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Neuropathology Lecture 2005-2006 KM Fung Page 1 2005-2006 Neuropathology Lecture Note for OU Medical Students Kar-Ming Fung, M.D., Ph.D. Assistant Professor Department of Pathology, College of Medicine University of Oklahoma Health Science Center, Oklahoma City, OK Questions and comment: [email protected] Content A Message to the Student Table of Content Chapter 1: Introduction to Pathology of the Neuromuscular System. Chapter 2: Infections of the Central Nervous System. Chapter 3: Tumor of the Central and Peripheral Nervous System. Chapter 4: Metabolic, Nutritional and Mitochondrial Diseases. Chapter 5: Demyelinating Diseases. Chapter 6: Malformation and Structural Abnormalities. Chapter 7: Vascular Disorders. Chapter 8: Neurodegenerative Disorders. Chapter 9: Peripheral Nerve and Muscle. Links are in blue or

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Neuropathology Lecture 2005-2006 KM Fung Page 1

2005-2006 Neuropathology Lecture Notefor

OU Medical Students

   

Kar-Ming Fung, M.D., Ph.D.Assistant Professor

Department of Pathology, College of MedicineUniversity of Oklahoma Health Science Center, Oklahoma City, OK

Questions and comment: [email protected]

Content

A Message to the Student

Table of Content

Chapter 1: Introduction to Pathology of the Neuromuscular System.

Chapter 2: Infections of the Central Nervous System.

Chapter 3: Tumor of the Central and Peripheral Nervous System.

Chapter 4: Metabolic, Nutritional and Mitochondrial Diseases.

Chapter 5: Demyelinating Diseases.

Chapter 6: Malformation and Structural Abnormalities.

Chapter 7: Vascular Disorders.

Chapter 8: Neurodegenerative Disorders.

Chapter 9: Peripheral Nerve and Muscle.

To download this lecture note: http://moon.ouhsc.edu/kfung/OUMS.htm

Links are in blue or gray.

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A Message to the Students

Welcome to the OU Neuropathology Lecture for Medical Students of year 2006. I will be teaching this course and can be reached at [email protected]

or at the Academic Office of the Department of Pathology at 405-271-2422. Please feel free to forward (preferably by e-mail) any questions and comment to me. I will response as soon as I can.

In order to facilitate your learning, this note is prepared in Microsoft Word® so that you can add your own note. This lecture note is also available as PDF format. Both versions can be downloaded at http://moon.ouhsc.edu/kfung/OUMS.htm. Different parts of this lecture note are also linked in order to save your time. Just click on any words that are blue or gray to go to the links. The text being printed out represent the core material that we expect you to master after you have finished this course. Keywords are bold. Additional material for our students with additional interest in neuropathology is available on the web when you click on the icons below that would appear in the text:

Bonus information. ? Quiz question.

Pictures and photos. Case study material.

The salient objective of this lecture series is to introduce the basic concept of neuropathology through discussion of a variety of diseases of the nervous system. The principal goal of these lectures is to help you to develop an anatomically based overall understanding of neuropathology. You will benefit greatly if you briefly review your neuroanatomy and neurohistology prior to the lectures. You are required to read the two chapters on pathology of the Central Nervous System and Peripheral Nerve and Skeletal Muscle in Robbin’s Pathologic Basis of Disease. I also want to emphasize that the areas being covered represent only a very small volume of what we know on neuropathology. You should consult other reference books, periodicals, and websites (Appendix 1, Chapter 1) for further details. You can also click on the following icons to link to web-based learning material developed in our department.

   

You job is to develop a bird’s eye view on neuropathology and to learn the overall architecture of the big picture. I encourage you to set such understanding as your learning goal for this course.

I hope you enjoy my lectures.

Kar-Ming Fung, M.D., Ph.D.Assistant Professor, PathologyDirector, NeuropathologyNovember 30, 2005, Oklahoma City, OK

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Table of Content

Chapter 1: Introduction to Pathology of the Neuromuscular System. . . . . . . . . . 6

Introduction Fundamentals of investigation in neuropathologyMajor periods of lifeDevelopment of the nervous systemAppendix 1: Books, periodicals and websitesAppendix 2: Techniques in neuropathology

Chapter 2: Infections of the Central Nervous System. . . . . . . . . . . . . . . . . . . . . . . 13

IntroductionHighlightsBacterial pathogensBacterial infection and meningitisSubdural empyemaBrain abscessTuberculosis of the CNSSpirochetal infections and syphilisFungal infectionsParasitic infectionsViral infectionsHerpes encephalitisSubacute viral encephalitisCongenital and peirnatal infectionsCongenital viral infections

Chapter 3: Tumor of the Central and Peripheral Nervous System. . . . . . . . . . . . . 26

Overview of tumors of the CNSRisk factors and hereditary cancer syndromeClassification of tumors of the CNSCategory 1 (CNS): Neoplasia recapitulating features of the embryonal CNS

General characteristicsEntitiesMedulloepitheliomaMedulloblastomaSupratentorial primitive neuroectodermal tumor (PNET)Pineoblastoma

Category 2 (CNS): Neoplasia with features of mature glial and neuronal cellsGeneral characteristicsEntitiesAstrocytoma, anaplastic astrocytoma, glioblastomaPilocytic astrocytomaOligodendroglioma and anaplastic oligodendrogliomaEpendymomaChoroid plexus papillomaGlial-neuronal tumorNeuronal tumor

Category 3 (CNS): Neoplasia with features of leptomeninges and mesenchymal tissueGeneralEntitiesMeningioma

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ChordomaHemangioblastomaVon Hippel-Lindau disease

Category 4 (CNS): Primary neoplasia with features of tissue that are not normally found in the CNS

GeneralPrimary CNS lymphomaCraniopharyngioma

Category 5 (CNS): Secondary and metastatic neoplasiaGeneralMetastatic carcinomaTumor of the PNS, overviewNeuroblastic Tumors of Adrenal Glands and Sympathetic Nervous SystemNeurofibromaNeurofibromatosis 1 (NF1)SchwannomaNeurofibromatosis 2 (NF2)

Chapter 4: Metabolic, Nutritional and Mitochondrial Diseases. . . . . . . . . . . . . . . .46

OverviewPeroxisomal diseasesZellweger syndromeX-linked adrenoleukodystrophy (X-ALD)Lysosomal storage diseasesGloboid cell leukodystrophy (Krabbe disease)Mitochondrial disordersMitochondrial myopathy, encephalopathy, lactic-acidosis, and stroke-like

episodes (MELAS)

Chapter 5: Demyelinating Diseases. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56

OverviewMultiple Sclerosis (MS)Variants of multiple sclerosis (MS)Acute Disseminated Encephalomyelitis (ADEM)Acute Hemorrhagic Leukoencephalopathy (ALH)Central Pontine Myelinolysis (CPM)

Chapter 6: Malformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .51OverviewNeurotube defectsAnencephalyMeningocele and meningomyeloceleEncephaloceleTethered cord syndromeChiari malformationsHoloprosencephalyAgenesis of corpus callosumDandy-Walker syndromeMiller-Dieker Syndrome

Chapter 7: Vascular disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63OverviewHypoxic/ischemic changes and infarctionInfarction

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Strokes and infarctsAneurysmOther aneurysmArteriovenous malformationAneurysmal malformation of the great vein of GalenHypertensive brain hemorrhageCerebral amyloid angiopathy

Chapter 8: Neurodegenerative diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .70OverviewInclusion bodies and extracellular depositionCortical degenerationAlzheimer’s diseaseFrontotemporal dementiaPick’s diseaseBasal ganglia degenerationParkinson’s diseaseHuntington’s diseaseTrinucleotide diseasesAmyotrophic lateral sclerosis (ALS)

Chapter 9: Peripheral nerve and muscle . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 78OverviewPathologic changes in peripheral nervesGeneral considerations of muscle disordersInflammatory myopathiesDernatomyositisDystrophic myopathiesDystrophinopathies (Duchenne & Becker muscular dystrophy)Congenital myopathiesX-linked myotubular myopathyMetabolic and mitochondrial myopathyMyopathy, encephalopathy, lactic-acidosis, and stroke like episodes (MELAS)McArdle’s disease

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Chapter 1

Introduction to Pathology of the Neuromuscular SystemTable of Content

Introduction Fundamentals of investigation in neuropathology Major periods of life Development of the nervous system Appendix 1: Books, periodicals and websites Appendix 2: Techniques in neuropathology

Introduction: Top of the chapter

Anatomic pathology, also know as morbid anatomy, is a medical science that is built essentially on the comparison of anatomy of the normal and disease tissue at different level of details. Neuropathology is no exception to this general principle. It is of paramount importance to have a basic understanding of neuroanatomy, neuroembryology, and neurohistology before learning neuropathology. Your study will be much more efficient if you keep a neuroanatomy and histology book handy. You are requested to read the chapter on pathology of the nervous system in Robbin’s Pathologic Basis of Disease. Please refer to Appendix 1 for a list of reference books and periodicals in neuropathology.

The emphases of this course include:

The relationship between the brain and the adjacent anatomic structures. Correlate pathologic changes with normal gross, microscopic, and developmental anatomy. Notice how the nervous system responses differently in pathologic conditions than other systems. Clinicopathologic correlations.

Fundamentals of Pathologic Investigation in Neuropathology : Top of the chapter

The human body has only a very limited ways to manifest abnormalities. This is particularly true in neuropathology. Diseases with diverse etiologic and genetic features may have very similar pathologic and clinical features. This is particularly true in neuropathology. In order not to be confused as you encounter more and more different disease entities, you should pay attention to the overall all relationship between different diseases and their relationship to the normal central nervous system.

Basically, there are four ways to look at different diseases: Genetics Etiology Pathology Clinical features

As a result, they could be classified according to these criteria. It is important that you pay attention to these four aspects when you study diseases of the nervous system.

In some situations, the etiology is known and identification of the etiology is the key to successful diagnosis and investigation of a disease. This is particularly true in infections, metabolic and storage disease. In other situations, identification of the particular genetic abnormality is of great importance for the purpose of correct diagnosis and genetic counseling. These situations, however, belongs to the rarity in daily practice. In many situations, many diseases are classified according to the pathologic features. The etiology and genetic changes in these diseases are often not known or not yet identified.

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Pathologic investigations with multiple methods are often required in order to understand or diagnose a particular disease. These methods include:

Gross examination. Routine histology with hematoxylin-eosin stain. Special histology stains, particularly stains for myelin, silver stains, and immunohistochemistry. Frozen section, cytologic preparations for intraoperative diagnosis. Histochemical stains in frozen sections (muscle biopsies). Electron microscopy. Biochemical studies.

At the histology level, a variety of special stains are being used. A brief summary of the methodology is provided in Appendix 2.

Unique Features of Neuropathology: Top of the chapter

Many pathologic processes that occur in other system of the body also occur in the nervous system and the following is a list of these processes:

Malformation Infection Inflammation Neoplasm Vascular diseases Metabolic disease and mitochondrial disease Trauma Poisoning and intoxication Nutritional disorder Pathologic changes secondary to treatmentIn addition, some pathologic processes are unique to the neuromuscular system:

Demyelinating disease Dysmyelinating disease Neurodegenerative disease Peripheral neuropathy Primary myopathyThe nervous system is linked to the peripheral nervous system by long axons. The same is true in the

connections between the brain and spinal cord. Also in contrast to other solid organs, different parts of the brain and spinal cord have very different functions. These two anatomical features lead to three unique neuropathologic features:

Two similar, if not identical, pathologic processes can produce different biologic and/or clinical consequences if they occur in different locations.

Two different pathologic processes can produce similar, if not identical, biologic and/or clinical consequences if they occur in the same locations.

Remote secondary pathologic changes can be seen. (e.g., degeneration of the cortical spinal tract in the spinal cord caused by extensive cerebral cortical infarction).

Major periods of life : Top of the chapter

From the neuropathologic point of view, the types and incidences of neuropathologic changes and the diseases that they produce correlate with the major periods of life. The following is an oversimplified version

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of the type of neuropathologic changes and the diseases that they would cause in different age group. In addition, age, sex, race, and ethnical background must also be taken into account.

Fetal-Embryonal period: Congential malformations, disruption sequences, and congenital infections. Congenital tumors.

Perinatal period: Perinatal brain damage, physiological and physical. Perinatal infections. Congenital tumors. Congenital myopathies (some).

Infantile-Childhood: Many metabolic diseases, mitochondrial diseases, muscular dystrophies and congenital

myopathies would have their initial manifestations during this stage. Brain tumors, particular tumors arising in the posterior fossa, are the most common solid

tumors in the pediatric age group. Trauma and infection. Poisoning and intoxication (accidental).

Adolescence-Young Adult: Many neurologic diseases that are seen in the infantile-childhood stage are also seen in the

adolescence-young adult stage. Demyelinating diseases. Low-grade glial neoplasms are more common then high-grade glial neoplasms. Many metabolic diseases and primary myopathic diseases have a milder form that would

have their initial clinical manifestations in this age group.

Middle age: Demyelinating diseases are common among this age group although many of the patients

have onset in an earlier age. Brain tumors are common. As a general rule, glial neoplasms that occur in older age group

are more likely to be of high-grade and behave in a malignant fashion. Meningiomas are common in this age group. Some cases of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s

disease can have early onsetg cases and their initial manifestations in this age group. Many early onset cases are genetically linked to a mutated genes and occur in a kindred.

Elderly: Brain tumors are common. Glial tumors that are seen in this age group are usually of high-

grade; low-grade glial tumors is extremely rare. Neurodegenerative diseases such as Alzheimer’s disease are common. Cerebral vascular diseases, especially stroke, are far more common than other age groups.

Development of the Nervous System : Top of the chapter

There are 4 major processes that are involved in the formation of the central nervous system:

Formation of the neurotube Proliferation of neuronal and glial precursor cells Migration Synaptic connection and myelination The brain and spinal cord develop substantially during the first

two years of life as you could see in changes in the weight of the brain. While the architecture of the

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cerebral hemisphere and brainstem of a full term newborn is very comparable to that of the adult, the cerebellum has not attain this stage at the time of birth. Also, very small amount of myelin is present at the time of birth. So, development of the cerebellum and myelination of the central nervous system occur largely postnatally.Please refer to standard neuroanatomy textbooks for further details.

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Appendix 1: Books, Periodicals, & Websites. Top of the chapterRequired readingTop of the

chapterRobbins Pathologic Basis of Disease by Cotran RS et al. WB Saunders. You are required to read the chapter on Central Nervous System and Peripheral Nerve and Skeletal Muscle.Other Useful BooksTop of

the chapterHistology for Pathologists by Sternberg SS. Raven Press, 2nd edtition,1998. The chapters on histology of the central nervous system, peripheral nervous system and muscle are well written and supplemented by high-quality pictures.Neuropathology by Ellison D and Love S. Mosby,2003. This is a wonderful atlas supplemented with many tables and a skeleton volume of text. This book is highly recommended although it is expensive.Practical Review of Neuropathology by Fuller GN and Goodman JC. Lippincott Williams and Wilkins, 2001. This is a very nicely written book. The quality of the picture, however, does not match the high-quality of the written text. It is also inexpensive.Surgical Pathology of the Nervous System and its Covering by Berger PC, Scheithauer BW, Vogel FS. Churchchill Livingstone, 4th edition, 2002. This is a one volume medium sized book and is about 650 pages long. It is a book that is readable and enjoyable.Tumours of the Nervous System, Pathology and Genetics (WHO Classification of Tumours) by Kleihues P and Cavenee WK. IARC Press, 2000. This is a small and inexpensive book published by the World Health Organization (WHO). You will find the WHO classification on brain tumor here. The diagnostic criteria are well discussed. This book is highly recommended.Oppenheimer's Diagnostic Neuropathology: A Practical Manual by Margaret M. Esiri and D. R. Oppenheimer. Blackwell Science Inc., 2nd Edition, 1996. This is a wonderful and small book that is about 450 pages long. It covers all the major aspects of neuropathology. The writing is excellent.Greenfield’s Neuropathology by Graham DI and Lantos PL. Arnold, 7th edition, 2002. This is a two-volume major textbook. It is very readable and is also a good reference book.Russell and Rubinstein’s Pathology of Tumors of the Nervous System by Bigner DD, McLendon RE and Bruner JM. Arnold, 6th edition, 1996. This is a very exhaustive two-volume textbook dedicated to tumors of the nervous system.Congenital Malformations of the Brain by Norman M. et al. Oxford University Press, 1995. This book is a little old but it could enlighten you on your understanding on malformations of the nervous system. This book is highly recommended.Pathology of Skeletal Muscle by Carpenter S and Karpati G. Oxford University Press, 2nd Edition, 2001. This is a wonderful book on muscle pathology. The text is very well written and the pictures are of good quality. Structure and Molecular Basis of Skeletal Muscle Disease by Karpati G. ISN Neuropath Press, 2002. This is a small book that emphasize more on the molecular biology than traditional histopathology. It is a very good book and is highly recommended if you are interested in myopathology.PeriodicalsTop of the chapterThere are many periodicals and the followings are a few:Acta Neuropathologica: http://www.springerlink.com/app/home/journal.asp?wasp=hludm7qhrh5trl7hlhw3&referrer=parent&backto=linkingpublicationresults,id:100394,1 Journal of Experimental Neurology and Neuropathology:http://www.aanp-jnen.com/jnenframes.htmlBrain Pathology:http://brainpath.medsch.ucla.edu/Muscle & Nerve:http://libproxy-002.ouhsc.edu:2048/login?url=http://www.interscience.wiley.com/jpages/0148-639X/WebsitesTop of the chapterNeuroLearn, University of Oklahoma:http://moon.ouhsc.edu/kfung/JTY1/index.htm Pathology Case of the Month, University of Oklahomahttp://moon.ouhsc.edu/kfung/JTY1/Com/Index.htm Brain Pathology Case of the Month:http://brainpath.medsch.ucla.edu/International Association of Chinese Pathologists- Online Publicationhttp://www.iacp.us/olp Neuromuscular Center, Washington University:http://www.neuro.wustl.edu/neuromuscular/index.htmlNeruoanatomy and Neuropathology on the Internet:http://www.neuropat.dote.hu/document.htmInteractive Atlases:http://www9.biostr.washington.edu/da.htmlThe Human Brain: Dissection of the Real Brain:http://www.vh.org/Providers/Textbooks/BrainAnatomy/BrainAnatomy.html

