  • NMO-IgG.

Clinical - preferentially:

  • Eye (optic neuritis).
  • Spinal cord (myelitis).

Microscopic:

  • Inflammation - lymphocytes, macrophages.
  • Reactive astrocytes.

Images:

IHC:

  • Mixed lymphocyte population with CD3 > CD20.
  • Aquaporin-4 loss.

Progressive multifocal leukoencephalopathy

  • Abbreviated PML.
Main article: Progressive multifocal leukoencephalopathy


Cysts

General

  • All are "benign", but some may be fatal due to spatial constraints.

List of cysts

  • Colloid cyst.
    • Columnar epithelium.
  • Arachnoid cyst - considered precursor of meningioma.
  • Dermoid cyst.
    • Skin + adnexal structures.
    • ... think of ovarian dermoid.
  • Epidermoid cyst.
  • Choroid plexus cyst.
  • Neuroenteric cyst.
    • Foregut cyst with connection to dura.[66]
      • Gastrointestinal tract epithelium.
      • Usually seen with vertebral anomalies.
  • Epithelial cyst.
  • Cyst with a mural nodule tumor of the brain.
  • Others.

Colloid cyst

General

Classic presentation:[68]

Gross

  • Fluid filled cyst - classically in the third ventricle.

Images

  • Colloid cyst at autopsy. (Shaktawat et al.[70])

www:

Microscopic

Features:[71]

  • Simple epithelium with ciliated cells and goblet cells.

Images

  • Colloid cyst. (WC)

www:

Paediatric pathology

Kernicterus

General

  • Due to hyperbilirubinemia.[72]

Gross

  • Yellow staining:[73]
    • Basal ganglia.[74]
    • Hippocampus.[75]
    • Subthalamic nucleus.

Note:

  • May not be specific.[72]

Image:

Microscopic

Features - similar to HIE:[73]

  • +/-Red neurons.
  • +/-Gliosis.

Joubert syndrome

  • Malformation of the cerebellar vermis.[76]

Epidemiology

  • Autosomal recessive - mutation in a number of genes including NPHP1, AHI1, and CEP290.[76]

See also

References

  1. ↑ MUN. Feb 3, 2009.
  2. ↑ Yeung, J.C.; Leonard, Blair J. N. (2005). The Toronto Notes 2005 - Review for the MCCQE and Comprehensive Medical Reference (2005 ed.). The Toronto Notes Inc. for Medical Students Inc.. pp. NS7. ISBN 978-0968592854.
  3. ↑ R. Kiehl. 8 November 2010.
  4. ↑ URL: http://neuropathology-web.org/chapter2/chapter2aHIE.html. Accessed on: 10 December 2014.
  5. ↑ URL: http://moon.ouhsc.edu/kfung/iacp-olp/apaq-text/N1-MS-01-16-Ans.htm and http://moon.ouhsc.edu/kfung/iacp-olp/apaq-text/n1-ms-01.htm. Accessed on: 31 October 2010.
  6. ↑ URL: http://www.neuropathologyweb.org/chapter1/chapter1aNeurons.html. Accessed on: 22 December 2010.
  7. ↑ Holland GR (1996). "Experimental trigeminal nerve injury". Crit. Rev. Oral Biol. Med. 7 (3): 237–58. PMID 8909880.
  8. ↑ Piercecchi-Marti MD, Pélissier-Alicot AL, Leonetti G, Tervé JP, Cianfarani F, Pellissier JF (December 2004). "Pellagra: a rare disease observed in a victim of mental and physical abuse". Am J Forensic Med Pathol 25 (4): 342–4. PMID 15577526.
  9. ↑ URL: http://frontalcortex.com/?page=oll&topic=24&qid=602. Accessed on: 3 November 2010.
  10. ↑ Finnie JW, Manavis J, Blumbergs PC, Kuchel TR (November 2000). "Axonal and neuronal amyloid precursor protein immunoreactivity in the brains of guinea pigs given tunicamycin". Vet. Pathol. 37 (6): 677–80. PMID 11105962. http://vet.sagepub.com/content/37/6/677.full.
  11. ↑ MUN. 15 November 2010.
  12. ↑ URL: http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html. Accessed on: 2 July 2010.
  13. ↑ Klatt, Edward C. (2006). Robbins and Cotran Atlas of Pathology (1st ed.). Saunders. pp. 202. ISBN 978-1416002741.
  14. ↑ 14.0 14.1 Perry, Arie; Brat, Daniel J. (2010). Practical Surgical Neuropathology: A Diagnostic Approach: A Volume in the Pattern Recognition series (1st ed.). Churchill Livingstone. pp. 18. ISBN 978-0443069826.
  15. ↑ URL: http://path.upmc.edu/cases/case336.html. Accessed on: 15 January 2012.
  16. ↑ URL: http://www.neuropathologyweb.org/chapter1/chapter1bAstrocytes.html. Accessed on: 7 November 2010.
  17. ↑ Gray, Francoise; Poirier, Jacques; De Girolami, Umberto (2003). Escourolle and Poirier's Manual of Basic Neuropathology (4th ed.). Churchill Livingstone. pp. 173. ISBN 978-0750674058.
  18. ↑ Weedman Molavi, Diana (2008). The Practice of Surgical Pathology: A Beginner's Guide to the Diagnostic Process (1st ed.). Springer. pp. 254. ISBN 978-0387744858.
  19. ↑ Ludlow, M.; Kortekaas, J.; Herden, C.; Hoffmann, B.; Tappe, D.; Trebst, C.; Griffin, DE.; Brindle, HE. et al. (Feb 2016). "Neurotropic virus infections as the cause of immediate and delayed neuropathology.". Acta Neuropathol 131 (2): 159-84. doi:10.1007/s00401-015-1511-3. PMID 26659576.
  20. ↑ Tauber, SC.; Bunkowski, S.; Brück, W.; Nau, R. (Dec 2011). "Septic metastatic encephalitis: coexistence of brain damage and repair.". Neuropathol Appl Neurobiol 37 (7): 768-76. doi:10.1111/j.1365-2990.2011.01196.x. PMID 21696418.
  21. ↑ Bitsch, A.; Nau, R.; Hilgers, RA.; Verheggen, R.; Werner, G.; Prange, HW. (Oct 1996). "Focal neurologic deficits in infective endocarditis and other septic diseases.". Acta Neurol Scand 94 (4): 279-86. PMID 8937541.
  22. ↑ Lefkowitch, Jay H. (2006). Anatomic Pathology Board Review (1st ed.). Saunders. pp. 416 Q47. ISBN 978-1416025887.
  23. ↑ Takei, H.; Wilfong, A.; Malphrus, A.; Yoshor, D.; Hunter, JV.; Armstrong, DL.; Bhattacharjee, MB. (Aug 2010). "Dual pathology in Rasmussen's encephalitis: a study of seven cases and review of the literature.". Neuropathology 30 (4): 381-91. doi:10.1111/j.1440-1789.2009.01079.x. PMID 20051019.
  24. ↑ URL: http://medical-dictionary.thefreedictionary.com/neuronophagia. Accessed on: 11 April 2012.
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  27. ↑ 27.0 27.1 27.2 27.3 27.4 27.5 Wippold FJ, Perry A (March 2006). "Neuropathology for the neuroradiologist: rosettes and pseudorosettes". AJNR Am J Neuroradiol 27 (3): 488–92. PMID 16551982.
  28. ↑ URL: http://moon.ouhsc.edu/kfung/IACP-OLP/APAQ-Text/N1-TU-01.htm#17. Accessed on: 3 December 2010.
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  30. ↑ Gray, Francoise; Poirier, Jacques; De Girolami, Umberto (2003). Escourolle and Poirier's Manual of Basic Neuropathology (4th ed.). Churchill Livingstone. pp. 11. ISBN 978-0750674058.