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Appendix 2: Techniques in neuropathology. Top of the chapterGross Examination: Gross examination of the autopsy brain or the surgical specimen is of paramount importance. For the autopsy brain, it is usually fixed in formalin for 2 to 3 weeks before examination. The cerebral hemisphere is usually sectioned into coronal slabs, the cerebellum into sagittal slabs, the brainstem and spinal cord into horizontal slabs for examination. Other cutting plan may be used. For cases that are suspicious of poisoning, intoxication, or metabolic diseases, a small portion of the brain will be store as frozen tissue without fixation with formalin for future biochemical anyalsis. For infectious cases, culture would be taken. This is only a brief introduction. An excellent chapter on gross examination of the nervous system can be found in: Oppenheimer's Diagnostic Neuropathology: A Practical Manual by Margaret M. Esiri and D. R. Oppenheimer. Blackwell Science Inc., 2nd Edition, 1996. Light microscopy: Light microscopy is the cornerstone in neuropathologic diagnosis. Hematoxylin-eosin stain is the routine stain for initial examinations. However, many other stains are used. These stains make neuropathology a colorful world. Sliver based procedures (silver stains and silver impregnation): The principle of silver staining and silver impregnation is very similar to photography. While staining is performed on tissue sections, impregnation is performed in tissue blocks before sectioning. For the neuropathologic purpose, they are used to demonstrate filaments of the nervous system. Basically, the molecules in the specimen is activated by a chemical and allowed to reactive with silver ions. The silver ions will be reduced to silver metal and impregnate on the filaments. Excessive silver ions are removed, often by sodium thiosulfate. In the end, the silver impregnated fibers appear black or dark brown. Several versions of silver stain and silver impregnation are available and they are used to demonstrate different structures. Silver stains are very useful for the study of neuroanatomy, neurodegenerative diseases such as Alzheimer’s disease, demyelinating diseases, and others. Some of the more commonly used silver stains include: Bodian stain, Gallya’s stain, and modified Bielschowsky stain. Myelin stains: This is a family of stains that selectively stain the myelin. Some of them such as Marchi stain can be used to distinguish normal and degenerative myelin. The most commonly used one is the Luxol fast blue (LFB) method. This method has the advantage of being able to be combined with other stains such as LFB-hematoxylin-eosin, LFB-periodic Schiff, and LFB-cresyl violet, LFB-oil red O, and others. LFB gives normal myelin a blue-cyan color.Stains for microorganisms: A series of stains including Grimelius methamine silver (GMS), periodic acid Schiff (PAS) and mucicarmine stains are used to detect fungal organisms. Acid fast stain can be used to detect acid fast bacilli such as mycobacteria. Immunostains: Immunostain or better phrased as immunohistochemistry is a staining technique that utilizes immunologic recognition of a particular antigen or a family of antigens by immunoglobulin that that could recognize these antigens. The recognitions can be visualized by a color producing method such as immunofluoresence or enzyme linked color-producing technique. In neuropathology, the most commonly used antibodies are those that could recognize molecular phenotypes of glial and neuronal differentiations. The list of antibodies that can be used for diagnostic and research purpose is long. Muscle histochemistry: A series of enzymatic reactions are used in the study of muscle pathology. Electron microscopy: Electron microscopy is often used as a diagnostic tool in muscle and peripheralnerve biopsy. They are more important as a research tool than diagnostic tool in other fields of neuropathology.Molecular biology techniques: In situ hybridization allows detection of a particular sequence of DNA or RNA on tissue sections. For diagnostic purpose, this is particularly useful for detection of viral genome in infections. Fluorescence in situ hybridization (FISH) is useful for detection of deletion and translocation in tissue sections. Polymerase chain reaction (PCR) is useful in detection of viral genomes and mutations. These techaniques are also very useful in research.

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Chapter 2Infections of the Central Nervous SystemTable of ContentIntroduction Highlights Bacterial pathogens Bacterial infection and meningitis Subdural empyema Brain abscess Tuberculosis of the CNS Spirochetal infections and syphilis Fungal infections Parasitic infections Viral infections Herpes encephalitis Subacute viral encephalitis Congenital and peirnatal infections Congenital viral infections

Introduction: Top of the chapter

Just like any other organs in the human body, the central nervous system (CNS) can be infected by all kinds of infectious agents including prion, virus, bacteria, fungus, and parasites.

Similar to other organs of the body, infection of the CNS triggers inflammation in most cases. There are, however, some unique features regarding infections of the CNS:

Demyelination after infection or vaccination. Gliosis rather than fibrosis is seen in the CNS. Encephalitis without identified infectious agents. This is a class of diseases featured by

inflammation of the CNS that closely suggest infections but the infectious agents have never been isolated. Raussmussen encephalitis is a good example.

Infections of the central nervous system come in 4 major patterns:

Diffuse Localized Multifocal Disseminated infection form a primary source outside the CNS.

Three important factors take parts in casting the final pathologic features:

Virulence of the agent. Route of entry. Systemic factors such as compromised immunity.

In the end, infections of the CNS can be classified into the following categories:

Meningitis Meningoencephalitis Encephalitis, Myelitis, Encephalomyelitis Choroid plexitis Subdural empyema and epidural abscess Cerebritis Ventriculitis and ependymitis Brain abscess

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Highlights: Top of the chapter

Many infections of the central nervous systems are very similar in clinical and pathologic features. During your study on pathology of infections of the CNS, please pay attention to the following features:

Age and sex.Geographical origin of the patient.Race and ethnic group of the patient.Season of the year.Pathogen involved:

Prion Virus Bacteria Fungus Protozoa Metazoa

Method of diagnosis: Demonstration of organism on pathologic specimens Special stain on pathologic specimens Culture PCR In situ hybridization. Titer in CSF and blood.

Route of entry: Remote: Blood borne pathogen, abscess and source of infection in other part of the body. Local: Paranasal sinuses and middle ear, olfactory epithelium, infection in adjacent soft tissue

and bone, penetrating trauma, contaminated surgical procedures and/or hardware such as ventricular-peritoneal shunt.

Systemic factors: Acquired and congenital immunodeficiency Radiation therapy and chemotherapy Diabetes, malnutrition Steroid therapy Ogan transplantation and bone marrow transplantation Others

General pattern: Meningitis Meningoencephalitis Encephalitis, Myelitis, Encephalomyelitis Choroid plexitis Subdural empyema and epidural abscess Cerebritis Ventriculitis and ependymitis Brain abscess

Type of inflammation: acute suppurative, acute, acute and chronic, chronic, chronic granulomatous. Preferred anatomical locations of infection. (e.g., ependymal and periventricular cells in CMV

infection, bilateral temporal lobe in herpes simplex viral encephalitis, gray matter of the spinal cord and brainstem in poliomyelitis).

Prognosis.

Bacterial pathogens: Top of the chapter

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The following is a list of the more common bacterial pathogens. You do not have to know the whole list. However, please pay attention to the fact that different pathogens are associated with different type of infections.

Meningitis Pyogenic infections Mycobacterial infections Spirochetal infections Infections of cerebralspinal fluid shunts Miscellaneous bacterial infections CNS abnormalities caused by bacterial toxins

MeningitisNeonatal meningitis

Gram-positiveStaphylococci (particularly group B)Listeria monocytogenesStaphylococcus aureusStayphylococcus epidermidisSteptococcus pneumoniaeOthers

Gram-negativeEscherichia coliKlebsiella-Enterobacter speciesPseudomonas aeruginosaHaemophilus inlfuenzaeOthers

Acute meningitis in children and adultsGram-positive

Streptococcus pneumoniaeOther streptococciListeria speciesOthers

Gram-negativeNeisseria meningitidesHaemophilus influenzaeOthers

Pyogenic infectionsEpidural abscess

Gram-positiveStaphylococcus aureusStaphylococcus epidermidisStreptococciOthers

Gram-negativeAerobic bacilliAnaerobesOthers

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Subdural epyemaGram-positive

StreptococciStaphylococci

Gram-negativeAerobic gram-negative bacilliOthers

Brain bascessImmunocompetent host

Staphylococcus aureusOther aerobic and anaerobic streptococciGram-negative bacilli

Immunocompromised hostAerobic gram-negative bacteriaMycobacterium speciesNocardia asteroidsListeria monocytogenes

Mycobacterial infectionsTuberculosis

Mycobacterium tuberculosisNon-tuberulous mycobacterial infection

Mycobacterium avium complex (M. avium and M. intracellulare)Mycobacterium kansasiiM. fortuitum, M. chelonae, M. abscessus (rapidly growing mycobacteria)Others

Spirochetal infectionsTreponema pallidum (Syphilis)Leptospira interrogans (Leptospirosis)Borrelia burgdorferi (Lyme disease)Borrelia recurrentis and other Borrelia species (Relapsing fever)

Infections of cerebralspinal fluid shuntsGram-positive

Staphylococcus aureusStaphylococcus epidermidisOther staphylococcusStreptococcal species

Gram-negativeEscherichia coliKlebsiella speciesPseudomonas speciesProteus speciesNeisseria meningitidesHaemophilus influenzae

Miscellaneous bacterial infectionsWhipple’s disease

Tropheryma whippeliiBartonella infections

Bartonella bacilliformis (Oroya fever)

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Bartonella henselae (Cat-scartch fever)Bartonella quintana (B. henselae and B. quantana brain lesion associated with HIV infection)

Mycoplasmal infectionsMycoplasma pnuemoniae Mycoplasma salivariumMycoplasma hominis Ureaplasma urealyticum

Rikettsiae infectionsRickettsia rickettsii (Rocky mountain spotted fever)Rickettsia conorii (Boutonneuse fever)RickettsiaSibirica (North Asian tick typhus)Rickettsia australis (Queensland tick typhus)Rickettsia akari (Rickettsialpox)Rickettsia japonica (Oriental spotted fever)Rickettsia prowazekii (Epidemic typhus)Rickettsia typhi (R. mooseri) (Murine typhus)Rickettsia tsutsugamushi (Scrub typhus)Coxiella burnetii (Q fever)Ehrlichia species (Human monocytic/granulocytic enrlichiosis)

CNS abnormalities caused by bacterial toxinsClostridium botulinum (Botulism)Clostridium tetani (Tetanus)Bordetella pertusis (Pertusis)

Bacterial Infections and Meningitis : Top of the chapter

Bacterial infections usually take the following forms with meningitis as the most common one.

Acute meningitis: Inflammation of the meninges, or the subarachnoid space. Cerebritis: Acute inflammation of the brain parenchyma. Granulomatous meningitis and granuloma Ventriculitis, ependymitis and choroids plexitis: Inflammation of the ventricles and its lining

structures. Brain abscess: Suppurative nflammation of the brain parenchyma. Subdural empyema and epidural abscess: Suppurative inflammation of the subdural space. Changes associated with spirochetal infections

Acute bacterial Meningitis: Top of the chapter

Definition: An acute inflammatory process that is limited to the meninges and subarachnoid space.

Organism: Incidence varies with age.

51-22-10Listeria species

1-151-25Staphylococci

52-420-50Streptococci

1-101-250-60Gram(-) bacilli

30-5010-200-5S. Pneumoniae

10-3525-400-1N. Meningitidis

1-340-600-3H. Influenzae

(>15 years), %(1 month-15 years), %(<1 month), %

AdultChildrenNeonates Organism

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Epidemiology: About 25,000 cases/year in the U.S. Over 70% occur in children under 5 years-old. Mortality without antibiotics: 90-100% Mortality with antibiotic treatment: 5-15%. Morbidity: 43%.

Macroscopic: Brain edema and congested leptomeninges. Purulent exudate in the subarachnoid space and cisterna, especially the base of the brain. Thrombosis, hemorrhagic infarctions; secondary to the infection and destruction of the blood vessels.

Microscopic: Polymorphonuclear leukocytes infiltrating the leptomeninges, subarachnoid space, Vichow-Robin

space, and ventricles. Angiitis and thrombosis. Necrotic debris and macrophages. Fibrotic scarring of the leptomeninges.

Complications of bacterial meningitis: Cerebral edema will lead to increased intracranial pressure. When it is severe, it would compromise

cerebral blood supply to the brain and/or cause herniations. Cerebritis. Arterial and venous infarction of the brain. Mycotic aneurysm. Hydrocephalus, due to scarring of the arachnoid granulation leading to reduced absorption of the

CSF. Subdural effusion and empyema. Cranial nerve palsy and/or motor deficits. Seizures. Deafness. Mental retardation. Syndrome of inappropriate ADH secretion (SIADH).

Subacute, chronic, and granulomatous infections: Top of the chapter

They are often caused by a different set of bacteria. Very often, they do not occur as meningitis but parenchymal infections with and without involving the meninges. Some of them are listed here

Mycobacteria:Mycobacterium tuberculosis (Tuberculosis)

Spirochetes: Treponema pallidum (Syphilis)Leptospira interrogans (Leptospirosis)Borrelia burgdorferi (Lyme disease)

Others: Tropheryma whippelii (Whipple’s disease)

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Subdural Empyema: Top of the chapter

Definition: A localized, suppurative infection that is restricted to the subdural space.

Pathogenesis: Often, but not always, due to localized spread of infections from the sinus (sinusitis), middle ear

(otitis media), maxilla (dental infections and abscess). Penetrating injury, fracture of the skull base, and contaminated neurosurgical procedures. Less commonly from hematogenous origin. Bacterial meningitis. Bacterial profile is similar to that of brain abscess. Hemophilus influenzae and Streptococcus

pneumoniae are often associated with empyema secondary to bacterial meningitis.

Brain abscess: Top of the chapter

Definition: A localized suppurative infection within the brain parenchyma.Pathogenesis:

About 50% of the cases are due to localized spread of a septic focus in the paranasal sinuses, middle, or dental infection.

About 25% of the cases are secondary to hematogenous spread from an infectious source outside the head. Example: congenital heart disease with right-to-left shunt.

The rest are due to trauma and miscellaneous etiology such as compromised immunity such as transplantation.

Bacterial profile is related to the route of spread and includes Streptococcus milleri anaerobic bacteria, Actinomyces israelii and others.

Clinical features: Brain abscess represents about 1% of all intracranial masses. Present as Intracranial mass lesion, hemiparesis, hemianopia, seizures Medically managed: usually smaller abscesses; deep-seeded, over-all success, 74%; mortality is

about 4% Surgically managed: typically larger; no abscess larger than 2.5 cm resolved without surgery Resolution: 3 to 4 months usually, contrast enhancement may last 6 to 9 months.

Tuberculosis of the CNS: Top of the chapter

Special feature: Tuberculosis can present as diffuse or localized infection in the CNS.Age: In the pre-antibiotic era, tuberculosis of the CNS is often a childhood disease.Incidence: Uncommon but not rare in the US and Canada. Common in the developing and under developed

countries.Pathogen: Mycobacterium tuberculosis.Route of Entry: Systemic and hematogenous.Pathology: Chronic granulomatous inflammation in immunocompetent host. May have acute suppurative

inflammation in immunocomprised host.Diagnostic techniques: Acid fast stain and PCR.Pathology:

Diffuse involvement: Tuberculous meningitis: A granulomatous meningitis with predilection at the cranial base.

Narrowing and occlusion of blood vessels leading to a “beaded pattern” in angiogram is common. Often seen in immunocompetent host. Hydrocephalus is a very frequent complication.

Localized involvement:

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Tuberculoma: A space-occupying lesion composed of fibrotic tissue, caseous necrosis, and rimmed by granulomatous inflammation. Often seen in immunocompetent host. Only scant acid fast bacilli can be demonstrated by acid fast stain.

Tuberculous abscess: An abscess that contain pus with or without granuloamtous inflammation at the periphery. Often seen in immunocomprimised host. Many acid fast bacilli can be demonstrated by acid fast stain.

Spirochetal Infections and syphilis : Top of the chapter

Characteristic features: All spirochetal diseases are characterized by local inoculation (contact with skin or mucous

membrane or insect bite) followed by systemic dissemination (with antibody response). Clinically and pathologically, they often occur as a bi- or triphasic diseases.

Syphilis Leptospirosis Lyme disease

Agent Treponema pallidum Leptospira interrogans Borrelia burgdorferi

Size of pathogen

5-15 m long, up to 0.3 m wide 6-20 m long (average 10 m) 10-30 m long, 0.2-0.3 m wide.

Geographic distribution

Worldwide. Worldwide distrubtion, more common in the tropics.

World wide distribution. Most common in the northest in the USA.

Port of entry Sexual intercourse and mucosal contact.

Contact of contaminated water through skin abrasion and mucous membrane.

Tick bite by Ixodes dammini in the USA and Ixodes ricinus in Europe. Deer, sheep, and cattles are the common natural hosts for ixodid ticks. Symptoms usually begin in late spring or summer.

Congenital infection

Yes. Brain involvement is surprisingly mild when compared to the other organs of the body.

Unknown, probably not. Unknown, probably not.

Number of stages

Triphasic Biphasic Triphasic

Stages 3 Stages: Primary syphilis Secondary syphilis Tertiary syphilis

Asymptomatic CNS involvement can occur in all untreated cases in any phase of the disease. Syphilis and HIV infection: Patients have an accelearated course of disease and are more likely to progess to progress to sympatomatic neurosyphilis.

2 Stages: Initial phase Immune phase

Severe icteric leptospirosis (Weil’s disease)

3 Stages: Early localized: Early disseminated Late phase

CSF Culture: T. pallidum is present in 30% of untreated primary and secondary syphilis.Diagnosis: Analysis of the CSF is crucial for the diagnosis of neurosyphilis and positive findings include positive fluorescent treponemal antibody absorption tests (FTA-ABS) and T. pallidum hemagglutination assay (TPHA).

Leptospira can be recovered from the CSF during the first 8 days of clinical disease.

Lymphomonocytic pleocytosis of 30-150 x 106 cells/L. Together with the adenopathy, these findings can suggest a hematologic malignancy.Rise in protein level and a normal or slightly lowered glucose concentration.

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Pathology General consideration: Involvement of the CNS in syphilis

is not limited to the tertiary phase. Damage of the brain can be

caused by direct inflammatory changes, ischemic insults due to vascular inflammation, and progressive neuronal destruction unrelated to the ischemic insults (tabes dorsalis and general paresis).

Types: Syphilitic meningitis Meningovascular syphilis Parenchymatous neurosyphilis

(paralytic dementia and tabes dorsalis.

Gummatous neurosyphilis:

Gross pathology: Congested and swollen brain with petechial hemorrhages in the meninges and cortex.Histology: Thickened meninges with mononuclear inflammatory cell infiltration and perivascular lymphocytic infiltration in the brain and spinal cord. Chromatolysis of cerebral crotical neurons and gliosis of the grey matter along with patchy demyelination in the pons. Systemic: Petechial and large hemorrhage with necrosis in liver, focal hemorrhagic myocarditis, and swelling and vacuolization of skeletal muscle.

Unclear, periventricular demyelination was found on MRI scans in patients with the late phase of the disease.

Syphilis: Top of the chapter

Syphilitic meningitis: Basically a lymphoplasmocytic meningitis. Peak occurrence at 1-2 years after infection and often associated with cranial nerve syndrome.

Meningovascular syphilis: Characterized by obliterative enarteritis and its complications such as strokes. Peak occurrence at 5-7 years after infection, often associated with focal neurologic signs.

Gummatous neurosyphilis: A space occupying lesion (tumor-like) with central necrosis and rimmed by granulomatous

inflammation. Can occur at anytime after infection.

Parenchymal syphilis: They are irreversible and progressive processes that occur 10-20 years after infection.

General Paresis (Paralytic Dementia): Gross: Cortical atrophy with thickened leptomeninges. Histology: Neuronal loss, gliosis, microglial proliferation, lymphocytic infiltration.

Tabes Dorsalis: Gross: “Compressed cord” with Selective degeneration of the dorsal nerve roots, dorsal root

ganglia and dorsal column. Histology: Secondary wallerian degeneration with demyelination.

Fungal Infection: ? Top of the chapter

General: They can occur as fungal meningitis or space occupying lesions such as abscess or solid inflammatory mass.

Shape of the fungus: The pathology is often related to the shape of the fungus. Fungi that exist only as yeast form in human body often cause meningitis, those with filamentous form often causes infarction and abscess, those that can exist as both forms can cause both.

Epidemiology: Some species are more common than the other and the incidence is geographically related.

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Predisposing factors: Unlike bacterial infections that predisposing factors play a relatively minor role, predisposing factors and underlying systemic disorders play a major role. Particularly, patients are not always immunocompromised.

Pathogens: The two most commonly seen ones are boxed in gray.

Parasitic Infection: ? Top of the chapter

General characteristics: Like bacterial and fungal infections, parasitic infections can also be focal, disseminated and diffuse. The organism can often be seen without the help of special stains. However, special stains and

immunohistochemistry are often useful in making correct diagnosis. Protozoan Infection:Amoebiasis: Entamoeba histolytica- brain abscess Naegleria fowleri- Primary amoebic meningoencephalitis Acanthoamoeba spp. & Leptomyxid- Granulomatous amoebic encephalitis

Cerebral malaria: Plasmodium falciparum

Toxoplasmosis: Toxoplasma gondii

Trypanosomiasis: Trypanosoma burcei spp.- African trypanosomiasis Typanosoma cruzi- South American trypanosomiasis

Metazoan Infection:

Cestodes:

Taenia solium- Neurocysticercosis Echinococcus granulosus- Hydatid cyst Taenia multiceps- Coenuriasis Spirometra- Sparganosis

Trematodes:

-++++++Pseudoallescheria

-++++±++++Dermatiaceous spp

-±+±+Paracoccidioides

--++++Sporothrix

-+++++Blastomyces

+

+

+

++

++++

++++

Meningitis

+

+++

+++

++

+

+

Abscess or Infl. mass InfarctPredi-lectionIncidenceOrganism

++++Histoplasma

++++++++Zygomycetes

++++++++Aspergillus

-+++++Candida

++++++++Coccidiodes

++++++++Cryptococcus

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Paragonimiasis- Paragonimus westermani Schistosomiasis- Schistosoma spp.

Nematodes:

Angiostrongylus cantonesis, Gnathostoma spinigerum-Eosinophilic meningoencephalitis Others

Viral Infections: Top of the chapter

General: Many of them occur as viral meningitis or meningoencephalitis, a few (such as herpes simplex encephalitis) manifest as a necrotizing mass-like lesion.

Direct cytotoxic effects vs. necrosis and inflammation.Distribution: Different viruses, often but not always, have a predilection on different parts of the nervous

system.Reactivation: Reactivation of an indolent or subclinical infection occurs in some viruses such as herpes

simplex virus and JC virus.CSF: There is usually marked elevation of lymphocytes without reduction in glucose level.Detection: The viral genome is often detectable by molecular techniques such as in situ hybridization (on

tissue) and PCR (on tissue and CSF). Immunostaining is also useful.Shared pathologic features:

Perivascular lymphocytic infiltration: the extent of inflammation may vary greatly. Microglial formation and reactive gliosis. Necrosis usually occurs as a later event than inflammation. Inclusion bodies can be nuclear or cytoplasmic. Demyelination is associated with some viral infections such as HIV encephalopathy and progressive

multifocal leukoencephalopathy (PML).

Pathogens:

DNA virus: Herpesviridae (Herpesvirus) HerpesvirusHerpes simplex virus 1 (HSV-1)Herpes simplex virus 2 (HSV-2)Varicella-zoster

virusCytomegalovirus (CMV)Human herpesvirus 6Epstein-Barr virus (EBV)RNA virus:

Arbovirus (mosquitoes and ticks): Western equine encephalitis virus, Japanese ence-phalitis virus, West Nile fever virus

Picornaviridae (enterovirus): Poliovirus, Coxsackievirus A and B, Echovirus. Paramyxoviridae (xanthematous virus): Measles virus,Mumps virus Rhabdoviridae: Rabies virus Retroviridae:Human immunodeficiency virus (HIV), Human T-cell leukemia/lymphoma virus

(HTLV-1)

Herpes Simplex Encephalitis: Top of the chapter

Characteristics: The only common form of encephalitis that can occur around the year. Typically presents as spacing occupying lesion in the temporal lobe.

Pathogen: Herpes simplex virus, mainly type I.Detection: PCR of CSF has largely replaced brain biopsy as the diagnostic procedure.Pathogenesis:

Primary mucocutaneous infection. Establishment of latency in ganglion. Reactivation of virus.

Routes of entry to the CNS:

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Primary mucocutaneous infection. Reactivated latent infections from trigeminal ganglions and dorsal root ganglions. Olfactory bulb.

Gross pathology: Characteristic widespread, bilateral but asymmetrical involvement. Necrosis, particularly in the

temporal lobe and the hippocampus.Cingulate gyrus may also be involved. The brain stem is rarely

involved.Subacute and chronic viral encephalitis: Top of the chapterGeneral: They tend to progress slowly over months or years rather than weeks or days. The incubation period is often longer.

Reactivation of a latent infection in an immunocompromised host is responsible in some of them.Pathogens:

Virus type DiseaseMeasle virus Subacute sclerosing panencephalitis (SSPE) Measle virus Measle inclusion body encephalitis Rubella virus Progressive rubella panencephalitis JC virus Progressive multifocal leukoencephalopathy (PML) HIV HIV encephalitis, vacuolar myelopathy, etc.

Congenital and perinatal infections: Top of the chapter

General: The better known ones are resulted from viral, parasitic, or spirochetal infections. The clinical and pathologic features may be different from non-congenital cases. Clinical outcome: It is variable and ranges from fetal demise to obvious neurologic damage at birth to

minor consequences such as hearing loss. Depending on the agent, the full clinical picture may not be developed at the time of birth or early

infancy.Pathology: The time of infection play an important role. The final outcome is an interplay between the teratogenicity and destructive damage inflicted by the

infectious agents. Usually, it is the inflammatory and destructive process that dominate the pathologic picture.

The full consequences of neurologic damage may not be fully developed or appreciated at the time of birth.

Pathogens:Bacterial:

Congenital syphilisParasitic:

Congenital toxoplasmosisViral:

Congenital and neonatal herpes simplex infection Congenital cytomegalovirus Congenital rubella

Congenital HIV infectionCongenital viral infections: Top of the chapterShared common features:Acute or subacute signs of infection.

May have no immediately evident signs of disease at the time of birth, especially for the milder cases.Multiple organ/system malformation (congenital viral syndromes).

Intrauterine growth retardation. Premature birth.

Congenital Cytomegalovirus Infection: Top of the chapter

Clinical: Over 90% of infected newborns are asymptomatic at the time of birth.

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In symptomatic newborns, the observed illness varies in severity. Delayed manifestions, particularly sensorineural deafness, can occur. In contrast to the neurologic damages, extraneural damages are usually reversible and without

significant consequences. Continue to shred CMV virus for years.

Macroscopic Pathology of the CNS: Microcephaly (in 50% of cases), polymirogyria and other malformation.

Histopathology of the CNS: Inflammation and necrosis. Viral inclusions (“bull’s eye” inclusions). Loss of progenitor cells in the ventricle: CMV has a high tendency to involve the periventricular

areas. Migration disorders such as polymicrogyria. CMV chroioretinitis and sensorineural deafness.

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Chapter 3

Tumor of the Central and Peripheral Nervous System Table of Content

Overview of tumors of the CNS Risk factors and hereditary cancer syndrome Classification of tumors of the CNS Category 1 (CNS): Neoplasia recapitulating features of the embryonal CNS

General characteristicsEntitiesMedulloepitheliomaMedulloblastomaSupratentorial primitive neuroectodermal tumor (PNET)Pineoblastoma

Category 2 (CNS): Neoplasia with features of mature neuroepithelial cells (glial, neuronal cells and choroid plexus)

General characteristicsEntitiesAstrocytoma, anaplastic astrocytoma, glioblastomaPilocytic astrocytomaOligodendroglioma and anaplastic oligodendrogliomaEpendymomaChoroid plexus papillomaChoroid plexus carcinomaGlial-neuronal tumorNeuronal tumor

Category 3 (CNS): Neoplasia with features of leptomeninges and mesenchymal tissueGeneralEntitiesMeningioma ChordomaHemangioblastomaVon Hippel-Lindau disease

Category 4 (CNS): Primary neoplasia with features of tissue that are not normally found in the CNS

GeneralPrimary CNS lymphomaCraniopharyngioma

Category 5 (CNS): Secondary and metastatic neoplasiaGeneralMetastatic carcinoma

Tumor of the PNS, overviewNeuroblastic Tumors of Adrenal Glands and Sympathetic Nervous SystemNeurofibromaNeurofibromatosis 1 (NF1)SchwannomaNeurofibromatosis 2 (NF2)

O verview of tumors of the CNS : Top of the chapter

Terms: Top of the chapter

Although being used almost interchangeability, these terms should be distinguished.

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A tumor of the CNS is a mass (space occupying) of the CNS. A neoplasm of the CNS is a mass of abnormal tissue characterized by uncontrolled proliferation

within the central nervous system.

General aspects: Top of the chapter

Autopsy series: 50-70% of all CNS tumors are primary and 20-50% are secondary (metastatic).Childhood: 70% of primary brain tumors are located below tentorium, solid metastatic tumors are rare in

children. Intracranial tumors are second only to leukemia as a cause of childhood cancer, accounting for 20% of all childhood cancers.

Adults: 70% of primary brain tumors are located above the tentorium, 20% of all primary brain tumors are meningiomas. Solid metastatic tumors are common and frequency increases with age.

Signs and symptoms: related to both local tumor growth and secondary effects of edema (vasogenic).Incidence: The relative incidence of particular type of tumor is often correlated with age. For example,

medulloblastoma is predominantly seen in children and infants, glioblastomas are most often seen in middle aged to elderly subjects.

Location: Different classes of brain tumors tend to occur more frequently in some particular anatomical sites. For example, ependymomas are most often seen in a periventricular and subventricular location while pilocytic astrocytomas are most often seen in the cerebellum of children.

Clinical features: Top of the chapter

Early recognition of brain tumors relies on astute clinical evaluation since they are not associated with specific symptoms or signs.

Routine screening is impractical and may be impossible.Clinical presentation: Headache, new-onset seizures, focal neurologic signs such as hemiparesis,

and mental status changes are the more commonly seen pictures. But these symptoms and signs are very nonspecific.

Diagnosis: The diagnosis of brain tumor relies heavily on imaging studies such as MRI and biopsy.Treatment: Surgery, chemotherapy, and radiotherapy. The cornerstone of the treatment is dependent on

the tumor type and location. Very often, a combination of all three treatment modalities is employed.Undesirable features of treatment:

Hampered neurological development: This is a particularly important issue in children and infants with radiation therapy.

Hampered neuroendocrine function: This is particularly important when the pituitary gland is involved in the surgery or radiation treatment.

Focal neurologic defects: In some particularly sites such as the motor cortex, neurologic defects are often unavoidable side effects of surgery.

Radiation necrosis: This is common but delayed side effect of high dose radiation therapy. It usually occurs a few years after the initial treatment.

Second malignancy: Similar to radiation therapy and chemotherapy in other organ system, these patients have increased risk of developing a second malignancy. This is also a delayed side effect.

Outcome depends on: Biologic malignant potential: type and differentiation of tumor. Clinical malignant potential: location of the tumor. Surgical resectability. Responsiveness of the tumor to chemotherapy and radiation therapy.

Unique features of neoplasia of the CNS: Top of the chapter

They rarely metastasize outside the nervous system. Dissemination within the CNS, however, is common in some varieties.

Brain tumors can be biologically benign but clinically malignant. This usually occurs in tumors that arise in a non-resectable location such as the brain stem.

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Herniation and increased intracranial pressure is often associated with brain tumors, particularly fast growing tumors.

Sudden death can occur in patients with brain tumors at at strategic position. Some primary tumors may arise outside the CNS and have features identical to some neoplasia that

arise within the brain (e.g., meningioma arising in the lung).

Risk factors and hereditary cancer syndrome: Top of the chapter

Increased risk for neoplasm of the CNS: Top of the chapter

Immunosuppression (natural or iagrogenic): Greatly increased risk in developing primary lymphoma of the CNS is associated with AIDS, Wiskott-Aldrich syndrome, severe combined immunodeficiency and other status of compromised immunity.

Hereditary cancer syndromes: Greatly increased risk in developing primary neoplasm of the CNS and PNS is associated with a variety of hereditary cancer syndromes.

Hereditary cancer syndrome: Top of the chapter

You do not need to know all the details of this table but at least you should know the name of these syndromes.

Syndrome Pathology GeneticsTuberous sclerosis Nervous system: Cortical hamartomas (tuber),

subependymal hamartoma and subependymal giant cell tumor.Extraneural: Adenoma sebaceum and other manifestation of skin, retinal astrocytoma, renal angiolipoma, cardiac rhabdomyoma and other systemic manifestations.

Inheritance: Autosomal dominant.Prevalence: Between 1/5,000 and 1/10,000.Gene: TSC1 gene (tuberin) on chromosome 9q34 and TSC2 gene on chromosome 16p13.3.

Neurofibromatosis type 1 Nervous system: Neurofibromas and malignant peripheral nerve sheath tumor of the peripheral nerve, gliomas of the brain.Extraneural: Multiple café-au-lait spots, rhabdomyosarcoma, pheochromocytoma, carcinoid tumor, juvenile chronic myeloid leukemia, bone lesions and other manifestations.

Inheritance: Autosomal dominant.Prevalence: 1 in 3,000-4,000 of the general population.Gene: The NF1 gene (neurofibromin) is on chromosome 17q2.

Neurofibromatosis type 2 Nervous system: Bilateral vestibular schwannomas, peripheral schwannomas, meningiomas and meningioangiomatosis, ependymos, astrocytomas, glial hamartoma, and cerebral calcifications.Extraneural: Posterior lens opacity.

Inheritance: Autosomal dominant.Prevalence: 1 in 50,000 of the general population.Gene: NF2 gene (merlin) is on chromosome 22q12.

Von Hippel-Lindau disease

Nervous system: Hemangioblastoma of the retina and CNS.Extraneural: Renal cysts and renal cell carcinoma, pancreatic cysts, islet cell tumors, pheochromocytoma, and other manifestations.

Inheritance: Autosomal dominant.Prevalence: 1/36,000 to 1/45,500 of general population.Gene: VHL gene is located on chromosome 3p25.3.

Naevoid basal cell carcinoma syndrome (Gorlin’s syndrome)

Nervous system: PNET in the posterior fossa. Extraneural: Multiple basal cell carcinoma and keratocyst of the jaw. Abnormal ribs and other skeletal abnormalities, epidermal cyst, ovarian cysts and other features.

Inheritance: Autosomal dominant.Incidence: 1 in 57,000 of the general population.Gene: Mutation in the human homologue of the Drosophilia segment polarity gene patched (PTCH) on chromosome 9q22.3.

Cowden disease Central nervous system: Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos disease). Other pathologic changes include megalencephaly and heterotopic gray matter. Meningiomas and medulloblastomas have also been described. Peripheral nervous system: Mucosal ganglioneuromatosis

Inheritance: Autosomal dominant.Gene: PTEN/MMAC1 gene on chromosome 10q23.

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may be present.Extraneural: Hypoplastic mandible and prominent forehead, verrucous skin changes, papules and fibromas of oral mucosa, multiple facial trichilemmomas arising predominantly about the mouth, nose, eyes and ears, hamartomas polyps of the colon, thyroid tumor and breast cancer.

Turcot syndrome (type 1) Nervous system: Usually glioblastoma.Extraneural: Café-au-lait spots. Small number of large colorectal polyps and high incidence of colorectal carcinoma. Some patients are associated with hereditary non-polyposis colorectal carcinoma syndrome (HNPCC).

Inheritance: Autosomal dominant.Gene: Several genes involved in mismatch repair including hMLH1 at chromosome 3p21, hMLH2 at 2p16, hMSH3 at 5q11-q13, hMSH6/GTBP at 2p16, hPMS1 at 2q32, and hPMS2 at 7p22.

Turcot syndrome (type 2) Nervous system: Usually medulloblastoma.Extraneural: Associated with familial adenomatous polyposis syndrome (FAP). Patient has innumerable adenomatous colorectal polyposis and high incidence of colorectal carcinoma.

Inheritance: Autosomal dominant.Gene: Germline mutation of the APC gene on chromosome 5q21 that is associated with familial adenomatous polyposis syndrome (FAP).

Retinoblastoma (RB) gene deletion syndrome

Nervous system: Retinoblastoma in the retina with or without PNET in the pineal gland (pineoblastoma).Extraneural: Increased incidence of second malignancy, multiple congenital abnormalities and mental retardation.

Inheritance: Autosomal dominant. Gene: Germline deletion of RB1 gene on chromosome 13q14.2.

Rhabdoid predisposition syndrome

Nervous system: Atypical teratoid rhabdoid tumor, choroid plexus carcinoma, posterior fossa PNETs, and renal rhabdoid tumor. Tumor occurs under the age of 3 years.

Inheritance: May be all de novo mutations. The pattern of inheritance is not clear.Gene: Germline mutation or deletion of hSNF5/INI1 gene on chromosome 22q11.2.

Classification of brain tumors: Top of the chapter

Principle: Top of the chapter

Tumors are classified according to the phenotypic features that they express in comparison to the normal counterpart.