  31. ↑ Rossi, ML.; Jones, NR.; Candy, E.; Nicoll, JA.; Compton, JS.; Hughes, JT.; Esiri, MM.; Moss, TH. et al. (1989). "The mononuclear cell infiltrate compared with survival in high-grade astrocytomas.". Acta Neuropathol 78 (2): 189-93. PMID 2750489.
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  34. ↑ 34.0 34.1 URL: http://www.pakmed.net/academic/age/alz/alz030.htm. Accessed on: 12 November 2010.
  35. ↑ 35.0 35.1 URL: http://faculty.washington.edu/alexbert/MEDEX/Fall/NeuroPath_Obj.htm. Accessed on: 13 November 2010.
  36. ↑ Blümcke, I.; Müller, S.; Buslei, R.; Riederer, BM.; Wiestler, OD. (Aug 2004). "Microtubule-associated protein-2 immunoreactivity: a useful tool in the differential diagnosis of low-grade neuroepithelial tumors.". Acta Neuropathol 108 (2): 89-96. doi:10.1007/s00401-004-0873-8. PMID 15146346.
  37. ↑ Paulus, W. (Nov 2009). "GFAP, Ki67 and IDH1: perhaps the golden triad of glioma immunohistochemistry.". Acta Neuropathol 118 (5): 603-4. doi:10.1007/s00401-009-0600-6. PMID 19847448.
  38. ↑ Reuss, DE.; Sahm, F.; Schrimpf, D.; Wiestler, B.; Capper, D.; Koelsche, C.; Schweizer, L.; Korshunov, A. et al. (Jan 2015). "ATRX and IDH1-R132H immunohistochemistry with subsequent copy number analysis and IDH sequencing as a basis for an "integrated" diagnostic approach for adult astrocytoma, oligodendroglioma and glioblastoma.". Acta Neuropathol 129 (1): 133-46. doi:10.1007/s00401-014-1370-3. PMID 25427834.
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  41. ↑ Otero, JJ.; Rowitch, D.; Vandenberg, S. (Sep 2011). "OLIG2 is differentially expressed in pediatric astrocytic and in ependymal neoplasms.". J Neurooncol 104 (2): 423-38. doi:10.1007/s11060-010-0509-x. PMID 21193945.
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  43. ↑ 43.0 43.1 Parizel, PM.; Makkat, S.; Jorens, PG.; Ozsarlak, O.; Cras, P.; Van Goethem, JW.; van den Hauwe, L.; Verlooy, J. et al. (Jan 2002). "Brainstem hemorrhage in descending transtentorial herniation (Duret hemorrhage).". Intensive Care Med 28 (1): 85-8. doi:10.1007/s00134-001-1160-y. PMID 11819006.
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  65. ↑ Kim, W.; Kim, SH.; Kim, HJ. (Sep 2011). "New insights into neuromyelitis optica.". J Clin Neurol 7 (3): 115-27. doi:10.3988/jcn.2011.7.3.115. PMID 22087205.
  66. ↑ URL: http://bhj.org/journal/2003_4502_april/neurentericcyst_373.htm. Accessed on: 19 December 2011.
  67. ↑ Raz, E.; Zagzag, D.; Saba, L.; Mannelli, L.; Di Paolo, PL.; D'Ambrosio, F.; Knopp, E. (Aug 2012). "Cyst with a mural nodule tumor of the brain.". Cancer Imaging 12: 237-44. doi:10.1102/1470-7330.2012.0028. PMID 22935908.
  68. ↑ Spears, RC. (Aug 2004). "Colloid cyst headache.". Curr Pain Headache Rep 8 (4): 297-300. PMID 15228889.
  69. ↑ Kava, MP.; Tullu, MS.; Deshmukh, CT.; Shenoy, A.. "Colloid cyst of the third ventricle: a cause of sudden death in a child.". Indian J Cancer 40 (1): 31-3. PMID 14716130.
  70. ↑ Shaktawat, SS.; Salman, WD.; Twaij, Z.; Al-Dawoud, A. (2006). "Unexpected death after headache due to a colloid cyst of the third ventricle.". World J Surg Oncol 4: 47. doi:10.1186/1477-7819-4-47. PMID 16867192.
  71. ↑ 71.0 71.1 71.2 Armao, D.; Castillo, M.; Chen, H.; Kwock, L. (Sep 2000). "Colloid cyst of the third ventricle: imaging-pathologic correlation.". AJNR Am J Neuroradiol 21 (8): 1470-7. PMID 11003281.
  72. ↑ 72.0 72.1 Turkel, SB.; Miller, CA.; Guttenberg, ME.; Moynes, DR.; Godgman, JE. (Mar 1982). "A clinical pathologic reappraisal of kernicterus.". Pediatrics 69 (3): 267-72. PMID 7063283.
  73. ↑ 73.0 73.1 URL: http://neuropathology-web.org/chapter3/chapter3eBilirubinencephalopathy.html. Accessed on: 30 May 2012.
  74. ↑ Hansen, TW.; Hervieux, JF.; Orth, J.; Schmorl, CG.; Baumes, JB. (Aug 2000). "Pioneers in the scientific study of neonatal jaundice and kernicterus.". Pediatrics 106 (2): E15. PMID 10920171.
  75. ↑ Paksoy, Y.; Koç, H.; Genç, BO.. "Bilateral mesial temporal sclerosis and kernicterus.". J Comput Assist Tomogr 28 (2): 269-72. PMID 15091133.
  76. ↑ 76.0 76.1 http://www.ninds.nih.gov/disorders/joubert/joubert.htm

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