The essential objective is to generate a classification system that can predict biologic malignant potential.World Health Organization (WHO) classification: Top of the chapterThis is probably the most widely accepted classification system.

Simplified classification for this lecture: Top of the chapter

Category 1: Neoplasia recapitulating features of the embryonal CNS (e.g., medulloblastoma). Category 2: Neoplasia recapitulating features of the mature CNS (e.g., astrocytoma, ganglioglioma). Category 3: Neoplasia recapitulating features of the meninges and supportive tissue. (e.g.

meningioma) Category 4: Neoplasia recapitulating features of tissues that are not normally found in the CNS.

(e.g., germ cell tumor) Category 5: Metastatic and secondary neoplasia. (e.g. metastatic carcinoma, leukemia)

Category 1 (CNS): Neoplasia recapitulating features of the embryonal CNS Top of the chapter

General characteristics Entities Medulloepithelioma

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Medulloblastoma Supratentorial primitive neuroectodermal tumor (PNET) Pineoblastoma

General characteristics : ? Top of the chapter

Highly malignant, but some of them such as medulloblastoma are quite responsive to radiation therapy.

Most often seen in infants and children. Uncommon in adults. Most of them are composed of primitive appearing neoplastic cells (small blue cells) that

resemble the early developmental stages of the CNS. May, but not always, display a spectrum of morphological and immunohistochemical differentiation

within the same tumor. Often, but not always, have highly preferred locations. For examples, medulloblastomas are seen

in the cerebellum and pineoblastomas are seen in the pineal areas. Often associated with specific genetic defects than other brain tumors. For example,

medulloblastomas are associated with isochromosome 17 and epithelial growth factor receptor (EGFR) amplification, atypical teratoid rhabdoid tumors are associated with INI1 gene deletion on chromosome 22q.

Entities: Top of the chapter

Medulloepithelioma Medulloblastoma and its variants Supratentorial primitive neuroectodermal tumor (PNET) and its variants Atypical teratoid rhabdoid tumor (ATRT) Esthesioneuroblastoma Ependymoblastoma Pineoblastoma Retinoblastoma Medulloepithelioma: Top of the chapterHighlight: This is a rare tumor.

However, it is also the tumor that recapitulate the earliest (neuroepithelial or neuroectodermal stage) of the developing nervous system. I include this tumor here to highlight this point.

General: Highly malignant tumor that recapitulate features of the primitive neuroepithelium. Incidence: Very rare. Age: Usually seen under 5 y/o. Location: Can be seen in both supra- and infra-tentorial locations. May also be seen inside the

globe and along nerve trunks. Gross pathology: Large friable tumor that often infiltrate into the leptomeninges and even bone. Histopathology: Highly anaplastic cells that have features of epithelium, i.e., they arrange

themselves into tubes, strands, and gland-like structure.Medulloblastoma: Top of the chapter

Highlight: Malignant brain tumor of children with features of the developing nervous system. Medulloblastoma is also known as primitive neuroectodermal tumor (PNET) of the posterior fossa.

Biology: Highly malignant tumor that recapitulate features of the developing CNS. Quite responsive to treatment. Has a strong tendency to disseminate along the CSF. Irradiation of the entire neuroaxis is

performed in cases over 3 years of age.Prognosis: 5-year survival rate is 60-80% with treatment.Variants: Some variants behave more aggressively than the classic type (large cell medulloblastoma),

some behave less aggressively than the classic type (desmoplastic medulloblastoma).Incidence: Relatively uncommon but they are the most common malignant pediatric brain tumor.Age: Most are seen in infants and children. A small number is seen in adults.

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Genetically associated syndrome: Nevus basal cell carcinoma syndrome (Gorlin syndrome), and some cases of Turcot syndrome.

Location: By definition, they are found in the posterior fossa and cerebellum. They tend to occur in the midline, affecting the vermis, and presents with gait instability,

headache, nausea and vomiting,Gross pathology:

They occur most often as soft friable tumor with or without discrete margins.

They often extend into the 4th ventricle and cause hydrocephalus. Massive hemorrhage into them can occur and can lead to rapid expansion of the tumor,

compression of the brainstem and sudden death.Histopathology: The tumor cells are small and with hyperchromatic, small nuclei (small blue cells). Cytoplasmic border is very in distinct.

The tumor cells most often arrange in a solid “patterness” sheet. Homer Wright rosettes can occur but is relatively uncommon.

Numerous mitotic figures and apoptotic cells. Cell cycling rate is high (can be over 50%). Although no morphologically features of neuronal differentiation, immunohistochemistry often

demonstrate neuroendocrine, astrocytic and neuronal differentiation. Expression of Trk-C (a high affinity neurotrophins receptor) in some tumor.

Molecular pathology:

Supratentorial primitive neuroectodermal tumor (PNET): Top of the chapter

Highlight: The pathology of these tumors is very similar if not identical to the medulloblastoma. When they occur in supratentorial locations, brainstem and spinal cord, they are called primitive neuroectodermal tumor (PNET).

Pineoblastoma: Top of the chapter

Highlight: They are extremely rare tumors arising from the intrinsic neuronal elements of the pineal gland. They have features of PNETs and are really PNETs arising from the pineal gland. They may have a mixed pineoblastoma/pineocytoma type of differentiation. Pineocytoma, however, is the more mature form and have features more of the mature CNS than

the developing CNS. They are immunoreactive for antigens that could be seen in the photoreceptors such as S-

antigen, rod-opsin and inter-retinal binding protein (IRBP). Expression of these antigens, however, can also be seen in medulloblastomas and PNETs.

Category 2 (CNS): Neoplasia with features of mature neuroepithelial cells (glial, neuronal cells and choroids plexus): ? ? Top of the chapter

Deletion of INI1 gene on chromosome 22q.Atypical teratoid/ rhabdoid tumor

Deletion of RB1 gene.Retinoblastoma

Isochromosome 17q, and less commonly other chromosomal abnormalities.c-MYC amplication.Associated with Gorlin syndrome and some of the Turcot syndrome.

Medulloblastoma

Genetic FeaturesTumor

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General characteristics Entities Astrocytoma, anaplastic astrocytoma, glioblastoma Pilocytic astrocytoma Oligodendroglioma and anaplastic oligodendroglioma Ependymoma Choroid plexus papilloma Glial-neuronal tumor Neuronal tumor

General characteristics : Top of the chapter

This category focuses on tumors with glial and neuronal differentiation. As being mentioned earlier, tumors are classified according to the phenotypic features that they express in comparison to the normal counterpart. So, how do we know if the tumor is of glial or neuronal differentiation? Or is this something else? The phenotype of the cell type can be determined by the following methods:

Light microscopic featuresUltrastructural features:

Neuronal/ neuroendocrine differentiation: dense core granules (neurosecretary granules). Ependymal: Intercellular adhesion structures, microvilli, and cilia.

Molecular phenotype, usually by immunostaining: Neuroendocrine differentiation: synaptophysin and chromogranin. Neuronal differentiation: Neurofilament, Neu-N. Glial differentiation: Glial fibrillary acidic protein.Histologic grade:These tumors may be

seen as tumors that demonstrate a spectrum of biologic behavior from benign (e.g., pilocytic astrocytoma) to low-grade malignant (e.g., astrocytoma) to high-grade malignant (anaplastic astrocytoma) to very high grade malignant (e.g. glioblastoma).

The histologic grade often, but not always, reflects the biologic behavior. Please note that the term “benign” and “malignant” are not used in the WHO classification.

WHO tumor grade:I: BenignII: Low-grade malignancy.III: High-grade malignancy. IV: Very-high grade malgnancy.

Entities: Top of the chapter

Attention: The ones that are in italics as they are the most commonly seen brain tumors.

Astrocytic tumorsAstrocytic tumors with no specific histologic features

Diffuse Astrocytoma (WHO II) Anaplastic astrocytoma (WHO III) Glioblastoma (WHO IV)

Astrocytic tumors with specific histologic features Pilocytic astrocytoma Pleomorphic xanthoastrocytoma Desmoplastic infantile astrocytoma Subependymal giant cell astrocytomaOligodendroglial tumorsOligodendroglioma Anaplastic oligodendroglioma

Mixed gliomas

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Oligoastrocytoma Anaplastic oligoastrocytoma

Ependymal tumors Subependymoma Myxopapillary ependymoma Ependymoma Anaplastic ependymoma

Astrocytoma, anaplastic astrocytoma, and glioblastoma ? ? ? Top of the chapter

General: These tumors occur as astrocytic tumors that demonstrate a spectrum of malignant behavior

from low (astrocytoma) to very high (glioblastoma). It should be noted that glioblastoma is not limited to astrocytic differentiation. Other malignant

glial neoplasm such as oligodendrogliomas and ependymomas may also have morphologic features of glioblastoma.

Location: The incidence is roughly proportion to the volume of white matter. So most of them occur in the cerebral hemispheres.

Age: Astrocytoma: Most common in young adults, peak incidence at 30-40 years of age. Anaplastic astrocytoma: In general, the peak incidence occurs at 10 years later than that of

astrocytoma. Glioblastoma: In general, the peak incidence occurs at 10 years later than that of anaplastic

astrocytoma. Children: They can occur in children but are less common than that of adults.

Prognosis: Astrocytoma (WHO II): Guarded, often recurr as high-grade tumor. Anaplastic astrocytoma (WHO III): Bad. Glioblastoma (WHO IV): Poor, very few patients survive more than two years even with

treatment.Etiology and pathogenesis:

Several genes have been associated with tumorigenesis. The study has lead to the concept of primary and secondary glioblastoma.

Primary (de novo) glioblastoma: Glioblastoma without precursor lesion. Secondary glioblastoma: Glioblastomas that arise from a pre-existing low-grade glial tumor,

most often an astrocytoma. P53 gene mutation is the most common genetic event.

Differentiated astrocytes or neuroepithelial precursor cells

Low grade Astrocytoma (WHO Grade 2)

Anaplastic Astrocytoma(WHO Grade 3)

Secondary glioblastoma(WHO Grade 4)

Primary Glioblastoma(WHO Grade 4)

Other primary Glioblastomase.g.Giant Cell

p53 mutation > 65%PDGF-A, PDGFR-overexpression ~ 60%

LOH 19q ~ 50%Rb alteration~ 25%

LOH 10/PTEN/MMAC1DCC loss of expression ~ 50%PDGFR- amplification <10%

EGFR amplification ~ 40%overexpression ~ 60%

MDM2 amplification < 10%overexpression ~ 50%

p16 deletion ~ 30-40%

LOH 10 /PTEN/MMAC1 ~ 80%

RB alteration

p53 mutation > 70%

LOH 10

?

?

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Gross pathology: General: They all have a diffuse margin. Separation of normal tissue from tumor tissue is often

difficult and particularly so in the low-grade tumors. The high grade tumors typically enhances on MRI (e.g., ring enhancement in glioblastom). New onset seizures and headache are the most common presentation.

Crossing the midline: The high-grade tumors (anaplastic astrocytoma and glioblastom) have a tendency to cross the midline through the corpus callosum and generate the so –called butterfly tumors.

Mass effect: This is common particularly among the high-grade tumors. Astrocytoma: Effacement of the white matter and deep gray matter, blurring and “melting” of the

gray white junction. The consistency and texture of the tumor is very similar to that of normal white matter. They do not enhance on MRI.

Anaplastic astrocytoma: They are similar to astrocytomas but they may appear darker than astrocytomas because of a rich vascular supply. They enhance on MRI.

Glioblastoma: They are extensively infiltrating tumors that often appear hemorrhagic and necrotic.

Histology: Shared histologic features: They are all diffusely infiltrative tumor and the margin of the tumor

is impossible to be determined. Unique features:

Astrocytoma: The neoplastic cells resemble mature astrocytes with low nuclear pleomorphism. There is no necrosis or endothelial proliferation. Mitotic activity is low. (WHO grade II)

Anaplastic Astrocytoma: There is increased mitotic activity and nuclear pleomorphism. (WHO grade III)

Glioblastoma: Features of anaplastic astrocytoma plus endothelial proliferation and/or necrosis. (WHO grade IV)

Pilocytic astrocytoma: ? Top of the chapter

Highlight: This is a benign astrocytic tumor that can be cured by resection alone. It is common in children and also seen in young adults. Please pay attention to the difference between pilocytic astrocytoma and astrocytoma, anaplastic astrocytoma, and glioblastoma.

General: This is a biologically benign astrocytic tumor with peculiar fibrillary structures that look like hair. (pilo-). They are seen mostly in children and infants and occur most commonly in the cerebellum.

Age: Over 80% occurs under 20 years of age, peak incidence between 8 to 13 years old.Associated syndrome: Increased incidence of pilocytic astrocytoma is associated with

neurofibromatosis 1 (NF1). In contrast to the sporadic cases, these tumors occur most frequently in the optic nerve and in the optic track-hypothalamic pathway.

Location: Most commonly seen in the cerebellum. Cases associated with neurofibromatosis 1 (NF1) often occur in the optic nerve and hypothalamus.

Gross pathology: In contrast to astrocytoma, anaplastic astrocytoma, and glioiblastoma, pilocytic astrocytomas are well-demarcated tumor. Cystic change with mural nodule formation is often seen.

Imaging: They are often, but not always, found in the cerebellum. Many of the cerebellar tumors have a cystic component and mural nodule. In contrast to low-grade astrocytoma, they enhance.

Histology: Hair-like elongated pilocytic tumor cells. Low mitotic activity. Formation of glomeruloid vascular structure (must be distinguished from endothelial

proliferation).

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Formation of Rosenthal fibers and granular eosinophilic bodies.

Oligodendrogliioma and anaplastic oligodendroglioma : Top of the chapter

General: Oligodendrogliomas (WHO grade II) and anaplastic oligodendroglioma (WHO grade III) are the low- and high-grade malignant glial neoplasms that have morphologic features of oligodendrocytes.

Age: Mostly seen in middle aged adults, peak incidence at 40 to 50 years of age.Location: The incidence is roughly proportion to the volume of white matter.Gross pathology: Poorly demarcated soft friable tumor that may be mucoid in consistency. Histopathology: Solid sheets of polygonal cells with centrally located, small, and round nuclei with a

perivascular halo that give a “fried-egg” appearance. Characteristically, there is a delicate vascular network and calcifications.

Anaplastic oligodendroglioma: Features: They have morphologic features of aggressive tumors such as increased

pleomorphism, increased mitotic activities, and endothelial proliferation. 1p 19q deletion: Anaplastic oligodendrogliomas that have deletion of chromosome 1p and 19q

are responsive to chemotherapy with PVC.

Ependymoma: Top of the chapter

General: Ependymoma is a low-grade glial tumor with ependymal differentiation. They are more often seen in children and young adults. Spinal dissemination is not uncommon.

Age: Ependymoma has a bimodal distribution in the infants and children as well as young adult.Location:

They are found along along the ependymal lining with the 4th ventricle and spinal cord as the most common locations.

In chidlren, mostly infratentorial tumor. In adults, infratentorial and supratentorial tumors are equally frequent.

Gross pathology: Most commonly occur as grayish cauliflower- like exophytic growth that protrude into the ventricles leading to hydrocephalus.

Histopathology: The tumor cells are usually of low-nuclear grade with a strong tendency to arrange in form of

rosettes around blood vessels. Formation of ependymal canal (resembling the normal ependyma) is also a diagnostic feature.

Electron microscopy: Ependymoma is one of the very few tumors glial tumors that has specific ultrastructural features. These features include junctional complexes, microvilli, and cilia in a 9+2 arrangement. No basement membrane is present.

.Choroid plexus papillom a : Top of the chapter

General: They are benign tumors that recapitulate features of the choroid plexus and are most common in children. Although the epithelium of the choroids plexus has all the bone fide features of an epithelium, it is of neuroepithelial origin and can be seen as a modified ependyma.

Incidence: Common in children but uncommon in adults.Age: Most of them occur before the age of 10 year. Location: They are found in areas where the choroid plexus are found, most common in the lateral

ventricle and 4th ventricle. Also found in the third ventricle and cerebellar pontine angle.Gross pathology:

Well demarcated pink cauliflower like exophytic mass that often fill the ventricle. Hemorrhage and calcification are frequently and often well detected on imaging. Hydrocephalus: They often cause hydrocephalus by obstruction of flow. In rare occasions, they

may produce hydrocephalus by overproduction of CSF.Histology: They closely resemble normal choroids plexus: they are papillary in architecture and has only one layer of cells.

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Choroid plexus carcinoma: Top of the chapter

General: In contrast to choroids plexus papilloma, they are highly malignant..Incidence: They are rare tumors. Age: Almost all of them occur in children particularly young infants. Choroid plexus carcinoma is one

of the very few carcinomas that occur almost exclusively in infants, and less commonly children.Histology:

In contrast to choroids plexus papilloma that has single layer epithelial cells and bland cytoplasm, choroids plexus carcinoma are highly pleomorphic and mitotically active. They often lost, at least focally, the papillary architecture and form solid tumor sheets.

Glial-neuronal tumor: Top of the chapter

General: This is a class of tumor featured by two neoplastic components that display neuronal and glial differentiation. Ganglioglioma is the most common entity as well as the prototype.

Entities: Ganglioglioma (most common) Anaplastic ganglioglioma Demoplastic infantile ganglioglioma (DIG) Dysembryoplastic neuroepithelioma (DNET) Other uncommon entities.

Ganglioglioma and gangliocytomor:General: Well-differentiated, slow growing tumor with ganglionic (neuronal) component alone

(gangliocytoma) or in combination with neopalstial glial cells (ganglioglioma), usually astrocytic.Behavior: Gangliocytomas are benign. Most gangliogliomas but anaplastic variants has also been well

documented. In most cases, it is the glial component that behave aggressively.Age: Most common in children or young adults.Location: Most common in the temporal lobe but may occur anywhere along the CNS.Clinical: Tumors of the cerebral hemispheres, especially those in the temporal lobe are associated with

chronic, often intractable, seizure.Gross Pathology:

Solid or cystic tumors that are often relatively well demarcated. Usually do not produce a lot of mass effect. Calcification is common.

Histopathology: Neoplastic ganglionic cells and neoplastic glial component. May have features suggestive of dysplastic gray matter or hamartoma.

Neuronal tumor: ? Top of the chapter

General: This is a class of tumor that is composed exclusively of neoplastic neuronal cells. They are quite uncommon. The most common one is probably central neurocytoma.

Entities: Central neurocytoma Cerebellar liponeurocytoma Pineocytoma Gangliocytoma Dysplastic gangliocytoma of cerebellum (Lhermitte-Duclos disease)Central

neurocytoma:General: Neurocytomas are mostly benign but aggressive variants have been described. Although they are uncommon, they are the most common intraventricular tumor in adults.Age: They can be seen in all ages but peak in the third decade.Neruoimaging: They occur most often as exophytic tumors with their epicenter at the septum pellucidum and protrude into the ventricle. Hydrocephalus is common.Gross Pathology:They can appear as soft tumor but calcification can be extensive enough to give them a stone-like consistency.

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Often lead to hydrocephalus by compression of the foramen of Monro.Histopathology:

The histologic features closely resemble oligodendroglioma. Rosette like structures and neuropils may be present. However, they have immunohistochemical and ultrastructural features of neuronal

differentiation.

Category 3 (CNS): Neoplasia with features of leptomeninges and mesenchymal tissue Top of the chapter

General Entities Meningioma Chordoma Hemangioblastoma Von Hippel-Lindau disease

General: This category includes meningioma and a long list of mesenchymal tumors. Meningioma and

primary melanocytic tumors arise predominantly from the leptomeninges. Mesenchymal tumors (soft tissue tumors, bone tumors, etc) arise from the surrounding cranial tissue.

Meningioma is a very common tumor.

Entities:

Meningiomas

Meningioma Atypical meningioma Anaplastic (malignant) meningioma

Primary melanocytic tumorsMesenchymal tumor

Tumors with features of soft tissue (e.g., fibrosarcoma) Tumors with features of hard tissue (e.g., osteosarcoma) Tumor with features of the notocord (Chordoma) Vascular tumors

Tumor of uncertain origin Hemangioblastoma Hemangiopericytoma

Meningioma: ? Top of the chapter

General: Meningiomas are tumors that have features of the meningothelial (arachnoid) cells. Most of them are benign but some of them can have borderline (atypical meningioma) or malignant biologic behavior (anaplastic meningioma).

Incidence: One of the most commonly seen tumor of the CNS, represent about 18% of all intracranial tumors. Overall incidence is about 6/100,000 of the general population. More common in female.

Age: The peak incidence is between 45 to 55 years of age, rarely seen in children and almost unknown in infants.

Risk factor: Radiation is a well documented risk factor for intracranial meningioma.Genetic association: Associated with neurofibromatosis 2 (NF2).Location:

Their distribution corresponds to the distribution of the arachnoid cells and most of them are dural based tumors. However, rare meningioms that occur inside the ventricle or outside the CNS can occur.

About one-tenth of them are found in the spinal cord.

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Most of them are found in the leptomeninges and dura. Some of them arise from the ventricular lining. They may also be found in subcutaneous tissue in the scalp and along the spine.

Gross pathology: Most of them occur as well demarcated dural based tumor that do not adhere or invade to the brain. The cut surface is usually solid. The consistency varies from soft to firm.

Histopathology: Meningiomas occur in a broad spectrum of histologic pattern. While most histologic patterns are

not indicator of biologic behavior, a small number of histologic patterns are correlated with aggressive or malignant behavior.

Formation of concentric cellular whorls, a structure similar to the arachnoid granules is the most characteristic feature.

Invasion: They may invade into bone, sinuses, and soft tissue but this is not an indication of malignant behavior. In the contrary, brain invasion is a sign of malignant behavior.

Chordoma: Top of the chapter

General: Chordoma is a locally aggressive tumor that has features of the notocord tissue. It occurs most commonly as a midline, cranial base tumor and in the lumbosacral spine.

Pathogenesis: Features recapitulate morphology of the notochord. It also arises in areas where residual notochord tissue can be found- cranial base and in the spine.

Incidence: Relatively uncommon.Age: Mostly seen in adult.Gross pathology: Usually occurs as a soft tumor with translucent cut surface.Histopathology: Cells with bubbly cytoplasm within a matrix of bluish mucoid background.

Ultrastructurally and immunohistochemistry, they have some features of epithelial cells such as intercellular adhesion and cytokeratin filaments.

Hemangioblastoma: Top of the chapter

General: The origin of this tumor is not clearly known. Although they look like tumor of vascular origin,

they do not express ultrastructural and immunohistochemical features specific for vascular tumor. Biologic behavior: It is a benign tumor that occurs most often in the cerebellum but may also occur in

other part of the nervous system.Genetic association: Associated with the von Hippel-Lindau disease (VHLD). Incidence: Uncommon in the general population. Greatly increased incidence in patients with VHLD.Age: Mostly seen in young adult. The age of incidence in patients with VHLD is younger than sporadic

cases.Number of tumors: Solitary tumors are usually seen in sporadic cases. Patients with VHLD may have

multiple tumors.Location: Over 80% of them occur in the paramedian location of the cerebellum, the rest occur in other

parts of the cerebellum. Suprtentorial and spinal hemangioblastomas are very uncommon.Gross pathology: They occur as bluish red to brownish red "liver like", well circumscribed tumor. Cystic

changes are seen in about 2/3 of the cases.Histopathology: The tumor is composed of medium sized tumor cells with clear cytoplasm and bland

nuclei. The tumor cells arrange in nests that are embedded within a rich vascular network.

Von Hippel-Lindau disease: Top of the chapter

Genetics: Autosomal dominant. The VHL gene is a tumor suppressor gene located on chromosome 3p25.3.

Features: Retinal angiomatosis and angioma that is histologically identical to hemangioblastoma Multiple hemangioblastomas . Pheochromocytoma.

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Pancreatic cysts and islet cell tumor. Renal cysts and bilateral, often multiple renal cell carcinoma. Bilateral papillary cystadenoma of the epidydimis Hepatic cyst. Endolymphatic sac tumor (low-grade adenocarcinoma probably of endolymphatic origin).

Category 4 (CNS): Primary neoplasia with features of tissue that are not normally found in the CNS Top of the chapterGeneral

Primary CNS lymphoma Craniopharyngioma

General: Top of the chapter

This is a family of tumors that have features of tissue that are not found in the normal central nervous system. The occurrence of these tumors, however, can also be explained on an anatomical and embryological basis.

Craniopharyngioma: They arises from epithelial cell rests derived from Rathke's pouch. However, many of them have histologic features very similar if not identical to ameloblastoma or squamous odontogenic tumor of the jaws.

Germ cell tumor: They arise from residual germ cell tissue that are left behind during migration of the germ cell from the midline to their peripheral location. A similar mechanism shared by the pathogenesis of the mediastinal germ cell tumor and other germ cell tumors along the spine.

Lymphoma: There is no lymphoid tissue or lymphnodes inside the brain. However, lymphoma can be found in practical any organ.Primary CNS lymphoma: Top of the chapterGeneral: They are rare in the general population and occur most commonly in the elderly. In the immunocompromised group, however, they are relatively common and can occur in any age group.Risk factors: Severe combined immunodeficiency, Wiskott-Aldrich syndrome, and other congenital immunodeficiency. Solid organ transplantation, incidence is related to the type of transplantation and protocol of

immunosuppression. HIV infection.

Survival: They are almost exclusively stage I extranodal non-Hodgkin’s lymphoma (NHL). However, the survival is much worse than stage I extranodal NHL in other part of the body.

Association: EB virus sequences are consistently found in cases associated with immunodeficiency but not in immunocompetent cases.

Type: Diffuse large B-cell type (a type of non-Hodgkin’s lymphoma) is the most common type.

Other types may also occur but are uncommon. T-cell lymphoma is extremely rare. Hodgkin’s disease involving the CNS is extremely rare. Lymphoma associated with post-transplantation patients often evolve from post-transplantation

lymphoproliferative disorder (PTLD).Gross:

Bilateral solitary or multifocal well circumscribed or infiltrating tumors. The surrounding brain parenchyma is usually intact. The cerebrum, the lateral and third ventricles are more frequently involved than the cerebellum. Rarely occur in the brain stem.

Histology: Intense perivascular clustering of anaplastic lymphocytes in the Vichow-Robin space with

infiltration into the surrounding brain parenchyma. Sub-typing: Immunostaining and flow cytometry are very helpful. In situ hybridization for EB

virus is helpful particularly in post-transplantation cases. Craniopharyngioma: Top of the

chapterGeneral: They probably arise from epithelial cell rests derived from Rathke's pouch.

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They grow slowly but they are locally aggressive. They may compress the optic chiasma and lead to visual field loss. They can also compresse hypothalamic structures, 3rd ventricle, optic chiasm and pituitary.

Location: Suprasellar region, often extends into the sella.Gross: They are usually cystic, and contain areas of calcification, fibrous connective tissue, and epithelium

resembling squamous epithelium.Histology: The most common ones have histologic features very similar if not identical to ameloblastoma

or squamous odontogenic tumor of the jaws.

Category 5 (CNS): Secondary and metastatic neoplasia Top of the chapter

General Metastatic carcinoma

General: Top of the chapter

Incidence: High in patients with cancer and may be the most common type of brain tumor.Type: The most common metastatic tumors are carcinoma, especially adenocarcinoma, and malignant

melanoma. Other tumors such as germ cell tumor, particularly choriocarcinoma, and sarcomas may also metastasize to the brain.

Location: The relative incidence is generally proportional to the mass of the CNS, therefore, there are far more metastases found in the brain than spinal cord. Also seen in the dura.

Age: It corresponds to the relative incidence of primary carcinoma and is most common in middle aged to elderly population.

Risk factors: Primary carcinoma. Right-to-left shunt.Survival: Median survival for patients with multiple brain metastases with treatment is 3-6 months.

Patients with resectable solitary lesions have better prognosis.Differential diagnosis: Metastatic melanoma is also common and must be distinguished from

metastatic carcinoma.

Metastatic carcinoma: ? Top of the chapter

Gross pathology: Can occur anywhere in the CNS, often but not always multiple. The smaller tumors are often found at the gray-white junction where there is a reduction of

caliber of blood vessels. The larger lesions often undergo necrosis and mimic glioblastoma on imaging.

Source of primary tumor:

Brain metastases:

Primary tumor site % of Metastasis Lung 50%Breast 15%Skin/ melanoma 10%Unknown primary 11%

Metastases causing epidural spinal cord compression:

Primary tumor site % of Metastasis Breast 22%Lung 15%Prostate 10%Malignant lymphoma 10%Others 43%

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Special predilection: Adenocarcinoma has a far higher tendency to be found as metastases in the brain than

squamous cell carcinoma. Renal cell carcinoma has a high and unexplained tendency to metastasize to the cerebellum. Prostate and breast carcinoma tends to generate epidural metastases that compress the

spinal cord. Choriocarcinoma has a metastatic rate of 83% but germ cell tumor has a metastatic rate of

about 15-25%.Histology:

It is not always possible to determine the origin by histology. Immunostaining might help. In general, the metastastic tumor has histology similar to that of the primary tumor. Unlike gliomas, they are often well demarcated from the surrounding brain tissue. The histologic appearance could be altered by treatment.

Tumor of the PNS, Overview ? ? Top of the chapter

Similar to tumors of the CNS, tumors of the PNS also display features that recapitulate the embryonic and mature peripheral nervous system.

Entities:

Tumors with features neuroblasts and mature neurons: Neuroblastic tumors of the adrenal glands and sympathetic nervous system Ethesioneuroblastoma Ganglioneuroma and gangliofibroma

Tumors with features of paraganglia Paraganglioma and pheochromocytoma

Tumors with features of mature supporting elements: Neurofibroma Schwannoma Malignant peripheral nerve sheath tumor

Neuroblastic Tumors of Adrenal Glands and Sympathetic Nervous System Top of the chapter

General: Definition (WHO): Childhood embryonal tumors of migrating neuroectodermal cells derived from the

neurocrest and destined for the adrenal medulla and sympathetic nervous system.Incidence: Most common solid extracranial malignant tumors during the first two years of life.Age: 80% occurs within the first 4 years of life, occanionally seen in young adults.Location: Most common in the adrenals (40%) with the rest being found in the abdominal, thoracic,

cervical and pelvic sympathetic ganglia.Prognosis: Related to age, stage, and histology. Patients under 1 years old or of stage 4S have

favorable prognosis.Unique properties:

Young age of patients. Spontaneous regression in rare occasions. Maturation may be induced by chemotherapeutic agents.Molecular pathology:MYCN gene

amplification and extrachromosomal chromatin bodies (double minutes)- unfavorable prognosis. Trisomy for chromosome 17q- unfavorable prognosis. Expression of Trk A receptor (a neurotrophin receptor)- favorable prognosis.Gross pathology:

Usually occur as a fleshy/necrotic mass that destroy and replace the adrenal gland; also as soft fleshy/necrotic mass in the thorax or abdominal cavity.Histology: Both mature (ganglionic), immature (neuroblastic) component and schwannian component can be present.

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Homer Wright rossettes can be seen in the neuroblastic component.Subtypes: a spectrum of differentiation recapitulating the embryonic and mature PNS is seen.

Neuroblastoma (undifferentiated, poorly differentiated, differentiating)- most common Ganglioneuroblastoma (intermixed, nodular) Ganglioneuroma (maturing, mature)

Neurofibroma Top of the chapter

General: Biology: This is a benign tumor that is composed of neoplastic cells with features of Schwann cells,

perineurial-like cells, and fibroblasts. Association: Associated with neurofibromatosis 1 (NF1).Sarcomatous transformation: Can occur, particularly in cases associated with NF1.Incidence: Common, they occur either as sporadic solitary nodules or as multiple nodules associated

with NF1.Age: All ages can be affected.Location: Neurofibroma tends to occur in locations that are far from the CNS, rarely in spinal nerve

roots, and almost never in cranial nerves.Clinical forms:

Localized cutaneous neurofibroma- occurs as a cutaneous nodule. (most common) Diffuse cutaneous neurofibroma- occurs as a nodule with diffuse but localized involvement. Localized intraneural neurofibroma- occurs as a circumscribed mass in a peripheral nerve. Plexiform neurofibroma- occurs as a plexiform enlargement of a major nerve trunk. (NF1) Elephantiasis neurofibromatosa- extensive or massive involvement of soft tissue of a body area.

(NF1)Gross pathology:

The cut surface is solid and may appear myxomatous. When they occur within a nerve bundle, they are usually well demarcated. If the tumor is associated with a nerve, the nerve appears to be totally integrated into the tumor

(in contrast to schwannoma).Histology:

Characteristically, they are composed of interlacing bundles of collagen, elongated cells with wavy, dark-staining nuclei within a myxomatous background.

Entrapped axons may be present. The presence of hypercellular areas with nuclear pleomorphism should raise the question of

sarcomatous transformation.

Neurofibromatosis 1 (NF1) Top of the chapter

Summary: NF1 is a pleiotropic congenital multiple dysplasia syndrome characterized by multifocal focal hyperplasia and neoplasia in the supportive tissue throughout the entire nervous system. NF1 is the “true” von Recklinghausen's disease.

Incidence: 1:3,000-4,000, most common genetic disorder.Clinical features: A set of clinical criteria is applied for the diagnosis.

1st degree relative with neurofibromatosis. Café-au-lait macules that have a maximum diameter of >5 mm in prepubertal patients and >15

mm in postpubertal patients. Neurofibroma and/or plexiform neurofibroma. Optic nerve glioma. Unidentified bright objects on MRI scan of brain. Characteristic osseous lesion.

Genetics: Autosomal dominant. Mostly deletion, less commonly mutation, of neurofibromin gene on chromosome 17q.

Increase incidence of systemic malignancy: 200 fold increase risk of chronic myelogeneous leukemia (CML). Non-Hodgkin’s lymphoma and lymphoblastic leukemia.

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Carcinoma of the ampulla of Vater. Neuroblastoma and its variants, pheochromocytoma. Malignant transformation of neurofibroma to malignant peripheral nerve sheath tumor.

CNS lesions: Glioma (particularly in optic tract-hypothalmus area) and hamartomatous glial proliferation. Unidentified bright objects on MRI scans.

Bone lesion: Dysplasia of sphenoid wings and other non-neoplastic lesions.

Schwannoma Top of the chapter

Summary: Schwannoma, also known as neurilemmoma, is a benign tumor that can be found inside the cranium (cranial nerve roots), around the spinal cord (spinal nerve root) and in other parts of the body (peripheral nerve).

Cranial schwannoma: Consistitute about 8% of intracranial neoplasms.

Most common in the 5th and 6th decade.

Most common in the 8th cranial nerve, some in the 5th cranial nerve.Spinal schwannoma:

Predominantly arise in sensory nerve roots. Most common in lumbar sacral region. Mainly intradural and extramedullary. May be multiple in neurofibromatosis 2.Gross pathology:Nodular rubber tumor. Those arising in the spinal cord may have a dumbell shape. The tumor is encapsulated and a compress nerve is often at its periphery.

Histology: Palisading arrangement into Antoni A area, with Verucay bodies. Loosely packed Antoni B area. Myxomatous degeneration. Hyalinized blood vessels.

No collagen fiber.Neurofibromatosis 2 (NF2) Top of the chapterSummary: The cardinal features of neurofibromatosis are multifocal focal hyperplasia and neoplasia in the supportive tissue throughout the entire nervous system. Incidence: Only about 1/10 of the incidence of NF1.

Clinical features: A set of clinical criteria is applied for the diagnosis. 1st degree relative with neurofibromatosis.

Café-au-lait macules that have a maximum diameter of >5 mm in prepubertal patients and >15 mm in postpubertal patients.

Neurofibroma and/or plexiform neurofibroma. Optic nerve glioma. Unidentified bright objects on MRI scan of brain. Characteristic osseous lesion.

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Chapter 4

Metabolic, Nutritional and Mitochondrial Diseases Table of Content

Overview Peroxisomal diseases Zellweger syndrome X-linked adrenoleukodystrophy (X-ALD) Lysosomal storage diseases Globoid cell leukodystrophy (Krabbe disease) Mitochondrial disorders Mitochondrial myopathy, encephalopathy, lactic-acidosis, and stroke-like episodes

(MELAS)

Overview Top of the chapter

General: They are rare diseases. Not all the metabolic and mitochondrial diseases have infantantile or

neonatal onset. Many of them, particularly the milder variants, have onset in adults. The human body has only several ways to manifest abnormality of metabolism or energy

production at the cellular levels. It may be necrosis due to hypoxia or accumulation of abnormal mitochondria as in mitochondrial diseases or accumulation of storage material that cannot be metabolized as in lysosomal storage diseases.

In many occasions, organs outside the CNS and PNS, particularly the liver and skeletal muscle, can also be affected. Many of these diseases come in a syndromic setting.

Correct diagnoses of these diseases are more dependent on biochemical analysis and genetic analysis far more than morphologic studies. Traditional anatomic pathological studies, however, is very useful in understanding them and also assessing the damage of the disease to the body.

This lecture is only a very brief introduction. There are many metabolic and mitochondrial diseases and each of them has their variants. At your level, I recommend that you should learn how many major types are there and what are their shared features. I will take a few examples to illustrate this point. Pay attention to the similarities and differences between individual disease and syndrome of the same class.

Nutritional diseases will not be discussed because of the lack of time.

Types:

Organelle and biochemical level: Mitochondrial diseases: Leigh disease, Mitochondrial myopathy, encephalopathy, lactic-

acidosis, and stroke like episodes (MELAS), Leigh’s disease (subacute necrotizing encephalomyelopathy), Myoclonus epilepsy, ragged-red fibers (MERRF), etc.

Lysosomal: Globoid cell leukodystrophy, metachromatic leukodystrophy, Nieman-Pick disease, Fabry’s disease, etc.

Peroxisomal: X-linked adrenal leukodystrophy, Zellweger syndrome, Refsum disease, etc.Biochemical level:

Carbohydrate metabolism: Pompe disease and other glycogenosis. Fatty acid metabolism: X-linked adrenal leukodystrophy (also a perxoisomal disease), carnitine

deficiency, etc. Amino acid metabolism: Canavan disease, Hartnup disease, etc. Nucleic acid: Porphyria and related diseases. Trace elements: Wilson disease, Menke disease.

Nutritional, intoxication, and poisoning: Nutritional: Deficiency of B12, Vitamin E, Thiamine, niacin, etc. Intoxication and poisoning: methanol, ethanol, ethylene glycol, thallium, mercury, lead, etc.

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Peroxisomal diseases Top of the chapter

Attention: I put most of the information in this section to illustrate the complexity and for your interest, you do not need to memorize the details.

General properties: Ubiquitous: Peroxisomes are ubiquitous membrane bound subcellular organelles that

participate in multiple metabolic processes. Catalase and oxidase: They are biochemically defined by the presence of a catalase and

several oxidases, which can also be recognized by immunohistochemistry. Distribution: They are more numerous in cells that specialize in the metabolism of complex

lipids and in the developing nervous system than in other mature cells. Type of disorders: Peroxisomal diseases fall into two major catetory. The first category is

featured by abnormal biogenesis (assembly) of peroxisomes and is often associated with abnormal peroxisomes under electron microscopy. The second category is featured by failure of a single enzyme that is necessary for normal peroxisome function; abnormal peroxisome under electron microscope is not a usual feature in these diseases.

Genetics: Most of them are transmitted in an autosomal recessive pattern.

Biochemical pathways:

Peroxisomal -oxidation: the main substrates are very-long-chain-fatty acid (VLCFAs) and trihydroxycholestanoic acids (THCA) which are intermediate substrate in bile acid synthesis from cholesterol, pristanic acid and long-chain dicarboxylic acids. Plasmalogen biosynthesis: Plasmalogens belong to a special class of phospholipids. Their role is unknown, but they are especially abundant in the CNS.Phytanic oxidation: Phytanic acid is a branched-chain fatty acid derived from dietary sources. It is degraded into pristinic acid through -oxidation. Pristinic acid is further metabolized via the peroxisomal -oxidation pathway.Pipecolic catabolism: L-pipecolate oxidase is a peroximal enzyme which catalyses the hydrogenation of L-pipecolate.

Classification of peroxisomal diseases:

Group I (abnormal biogenesis and assembly): Genetics: This group constitutes the generalized peroxisomal disorders and are inherited as

autosomal recessive traits. The incidence in newborn is about 1:50,000 live births.Abnormal morphology: Loss of multiple peroxisomal enzyme activities often associated with morphological abnormalities of the organelle. Trilaminar inclusions within lysosomes can be seen under electron microscope.

Etiology: Many of the disorders in this group are due to defects in importing the protein into the peroxisomes resulting in defective peroxisomal biogenesis or defects in maintaining peroxisomal intergrity. Group I disorders:Zellweger syndrome Neonatal adrenoleukodystrophy Refsum’s disease Hyperpipecolic acidaemia Pseudo-infantile Refsum’s disease Rhizomelic chondrodysplasia punctata (classical type)

Group II (single enzyme deficiency): Characteristic: The structure of peroxisomes is intact and only one defective enzyme is

involved. Group IIa: -oxidation pathway X-linked adrenoleukodystrophy (ALD protein)Pseudo-neonatal adrenoleukodystrophy (Acyl-CoA oxidase)Pseudo-Zellweger (Thiolase)Bifuctional enzyme deficiency (Bifunctional protein)

Group IIb: Not involving -oxidation pathway Refsum’s disease (Phytanic acid oxidase)Pseudo-rhizomelic chondrodysplasia

(Plasmalogen synthesis)

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Di-(tri)-hydrocholestanoic acidemia (Bile acid synthesis)Mevalonic aciduria (Cholesterol synthesis)

Zellweger syndrome Top of the chapter

Characteristic: This is the first syndrome known in which malformations of the brain and other organs are associated with an inborn error of metabolism.

This is a cerebrohepatorenal syndrome associated with migration disorder, accumulation of long chain fatty acid.

This is a group I disorder (abnormal biogenesis and assembly) and biochemically characterized by accumulation of saturated very long chain (over 22 carbon) fatty acid (VLCFA).

Age: Neonatal onset.Genetics: Autosomal recessive.Biochemistry: The peroxisomal beta-oxidation is impaired and lead to the accumulation of saturated very

long chain (over 22 carbon) fatty acid (VLCFA). Measurment of VLCFA level is the mainstay of biochemical diagnosis. Other clinically useful markers include dihydroxyacetone phosphate acyl transferase (DHAP-AT), red blood cell plasmalogens, phytanic acid and piperocolic acid level.

Clinical features: Typical facial dysmorphism. Neurologic symptoms including failure to thrive, hypotonia, generlized seizure and others. Signs of Addison’s disease. Hepatomegaly and liver dysfunction, stippled calcification. Die within the first few months of live.Gross:CNS- neuronal migration disorder:Zellweger

syndrome, neonatal adrenoleukodystrophy (N-ALD), and infantile Refsum’s disease constitute a disease continuum of peroxisomal disorders.

Pachymicrogyria which is a combination of excessively numerous gyri that are too small as well as too broad.

Neuronal heterotopia. Dysplastic dentate and olivary nuclei.

Other organs: Kidney: cystic changes.Liver: Variable pathology. Usually a progressive fibrosis leading to a

micronodular cirrhosis.Muscle: morphologically normal but with very low succinate dehydrogenase activity.

Histology:CNS pathology:

Striated and globose PAS (+) macrophages in gray and white matter. White matter with dysmyelination. Reactive gliosis. EM: Electron-opaque membranous cytoplasmic bodies.

X-linked adrenoleukodystrophy (X-ALD) Top of the chapter

Characteristic: A progressive childhood onset X-linked recessive peroxisomal disease with combined

involvement of the CNS and adrenal glands. This is a group II disorder resulted from deficiency of the ALD-protein.

Age: Onset is most common in between 4 to 8 years of age, adult cases (adrenomyeloneuropathy) are uncommon.

Clinical features: Cortical disturbance of visual and hearing function. Gait disturbance and decrease in cognition. Signs of Addison’s disease. Death usually occurs in a few month to a few years.

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Biochemistry: Failure to form coenzyme A derivatives from long chain (> 22 carbon) fatty acid leading to widespread accumulation of very long chain fatty acid.

Molecular pathology: ALD gene: The ALD gene is located on chromsome Xq28 that encodes an ATP-binding cassette

transpoter. It is 21 - 26 kB in length and generate a mRNA of 3.7 - 4.3 Kb that yield a protein of 745-750 amino acids (ALD protein).

Mutations: A large number of mutations have been found, about half (54%)of them are missense mutations, half of the remaining half (25%) are frameshift mutation, the rest are nonsense (10%) and large deletions (7%). A mutation hotspot is identified on exon 5.

ALD-protein: ALD gene expression is highest in adrenal glands, intermediate in brain, and almost undectable in liver. ALDP is highly expressed in microglia, astrocytes, and endothelial cells; oligodendrocytes have little to none.

Gross: Caudorostral progression of lesion. Pathologic changes are bilateral and symmetrical, often extends across the corpus callosum. The frontal lobe is usually less affected. The white matter is gray and firm. Small and atrophic adrenal glands.

Lysosomal storage diseases Top of the chapter

General: Functions of lysosomes: The lysosome is the organelle that hydrolyses a large number of

complex molecules. Pathogenesis: Most but not all lysosomal diseases are due to a genetic defect of one of the

lysosomal enzymes involved in the degradation of a specific substance. Storage material: Such defect will lead to abnormal accumulation of the non-degraded

substance. Genetics: All known lysomal diseases are inherited as recessive traits, mostly autosomal

recessive. Two major classes: Lysosomal diseases affecting the CNS can basically divided into

sphingolipidoses and mucopolyasccharidoses. Classification: Two major types.

Sphingolipidoses

Gangliosidoses Gaucher disease Niemann-Pick disease Fabry’s disease Farber disease

Metachromatic leukodystrophy Mucosulfatidosis

Globoid cell leukodystrophy (Krabbe disease) Mucopolysaccharidoses (MPS)

Hurler (MPS IH) Scheie disease (MPS IS or V) Hunter (MPS II)Sanfilippo (MPS III)Morquio (MPS IV) Maroteaux-Lamy (MPS VI) Sly (MPS VII)

Globoid cell leukodystrophy (Krabbe disease) Top of the chapter

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Characteristic: Also known as galactosylceramide lipidosis. It is an autosomal recessive disorder due to reduced lysosomal galactocerebroside b-galactosidase activity. It affects both the CNS and PNS.

Biochemistry: Reduced enzymatic activity and decreased ability to degrade galactocerebroside that is found almost exclusively in myelin.

Genetics: Autosomal recessive.Clinical features:

Variants: Infantile form (most common), infantile/early childhood form, juvenile form. Infantile form presents with irritability and progressive stiffness (irratible-hypertonic presentation).

Followed by mental and motor deterioration. Usually die within the 1st and 2nd year of life.Gross:

Atrophy of both cerebrum and cerebellum. The brain is small and (600-800 grams). “Iron fist in a velvet glove”: The white matter is rubbery and covered by a cortex of normal

consistency. The subcortical arcuate fibers are typically spared.The ventricles are dilated.

Histology: Gray matter is relatively unaffected. Loss of myelin with sparing of subcortical arcuate fibers. Epithelioid cells/ globoid cells up to 100 mm in diameter and contain PAS (+) material. Epithelioid cells/ globoid cells around blood vessels. Reduction in myelinated fibers and segmental demyelination in PNS.

Electron microscopy: Curved hollow tubular structures of moderate electron density. Right-handed twisted tubules.

Mitochondrial disorders ? Top of the chapter

Diversity: The clinicopathologic features of mitochondrial diseases are very diversified. The reason of diversity is resulted from:

Genetics: mitochondrial vs. nuclear DNA Point mutation vs. deletion Dosage effect Distribution of abnormal mitochondria Mitochondrial function being affected

Classification: It is therefore inappropriate to classify mitochondrial disease based simply on genetics, enzymology, or clinicopathologic features.

Elevated lactate level: Often but not always.Manifestation: The muscle and the CNS are most affected.

Common pattern of presentation: Muscle and brain (MERRF syndrome type): Combinations of ataxia, seizures, and

myoclonus.Brain predominant (MELAS syndrome type): recurrent small strokes, migraine, and the unusual type of seizures.Visual and polyneuropathy: Ophthalmoplegic retinitis pigmentosa with polyneuropath, optic atrophy (Leber type), or deafness (Kearns-Sayre syndrome)

Some of the recognized entities: Myopathy, encephalopathy, lactic-acidosis, and stroke like episodes (MELAS)Myoclonus

epilepsy, ragged-red fibers (MERRF)Leigh's disease (subacute necrotizing

encephalomyelopathy) Kearns-Sayre syndrome (KSS)•Ragged red fibers polymyopathy (RRFP)Congenital lactic acidosis and recurrent ketoacidosis (CLARK)Leber's hereditary optic neuropathy (LHON)Neuropathy, ataxia, and retinitis pigmentosa (NARP)Chronic progressive external ophthalmoplegia (CPEO)Myoneurogastrointestinal encephalopathy (MNGIE)Luft syndrome

Mitochondrial myopathy, encephalopathy, lactic-acidosis, and stroke-like episodes (MELAS) Top of the chapter

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Characteristic: Myopathy, encephalopathy, lactic-acidosis, and stroke-like episodes (MELAS) is a multisystem disease associated with abnormal mitochondrial functions.

Age: Childhood onset is most common.Genetics: Point mutations of tRNALeu gene in mit-DNA.Clinical features:

Periodic stroke with seizures and progressive encephalopathy leading to dementia. Patients with full expression often die before 20 years old. Hearing loss is a common onset symptom. Stunt growth (short stature). Cortical blindness and hemianopia may also be seen. There is also exercise intolerance and episodic lactic acidosis.

Gross pathology: Small and atrophic brain with multiple and predominantly coritcal infarctions. The distribution does not follows the vascular territory CNS Histology: Stroke at different stages of evolution. Neuronal loss, mineralized neurons, and reactive gliosis.

Muscle Histology: Ragged red fibers and subsarcolemmal accumulations that are reactive for succinate dehydrogenase.

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Chapter 5

Demyelinating Diseases Table of Content

Overview Multiple Sclerosis (MS) Variants of multiple sclerosis (MS) Acute Disseminated Encephalomyelitis (ADEM) Acute Hemorrhagic Leukoencephalopathy (ALH) Central Pontine Myelinolysis (CPM)

Overview ? Top of the chapter

Incidence: Demyelinating diseases, particularly multiple sclerosis, are common.Demyelination: Loss of normal myelin that has already been formed.Dysmyelination: Failure to form normal myelin or maintain normal myelination as in leukodystrophies.

Classifications:

Primary demyelinating diseases (without known or associated etiology)

Multiple sclerosis Inflammatory demyelinating pseudotumor

Secondary demyelinating diseases (with known or associated etiology)

Central pontine myelinolysis Acute disseminated perivenous encephalomyelitis (acute perivascular myelinoclasis)Classic

(parainfectious; postimmunization; idiopathic)Hyperacute (acute hemorrhagic leukoencephalitis)Progressive multifocal leukodystrophy.

Tabes dorsalisLyme disease, 3rd stage LeptospirosisOthers

Multiple Sclerosis (MS) Top of the chapter

Characteristic: A chronic, often relapsing, demyelinating disease with onset most commonly seen in young adults.

Age: The mean age of onset is 30 year-old; unusual to have onset in children under 10 year-old.Sex: More common in females, male to female ratio is 1:2 in adults, 1:10 in children.CSF:

Mild to moderate mononuclear pleocytosis (usually <50 cells/mm3) in about 1/3 of the cases.Slight increase in protein level that rare exceeds 100 mg/dL.

Increased gamma globulin (mostly IgG) to the extent that they make up more than 12% of the total protein.Oligoclonal IgG bands.Clinical features: Chronic relapsing disease.

About 10% of the patients continue to progress without remission. Optic neuritis and double vision are very often. Severity of clinical manifestation may not reflect the extent of pathologic change.

Neuroimaging: MRI is the most sensitive method of detection. Periventricular white matter adjacent to the body and the trigones of the lateral ventricle. The plaques are often ovoid and with long axis parallel to the ventricles Enhancement is seen in acute plaques but not chronic plaque.

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Gross pathology: Plaque: Almond to oval lesions that range from a few mm to a few cm. Periventricular, optic nerve, spinal cord as most common locations. Affect predominantly the white matter.

Histology: Affect predominantly the white matter. Often with multiple lesions at different stages of evolution. Perivascular chronic inflammation with loss of myelin. Three stages: acute, subacute, chronic (burnt out) plaque. Reactive gliosis are more prominent in chronic plaques, inflammation is more prominent in acute

plaques.

Variants of Multiple Sclerosis (MS ) Top of the chapter

Attention: I put the information in this section to illustrate the complexity of MS and for your interest. You do not need to memorize the details.

Classic type: Charcot type. Relapsing disease in many patients. Some patients may have only one episode. Some patients may not have remission but continuous progression . Marburg type: Acute multiple sclerosis. This is a highly malignant form the progress to death in a few weeks to a few months without

remission in many cases.

Concentric sclerosis: Baló type. Characteristic concentric rings of demyelination and partial remyelination. May be more common in Asian. Clinically similar to Marburg type and progress to death rapidly.

Diffuse sclerosis: Schilder type. Often seen in children; also seen in adults. Large demyelinating lesions. Often progress to death in 1-2 years.

Neuromyelitis optica: Dévic type. Acute or subacute onset of blindness in one or both eyes preceded or followed within days or

weeks by a transverse or ascending myelitis. The course is frequently rapidly progressive.

May be more common in Asians.Acute Disseminated Encephalomyelitis (ADEM) Top of the chapterCharacteristic: An acute multifocal infalmmatory and demyelinating disease that is often associated with a preceding infectious illness. Association: Parainfectious, post-vaccination, idiopathic.Latency: A few days to up to 3 weeks between the infectious illness and ADEM.Clinical features:Generally no fever and normal peripheral white count if the primary infection has subsided.

CSF with lymphocytic pleocytosis. Acute onset of somnolence, confusion, and often convulsion. May progress to coma in severe

cases. Symptoms and signs often resolve over several weeks. Relapses are very rare.

Mortality: 20% during acute illness.Permenant neurologic deficits in some patients.Gross Pathology:

Swelling and edema; the brain is otherwise free of macroscopic pathologic changes.Histology:

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Multifocal perivenous lymphocytic infiltration. Inflammatory cells extend into surrounding parenchyma. Demyelination with the blood vessels as the epicenters.

Acute Hemorrhagic Leukoencephalopathy (ALH) Top of the chapter

Characteristics: The most fulminant form of demyelinating disease and the patients usually die within days. Age: Mainly young adults, sometimes children.Association:

May be preceded by an infectious illness. Rarely associated with ulcerative colitis and Crohn’s disease, septicemia associated with

immune complex deposition, methanol poisoning and other conditions.Clinical features:

Symptoms and sings are similar to ADEM but far more severe.

Leukocytosis sometimes reaching 30,000 cells/mm3. Elevated erythrocyte sedimentation rate (ESR).

CSF with polymorphonuclear leukocytosis, up to 3000 cells/mm3.Gross Pathology:

The brain is swollen and soft. Predominantly small but occasionally large hemorrhagic foci involving mostly the cerebrum and

cerebellum and white matter in the pons.Histology:

Mixed acute and chronic inflammatory cell infiltration. Rings and balls of hemorrhage: Blood vessels with fibrinoid necrosis rimmed by necrotic tissue

and a larger zone of hemorrhage. Perivascular demyelination.

Central Pontine Myelinolysis (CPM) Top of the chapter

Characteristic: A non-inflammatory, acute, demyelinating disease that typically affects the pons and often associated with hyponatremia in alcoholics.

Clinical Association: The classical association is associated with over rapid correction of hyponatremia in alcoholics. Otherwise, it is most frequently described in patients with Wernicke-Korsakoff syndrome. Non-alcoholic groups of patients can be affected and include with severe liver disease, liver

transplantation, severe burns, malnutrition, anorexia and severe electrolyte disorders and AIDS patients.Clinical presentation: It varies from rapidly evolving spastic paraparesis with pseudobulbar palsy, to changes in mental status with confusion or coma. "Locked-in" syndrome is typical.Gross Pathology: Affects the upper pons. Typically a butterfly or triangular shaped symmetrical midline lesion rimmed by areas with preserved myelination.Histology:No inflammation.

Macrophages are present. Preserved axons; axonal swelling may be present. Viable neurons in affected areas. Transverse (pontocerebellar) fibers are more affected than the rostral-caudal (cortical spinal and

cortical bulbar) fibers.

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Chapter 6Malformation and Structural Abnormalities Table of ContentOverview

Neurotube defects Anencephaly Meningocele and meningomyelocele Encephalocele Tethered cord syndrome Chiari malformations Holoprosencephaly Agenesis of corpus callosum Dandy-Walker syndrome Miller-Dieker Syndrome

Overview: Top of the chapter

General: A macroscopic structural defect is not always due to a malformation. Some of the structural defect

may be resulted from destruction of the precursor and lead to the lost of information for further growth. So the term structural abnormalities are not always resulted from a malformed embrogenesis.

When dealing with malformations and macroscopic structural abnormalities, it is very important to note that almost no two malformed CNS are the same. However, they may be separated into several major categories and pattern as listed here.

Every malformed CNS should therefore be treated as an individual case. It is very important to document clearly the malformation with word and photographs.

In many cases, it is very important to distinguish the primary events from the secondary events; with the same token, it is also important to distinguish malformation from disruption.

Break the complex situation into the smallest definable units. Correlate the structural anomaly with the developmental neuroanatomy.

Only a few classic examples are illustrated here.

Know the difference between these terms:

Association: Occurrence of a nonrandom combination of multiple abnormalities. One of the examples is CHARGE association that includes coloboma, heart disease, atresia choanae, and retarded growth and development. Other associated abnormalities include holoprosencephaly, genital and ear anomalies, tracheoesophageal fistula, facial palsy, micrognathia, cleft lip, cleft palate, omphalocele, and congenital cardiac defects.

Sequence: A pattern of cascade anomalies. In some instances, the constellation of anomalies may be explained by a single, localized aberration in organogenesis (malformation, disruption, or deformation) leading to secondary effects in other organs.

Syndromes: A constellation of congenital anomalies believed to be pathologically related, in contrast to a sequence, cannot be explained on the basis of a single, localized, initiating defect or insult.

Possible mechanisms of malformation at the tissue level: Different mechanisms may be involved in malformation. Some othem are listed here:

Agenesis or aplasia (e.g., agenesis of the corpus callosum) Hyperplasia or hypertrophy (e.g., hemimegaencephaly) Failure to fuse (e.g., anencephaly) Failure to divide (e.g., holoprocenphaly) or canalize (e.g., imperforate anus) Failure to arrange in correct pattern and/or position (e.g., polymicrogyria, lissencephaly) Multiplication of parts(e.g., dimyelia) Heterotopia or ectopia (e.g., glioneuronal heterotopia)

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Neurotube defects: Top of the chapter

General: Two major types: the closed neurotube defect and open neurotube defects. In the closed neurotube defect, the neurotube is closed, some of the examples are

meningomyelocele and meningocele. In the open neurotube defect, the neurotube remains open, some of examples are anencephaly and

myeloschisis. There are some midline defects and malformations that may be closely associated with neurotube

defects but cannot fit strictly into the neurotube defect category. Embryonic consideration in closing of neurotube:

Rostral neuropore closes around 22 days of gestation. Caudal neuropore closes at around 26 days of gestation; the closure occurs at the level of future

somite 31, sacral vertebra 2. Multiple simultaneous fusion sites.

Anencephaly: Top of the chapter

General: Definition: Congenital partial or complete absence of the cranial vault, with the cerebral

hemispheres completely missing or reduced to small masses. Timing: the onset of anencephaly is estimated to be no later than 24 days of gestation. Incidence: Most common congenital malformation of the brain in human fetus. Mechanism: The neurotube fails to close and therefore fail to induce the embryogenesis of the

overlying structures.

Gross pathology: Some of the calvarial bones are present but they are deformed, displaced, and flat. The anterior and middle fossae contain no recognizable tissue except for the trigeminal ganglia and

limited residual cranial nerve II to V. The brain is very soft and is destroyed in utero. Therefore, it is missing at the time of bitth. Frog face due to shallow orbit. Moderate or total absence of ganglion cells in the retina. Hypoplastic optic nerve. The pathology of the spinal cord and vertebral column can be quite variable. Extremely small adrenal gland. Hypoplastic lung. Malformation of pituitary, GI tract and heart. Increased in incidence of diaphragmatic hernia.

M eningocele and meningomyelocele : Top of the chapter

General: Myeloschisis: Cleaved spinal cord resulting from failure of the neural folds to close normally in the

formation of the neural tube, inevitably spina bifida is a sequel. The open neural plate ("open book" neuroplate) is not covered by skin, meninges, or vertebral arch.

Meningomyelocele: Both meninges and spinal cord herniate thorugh a large vertebral defect. The spinal cord or nerve roots are frequently involved in the formation of the wall and the dorsal part of the spinal cord often remains open.

Meningocele: Herniation of the meninges through a defect in the cranium or vertebral column. The spinal cord is not herniated.

Rudimentary (atretic) meningocele or meningomyelocele: The meningocele or meningocele is isolated from the spinal cord and vertebral canal. They usually occur as subcutaneous masses.

Spina bifida: This is the defect of the osseous spine.

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Encephalocele: Top of the chapter

General: Definition: Herniated protrusion of brain substance through a congenital or traumatic opening of the

skull. The brain tissue is covered by skin and soft tissue. Location: 80-90% of the cases are occipital. The next common is parietal. Basal and

frontoethmoidal encephaloceles are rare. Association: Congenital (non-traumatic) encephalocele is associated with many different

malformations, in particular hypoplastic changes of the lung.Pathology:

Gross: Many of the lesions can be seen from external examination. Some smaller midline ones may present as nasal sinus problem and is detected by imaging.

Histology: The brain tissue is disorganized and sometimes atrophic. The connective tissue is often directly adhered to the brain tissue.

Tethered cord syndrome : Top of the chapter

Etiology: Terminal fixation of the conus medullaris leading to restricted upward movement of spinal cord.

Multiple mechanisms can lead to this situation. The more common ones are lipoma, meningocele and meningomyelocele, and trauma.

Clinical: Usually seen in children, may be seen in adult. Tethering of the spinal cord results in progressive neurologic impairment as a result of recurrent

minor traction injuries. Dermatologic signs such as hairy patch skin dimple or sinus, capillary hemangioma or atrophic skin

may be found in the lumbar region. May be associated with other abnormalities such as VATER association.

Pathology: The site of attachment is often consisted of a fibrofaty mass with or without neurological tissue or

other tissues. Pathogenesis may be related to incomplete separation of neural from mesodermal components.

Some of them are related to other pathologic changes such as meningocele and meningomyelocele.

C hiari Malformations : Top of the chapter

Chiari I malformation: Conical elongations of the tonsils and neighboring parts of the cerebellar hemispheres extend into

the vertebral canal (i.e., below the foramen of magnum). Chiari II malformation:

Summary: One of the most common malformations in children. Displacement of the cerebellar vermis combined with deformities of the brainstem and typically associated with a spinal defect.

Cerebral hemisphere: Progressive hydrocephalus. Cerebellum: The herniated cerebellar vermis and the adjacent tissue that varies from short to long. Brain stem: Malformed. Spinal cord and vertebral column: The pathology varies from complete rachischisis to a

meningomyelocele (most common in lumbar-saral region). Other spinal malformations may occur. Others: Nerve roots cranial nerve symptoms. Arnold-Chiari Syndrome: Chiari type II malformation associated with meningocele.

Chiari III malformation: Encephalocele formed by herniation of the structures of the posterior fossa, including the cerebellum,

through an occipitocervical or high cervical bony defect. There may also be malformation of the brain stem and spinal bifida.

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H oloprosencephaly : Top of the chapter

General: Definition: A median holosphere with a single ventricular cavity instead of two hemispheres with

symmetrical lateral ventricles. The cardinal features include a single telencephalic ventricle and continuity of the cerebral hemisphere across the midline and associated with different degree of craniofacial malformations.

Mechanism: This is a developmental failure of cleavage of the proencephalon with, and sometimes without, a deficit in midline facial development. Holoprosencephaly is not purely a failure of hemispheric cleavage and other pathologic mechanisms may be involved.

The face predicts the brain: The degree of craniofacial malformation usually correlates with the degree of malformation of the brain. This association is only a general rules and there are many exceptions. It is frequently associated with cyclopia in the severe form; sometimes due to trisomy 13.

Incidence: 48-88/1,000,000 in live born but about 4000/1,000,000 in abortus.Gross pathology:

Graded severity: The malformation is of graded severity with respect to both the brain and the face. Alobar holoprosencephaly (the most severe form): A very small brain with a single cerebrum with

no lobe and no interhemisphere fissure. Semilobar holoprosencephaly: the interhemispheric fissure is present posteriorly but the

frontoparietal lobes are continuous. Lobar holoprsencephaly (the least severe form): The entire interhemispheric fissure is present and

the left and right cerebral hemispheres are completely separated. There is a continuation of gray matter between the left and right hemisphere and only one single hemisphere is found.

Association: Often associated with other malformations of the brain. About 75% of the holoprosencephaly are associated with abnormalities of cardiac, genitourinary, and gastrointestinal development.

Histology: Cortex: Degree of architectural disturbance is proportional to the degree of severity of the

malformation.

A genesis of corpus callosum : Top of the chapter

General: Definition: Agenesis of the corpus callosum should be reserved to the cases when mechanism(s) by

which the axons of the corpus callosum cross the midline in the usual position are absent of deficient (i.e., the agenesis is a primary event but not secondary to other damage or malformation of the neurons or axons up stream to the callosal axons).

Timing: critical event(s) must have happened no later than 9 to 20 weeks of gestation, the peak time of development of corpus callosum.

Clinical features: Agenesis of corpus callosum can be completely asymptomatic in some cases. Some cases are associated with marked ventricular dilatation and a large head. Some cases are assocaiated with a lipoma or hamartoma along the mimdline line.

Gross pathology: Agenesis can be partial or complete. In partial agenesis, the posterior part is usually missing. Probst bundle is present. They are abnormal bundle of fibers running in frontal occipital direction

along the in the lateral part of the roof of the lateral ventricles. They are often associated with other more severe malformations and are also part of other

syndromes such as Arcardi syndrome.

D andy-Walker syndrome : Top of the chapter

Gross pathology: Original description of gross pathology:

1. A cyst-like dilation of the 4th ventricle.

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2. An abnormal cerebellar vermis.3. An elevated tentorium cerebelli, lateral and transverse sinuses, and torcula.4. Lack of patency of the formaina of Magendie and Luschka.5. Enlargement of posterior fossa.6. Hydrocephalus.

No all 6 featrues are seen in all cases. The three most constant gross pathologic changes:

1. An abnormal or agenesis of cerebellar vermis.2. Cystic dilatation of the 4th ventricle. 3. Enlargement of the posterior fossa.

Pathogenesis: Agenesis of the vermis and cystic dilatation of the fourth ventricle may be the two primary

events. Obstruction of the foramina of Magendie and Luschka may not be present in every cases.

Other features may be secondary to the primary events.Genetics: no constant chromosomal abnormalities have been identified.

Prognosis:

Mortality varies from 12.6% to 57%. Mental retardation: IQ of 71% of patients are less than 83 with no significant relationship between

retardation and associated anomalies. Other cerebral and visceral anomalies: it is the presene or absence of other cerebral and viseral

abnormalies that determines the prognosis of individuals. About 68% of all cases have other developmental abnormalities of the CNS. Facial abnormalities may also be seen.

M igration disorders : Top of the chapter

Some terms: Migration disorder: Migration of cells plays an important part in the formation of the mature nervous

system. Disruption of this process will lead to disturbed architecture of cortical lamination and other malformation at the microscopic level. Such disorganization is often transformed into polymicrogyria and lissencephaly in macroscopic terms.

Lissencephaly: It means "smooth brain", the brain has very few or no gyri. The morphology of lissencephaly came in many different forms. The distribution of the lissencephaic or pachygyric parts is also an important clue for diagnosis.

Pachygyria: Broadening of the gyrus. Pachygyria denote macroscopical abnormalities of the cortical surface associated microscopically with a thickened cortical ribbon. The cortical ribbon is usually greatly thickened and the underlying white matter is markedly reduced. When the area being involved is large, it may be called agyria which has the same meaning of lissencephaly.

Polymicrogyria: Literally this term means too many gyri that are too small. Cortex with simply too many gyri that are too small are not justified for this term. Fusion of molecular layer is an important feature and is almost always present in polymicrogyria. Microscopically, the normal 6 layer architecture is also disturbed.

M iller-Dieker Syndrome : Top of the chapter

General: Miller-Dieker syndrome is a migration disorder characterized by lissencephaly. It is related to the

PAFAH1B1 on chromosome. The pathogenesis is resulted from abnormal migration of neurons which resulted in lissencpehaly

and other abnormalities in the brainstem and cerebellum.Clinical features:

Usually die in the first two years of life. The infants are often severely spastic, with infantile spasm, and profound mental retardation. Characteristic facial dysmorphism.

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Genetics: Deletion or translocation of chromosome 17p13.3 is the salient feature but Miller-Dieker

syndrome is a continuous gene syndrome and probably involves deletion of more than one gene. The critical gene is PAFAH1B1 (-subunit of platelet activating factor acetylhydrolase brain isoform

Ib; formerly known as lissencephaly-1 or LIS1).Gross pathology:

Abnormal architecture: The spectrum varies from diffuse agyria to frontal pachygyria with parietooccipital agyria to diffuse pachygyria. Typically the posterior part of the brain is more affected.

Large ventricles, and sometimes, ventricular heteropia are also seen.Histology:

The cerebral cortex show abnormal architecthre. The normal six layer architecture is replaced by abnormal lamination.

The inferior olivary nuclei are poorly convoluted, and heterotopic remnants of these nuclei lie in the migrator track of these nuclei from the rhombic lip whtere the young olivary neurons are generated.

Cerebellum may show mild dysplasia, subcortical Purkinje cell heterotopias, and Purkinje cell lost.

Tuberous sclerosis: Top of the chapter

General: Systemic disease: Tuberous sclerosis is a systemic disease with the brain as the most frequently

affected organ. Other organs including the skin, eye, kidney, heart, bone, and other organs are involved.

Classic clinical triad: Clinically it is characterized by seizures, mental retardation and adenoma sebaceum.

Pathologically, there is cortical tuber, subependymal nodules and subependymal giant cell astrocytoma (SEGA).

Prevalence: 1:6,000-10,000 in adult population.Genetics:

Autosomal dominant with very high penetrance. Occurrence of affected siblings with apparently unaffected parents is extremely rare.

TSC1 gene on chromosome 9q34 (gene product is hamartin) and TSC2 gene (gene product is tuberin) on chromosome 16p13.3 are involved. Sporadic cases were first thought of resulted from mutation but CT scans of asymptomatic family members revealed a significant numbers with abnormalities.

Clinical: Triad: Seizures, mental retardation and adenoma sebaceum (facial angiofibroma). Only about 1/3

of the patients express the entire triad. The patients may also have behavioural problems such as hyperactivity.

Seizures usually manifest in the first few months of life but adenoma sebacum will not appear until about 2 years of age and this will make the diagnosis difficult.

Pathology: Cortical tubers: Normal cortical architecture is effaced by collections of large bizarre cells.

These bizarre looking cells have amphophilic to slighly eosinophilic homogenous cytoplasm and well-defined cytoplasmic border. The cortuber are often associated with gliosis. In older individuals myelin staining stops abruptly like a flat plate beneath the abnormal cortex, while the gyral core is depleted of myelin and gliotic. Cortical tubers do not transform into neoplasm.

Subependymal hamartomas: These are small subependymal nodules that protrude into the ventricles. These nodules are covered by a thin ependyma and are composed elongated or markedly swollen glial cells that have features similar to the large bizarre cells in the cortical tubers.

Subependymal giant cell astrocytoma (SEGA): Subependymal hamartomas may transform into subependymal giant cell astrocytoma (SEGA). The histologic distinction between the two entities is not clear. SEGA are often found at the foramen of Monro can be highly calcified. Patients with hamartomas are followed up by imaging. Signs indicative of neoplastic transformation include increase in size and enhancement.

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Chapter 7

Vascular DisordersTable of Content

Overview Hypoxic/ischemic changes and infarction Infarction Strokes and infarcts Aneurysm Other aneurysm Arteriovenous malformation Aneurysmal malformation of the great vein of Galen Hypertensive brain hemorrhage Cerebral amyloid angiopathy

Overview: Top of the chapter

General: There is a supply and demand relationship between blood supply and tissue metabolism. Inadequate vascular supply or increased demand can both tip this relationship. The best examples

for inadequate vascular supply are atherosclerosis and embolism (focal) and hypotension and shock (systemic). The best examples for pathologic increase in demand (in efficient use in fuel and oxygen) are mitochondrial disorders (inefficiency in using oxygen) and glycogenosis/glycogen storage diseases (inefficiency in using fuel).

Not all tissues in the nervous system have the same metabolic rate. In general, tissues with high inherent metabolic rate are more likely to sustain hypoxic/ischemic damage. This variation is also age dependent.

Blood vessels share many similarities with the hose in your garden or backyard. Problem usually arise when there is abnormalities in the flowing fluid (emboli in blood vessels vs. tree leaves in a garden hose), leakage due to breakdown of the wall (eg. amyloid angiopathy), obstruction (e.g., atherosclerosis), ballooning due to local thining (e.g., aneurysm), obstruction due to compression (e.g., you lovely little brother is standing on the hose).

H ypoxic/ischemic changes : Top of the chapter

General: Ischemia refers to the insufficiency of blood supply. It can be focal or global.

DemandSupply

Circulating bloodOxygen

Fuel (Fat, glycogen, glucose)

Inherent metabolic ratePathologic increase in

metabolic demand

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Hypoxia refers to the reduced supply of oxygen while the blood flow is entirely normal or even increased.

The term ischemia and hypoxia are used interchangeably but they do not carry the exact same meaning.

The pathologic changes that they would have produced are very similar at the cellular level but the topographic distribution is not exactly the same. A combination of ischemia and hypoxia is quite common in many pathologic processes. In reality, it is quite impossible to separate ischemic from hypoxic injury at the histologic level.

Some neurons are more susceptible to ischemic/hypoxic injury than the others. In general, the larger the neuron the higher risk for ischemic hypoxic injury. The most notable example is the pyramidal neurons in the CA1 region of the hippocampus and subiculum. In contrast, the pyramidal neurons in the CA2 areas are quite resistant to ischemic/hypoxic changes. In the cerebral cortex, neurons of lamina III and V are more susceptible than the other neurons in the cortex. Purkinje cells and neurons of the dentate nuclei in the cerebellum are also very susceptible to hypoxic/ischemic injury.

Depending on the extent and severity of damage, hypoxic/ischemic damage may produce only microscopic finding (neuronal loss and gliosis) or small lesions in the brain (such as laminar necrosis) or large area of damage (such as bilateral watershed area infarction and multicystic encephalopathy).

Histopathology: Time sequence of neuronal ischemic death:

1. Minutes to a few hours: Microvacuolation will appear and then regresses.2. 6-24 hours: Shrinkage of the neuronal contour and the cytoplasm will turn eosinophilic. This

is classically believed to be the “point of no return” for irreversible damage.3. 24-72 hours: Small dense fragments of neuronal cytoplasm flakes from denderites, also

known as the incrustation phase.4. 24 hours to days: Homogenizing cell damage characterized by complete loss of

cytoplasmic details, nucleus disintegrates and pooly stained by hematoxylin. Time sequence of glial, microglial, and vascular reaction to ischemic injury:

1. If astrocytes survive, they react by swelling (12 to 36 hours) and multiplying (48 hours to months, leading to gliosis).

2. Polymorphonuclear leukocytes invade within hours, peaking at 48 to 72 hours and then regress.

3. Small blood vessels are prominent by 48 hours and vascular proliferation ensure. The proliferation is particularly prominent at interphase between the necrotic and viable tissue.

4. Macrophages appear within 48 hours and exhibit neurophagy (consumption of necrotic neurons). Their infiltration will peak at about 14 days. Macrophages can persist in the lesion for months to years.

I nfarction : Top of the chapter

Some terms: Stroke: The clinical term “stroke” describes a syndrome of rapidly evolving or sudden onset, non-

epileptic, neurologic deficit that lasts more than 24 hours. By convention, stroke has come to mean either brain infarction or hemorrhage.

Transient ischemic attack (TIA): TIA lasts less than 24 hours. A patient with a history of TIA has a high risk of developing a stroke.

Strokes are not limited to adults. It can occur in baby and is more common than you have expected. Infarction: An infarct is defined as a region of brain tissue in which all cellular elements undergo

necrosis (cell death), usually as the result of a cessation of flow of oxygenated blood to the region. Therefore, at the moment of the insult that leads to death of tissue the damage is completed. Unless an additional insult occurs, the process is not an ongoing process. The subsequent cellular events are secondary to the insult and are essentially the clean up process.

Acute infarction: This is the earliest phase that is immediately after the insult.

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Resolving infarction: This is the phase of cellular reaction for clean up. This phase is often known as subacute infarct. The term “subacute” is really inappropriate since there is no more infaction going on but the healing process. During this phase, there is substantial infiltration of macrophages to clean up the necrotic tissue.

Resolved infaction: As the macrophages clean up most of the necrotic tissue, a cavitary space will be left and is lined by gliotic tissue, the so called liquefactive necrosis.

Etiology: Common:

1. Large vessel or microvascular (arterial) disease such as thrombosis and obliteration due to atherosclerosis. Small vessel or microvascular (arterial) disease such as lacunar infarcts in hypertension.

2. Emboli, septic or non-septic. Aspergillosus has a high tendency to invade blood vessel and lead thrombosis and infarction.

3. Coagulopathy with increased risk for thrombus formation.4. Venous thrombosis.

Uncommon1. Vasculitis.2. Dissecting aneurysm.3. Amyloid angiopathy (more likely to cause hemorrhage).4. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephaly

(CADISIL)5. Malignancy

Gross pathology: The gross pathology simply reflects what happened at the histologic level. The

pathologic changes, however, is limited to the region being affected. Incase of global ischemia, these changes will be widespread.

When the major vessels of the brain are involved, the distribution of infracted tissue will follow a particular vascular territory.

The sequences of macroscopic changes are as follows and basically reflect the histologic changes:

1. At around 0-12 hours, there may not be much visual changes. 2. From 12-48 hours definite swelling and the tissue start to turn friable. Softening tends to

precede visual clues and it is important to examine an autopsy brain by palpation. Visually, there is discoloration and blurring of gray white junction.

3. Tissues are definitely friable by 72 hours due to tissue breakdown by polymorphonuclear leukocytes.

4. From 3 to 5 days, cerebral edema is maximal. The degree of edema is proportional to the volume of infracted tissue. Herniation may occur.

5. From days to weeks, the swelling subsides. Liquefaction of necrotic tissue results from the actions of macrophages takes days to weeks.

6. After all the necrotic debris is cleaned up, an empty, cystic space lined by gliotic tissue and traversed by delicate glial strands will result. Compensatory asymmetrical ventricular enlargement may be seen.

S trokes and infarcts : Top of the chapter

Hemorrhagic infarct: It is far more common for an infarct to be non-hemorrhagic at the early phase. Many hemorrhages

occur about three days later when the polymorphonuclear leukocytes infiltrate the brain and tissue breakdown starts (reperfusion hemorrhage). Rarely, hemorrhage due to rupture of a blood vessel may be the primary cause of a hemorrhagic infarct.

Atherosclerotic strokes:

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Atherosclerotic strokes result from dislodgement and embolizationof platelet-fibrin material, or occlusive thrombosis of the atherosclerotic artery.

The thrombus often originates extracranially and extends into the brain. Less commonly, an intracranial atherosclerotic plaque is the primary site of thrombosis.

Lacunar infarcts: They are resulted from processes leading to narrowing of deep basal perforating arterioles rather

than the large arteries and their distal branches. Lacunar infarcts range in sized from a few millimeters to a maxium of 1.5 cm. They are most common in the basal ganglia and surrounding white matter, and in the pons. Most commonly, they are associated with hypertension and are often asymptomaticm because of

their small size and location in the basal ganglia and pons. However, when a small lacunar infarct occurs in a strategic location, such as in a location that involve cortical spinal tract, the clinical manifestations will be disproportion to the size of the infarction.

Venous thrombosis and infarction: Prognosis: If not treated rapidly, the mortality is high. Mechanism: The mechanism is different from arterial infarction. In essence, there is thrombosis in

the vein that blocks the outflow of blood leading to ischemic changes. Coagulopathy plays an important role in forming the venous thrombosis that leads to infarction.

Age: It can occur in all ages including children. Distribution: The brain has very good venous collaterals. Therefore, thrombosis must usually be

fairly extnesive before an infarction can be resulted. Common sites are superior sagittal sinus (72%), lateral sinuses (70% combined), and straight sinus (13%). Thrombosis commonly extends to several sinuses and veins.

Etiology: Some of the thrombi are caused by an inherent coagulopathy. Others are secondary to certain clinical situations. The more common ones are use of oral contraceptives and pregnancy in woman in reproductive ages. Dehydration and nephrotic syndrome also play an important role in pediatric cases.

B erry (saccular) aneurysm : Top of the chapter

General: Key pathology: Defects of arterial media with dilatation and thin ballooning of vessel wall. Location: Usually located at proximal bifurcations. Distribution: 90% are in the proximal carotid distribution (1/3 at internal carotid artery termination,

1/3 on anterior communicating artery or anterior cerebral artery, 1/3 at first main branch of middle cerebral artery.

Incidence: 1-6% in large autopsy series. 0.5 -1% in adults undergoing cerebral angiography. Multiple aneurysms are seen in 20-30% (depending on different studies) of cases, they are mostly seen in the middle cerebral artery.

Clinical presentation: Aneurysm usually present clinically by rupturing. The classic sign is abrupt onset unbearable headache.

Clinical consequence: Ruptured aneurysm comprised about 80% of all non-traumatic subarachnoid hemorrhage. Hemorrhage may lead to ventricular dilataion and arterial spasm. The arterial spasm may lead to secondary stroke.

Age: The mean age of presentation is 50 years. Very uncommon in children. Overall mortality: 50-65%. Associated conditions: Increased incidence in patients with connective tissue or blood flow

disorders such as autosomal dominant polycystic kidney disease (5-10% of asymptomatic adults with autosomal dominant polycystic kidney disease have saccular intracranial aneurysms), cerebral arteriovenous malformations, moyamoya disease, and coarctation of aorta, fibromuscular dysplasia, Ehlers-Danos syndrome type IV and type VI, neurofibromatosis type 1, and Marfan's syndrome.

Hypertension is considered an important factor in the formation of berry aneurysms. Risk of rupture: Increases with size of aneuyrysm (7-8 mm is critical). However, aneurysms over 10

mm in diameter are far less likely to rupture. Giant aneyrysm (about 5% of berry aneurysm) are defined as those greater than 2.5 cm in diameter. Giant aneyrusm may have thrombus formation.

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Cocaine: Use of cocaine will induce very high blood pressure and may lead to rupture of aneurysm.

O ther aneurysms : Top of the chapter

Mycotic aneurysm: Resulted from bacterial and fungal infection in the walls of the vessel. Often a complications of endocarditis. Often multifocal. Usually occur at locations distals to berry aneurysms.

Atherosclerotic fusiform aneurysms: Most frequently seen in and the the supraclinoid segment of the internal carotid artery with or without

extension into the middle cerebral artery, followed by the basilar artery (which may show an S-shaped distortion).

They may compress the adjacent brain structures. Transient ischemic attacks or infarctions can be produced by small emboli originating in the walls of

the aneurysm, thrombosis, or atherosclerotic obstruction. Infarction, due to the involvement of the paramedian penetrating arteries or emboli, in the cerebellum and brain stem are also seen. Hemorrhage may also occur.

A rteriovenous malformation (AVM) : Top of the chapter

Prevalence: 0.1% of the general population. Ruptured AVM are responsible for about 1% of stroke. It is a very

common cause of spontaneous hemorrhage in young adults and has a markedly increased tendency to rupture in young cocaine users.

Clinical presentation: Bleeding from an AVM, especially after cocaine use, is still the most common cause of intrcranial

hemorrhage in young patients. Seizure may also occur but deep AVM in the basal ganglia or thalamus is less likely to cause seizure.

Age: Usually present before 40 years of age.

Pathophysiology: An AVM is a complex tangle of abnormal arteries and veins linked by one or more fistulas that allow

high-flow, rapid arteriovenous shunting, thereby inducing arterial hypotension in vessels feeding the arteriovenous malformation and neighbouting areas of the brain.

Gross Pathology: AVM are often large, wedge shaped mass on the cortical surface. Angiogram may show feeding

arteries.Histopathology:

Large caliber channels having both arterial and venous features. These vessels may be separated by some gliotic brain parenchyma. There are no intervening capillaries.

A neurysmal malformation of the great vein of Galen : Top of the chapter

General: Systemic effects: In contrast to other vascular disorder of the brain, aneurismal malformation of the

great vein of Galen causes high output cardiac failure. They do not rupture often. Their secondary effects, however, play a more important role then the malformationitself.

This is not a true aneurysm but a consortium of congenital vascular malformations of the neonate that all share dilatation of the vein of Galen as a common feature.

Abnormal communication: It is resulted from abnormal communication between one or several cerebral arteries and the vein of Galen. Such abnormal commuication can be deep-seated arteriovenous malformation, an arteriovenous fistula, or a verix.

Poor prognosis: The mortality is very high.The baby often dies of cardiac failure. Embolization appears to show some promise.

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Gross pathology: Dilated blood vessel, progressive hydrocephalus due to compression of aqueduct, widespread

damage of the brain including infarction and calcification. Hemorrhage can occur but not common.

H ypertensive brain hemorrhage : Top of the chapter

General: Systemic: May be associated with a documented history of hypertension and related visceral

complications particularly those from the kidney, heart, and retina. Incidence: About 5-10 times less common then cerebral infarction. Symptoms and signs: Depends on the site of hemorrhage but usually include a severe headache.

Hemorrhage at different locations may cause more specific focal signs (such as hemiparesis when hemorrhage occurs in the internal capsule).

Pathogenesis: Replacement of smooth muscle by fibrocollagenous tissue. Fragmentation of elastic tissue. Charcot-Bouchard microaneurysm formation, particularly in the basal ganglia and pons. They

occur on small arteries 100-300 microns in diameter and are seen as outpouchings of the vessel walls, often partly filled by thrombus. The aneurysms are often seen at branches of vessels and were multiple on some arteries.

Gross pathology: The most common site is basal ganglia. Small petechial areas or golden yellow spots corresponding to hemosiderin deposition due to prior

hemorrhage can be seen.Histopathology:

The changes reactive to the hemorrhage are similar to other parts of the body. In acute stages, there is fresh blood clot. Then macrophages will infiltrate and clean up the blood. Hemosiderin deposition and gliosis is common in sites with prior hemorrhage.

Hyalinized change and sclerotic, concentric thickening of blood vessels. Fibrinoid necrosis of vessel wall in malignant hypertension.

Cerebral amyloid angiopathy : Top of the chapter

General: Cerebral amyloid angiopathy (CAA) is a very common cause of intracerebral hemorrhage, perhaps

only second to hypertensive intracerebral hemorrhage in frequency. They are usually seen in normotensive adults over 60 years of age. They are almost always cerebral. Hemorhages due to CAA tend to be superficially located and have

a distribution distinctly different from those resulted from hypertension. The amyloid can be detected by Congo red, thioflavin S, and immunostaining.

The commonest form is due to deposition of A peptide in the blood vessels, the two known heditary types (Icelandic and Dutch types) are transmitted in an autosomal dominant fashion.

Gross pathology: Superficial: They tend to be more superficial and, in rare occasions, they may be subarachnoid. For

the larger hemorrhagee, if is often difficult to tell if they have a superficial origin or not. Location: Typically not seen in area that hypertensive hemorrhage is common. Multiple: On autopsy, there are often evidnce of hemorrhage at different stages of resorption in the

same brain. Distribution: They are almost always cerebral; the brainstem and cerebellum is seldom affected.

They have a distribution that is different from that of hypertensive intracerebral hemorrhage; deep structures are not usually affected. In addition, they do not rupture into the ventricle as often as does hypertensive intracerebral hemorrhage.

Histopathology: Heterogeneous: Usually, a spectrum of different stage of hemorrhage can be seen in multiple

areas.

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Deposition of amyloid in the vessel wall.

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Chapter 8

Neurodegenerative Disorders Table of Content

Overview Inclusion bodies and extracellular deposition Cortical degeneration Alzheimer’s disease Frontotemporal dementia Pick’s disease Basal ganglia degeneration Parkinson’s disease Huntington’s disease Trinucleotide diseases Amyotrophic lateral sclerosis (ALS)

O verview : Top of the chapter

Introductions: Neurodegenerative disorders must be distinguished from normal aging. The neurodegenerative disorders are characterized by loss of functionally related groups of neurons

anatomically. Clinical manifestations reflect the functional loss which can be correlated anatomically in many situations. The following is a brief correlation of symptoms to lost of specific neuronal populations:

1. Cortical neurons: Dementia2. Basal ganglia neurons: Movement disorder3. Cerebellar neurons: Ataxia4. Motor neurons: Weakness

The etiology is not clear but current attention has been paid to chronic cellular injury, neurotoxin, stress at the cellular level, cellular injury from excitoxicity, damage due to free radicals.

Trinucleotide repeats: Some of the neurodegenerative are genetically transmitted. Expansion of trinucleotide repeats in the gene involved is identified in these disorders (e.g., Hungtington’s disease, Kennedy’s disease; both associated with abnormal expansion of CAG repeats in exons).

Three major function of the CNS: cognition and affect, motor, autonomic function. Clinically, neurodegenerative diseases usually manifest as disturbance of one of these three

functions or in combinations as their chief manifestation. Examples are as follows:1. Alzheimer’s disease: Cognition2. Frontotemporal dementia: language skill and frontal lobe symptoms.3. Parkinson’s disease: Motor4. Amyotrophic lateral sclerosis (motor neuron disease): Motor5. Diffuse Lewy body disease: Motor and cognition.6. Multiple system atrophy: Autonomic dysfunction (including orthostgatic hyoptention,

impotance) and other dysfunctions such as Parkinsonism. Job of the pathologist: The job of the pathologist is to classify dementia and

neurodegenerative but not to diagnose neurodegenerative disease. For example, dementia is a functional state. No body can diagnose dementia in a dead body. Anatomical changes for Alzheimer’s disease, however, can be recognized through pathologic examination.

I nclusion bodies : Top of the chapter

General: Inclusion bodies are morphologically well defined bodies that can occur in the cytoplasm and

nucleus.

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Association: There is an interesting association between inclusion bodies and neurodegenerative diseases. They represent some of the earliest described histologic features of some neurodegenerative disorders. In particular, cytoplasmic inclusions are common in neurodegenerative disorders.

Nature: These inclusion bodies are more likely to be markers of cytologic stress and are composed of deranged cytoskeletal protein and hear shock proteins. The biochemical compositions of some of these inclusions are known. However, their relationship to neurodegenerative disorders and their biological effects are not certain.

Examples: Neurofibrillary tangles: Alzheimer’s disease. Lewy body: Parkinson’s disease. Picks body: Pick’s disease. Globose tangle: Progressive supranuclear palpsy (PSP)

C ortical degeneration : Top of the chapter

General: Neurodegenerative degenerative disorders characterized by cortical degeneration share the clinical

feature of deterioration of higher cortical function. Definition (from Ellison and Love): Dementia can be defined as an impairment of previously

attained occupational or social functioning due to an acquired and persistent impairment of memory associated with an impairment of intellectual function in one or more of the following domains- language, visuospatial skills, emotion, personality, or cognition- in the presence of normal consciousness.

Dementia, loss of previously acquired intellectual skills and information, is perhaps the most commonly seen clinical manifestations. The classical example is Alzheimer’s disease. Dementia is now recognized as a neurological disease regardless of age. The term “senile dementia” and “pre-senile dementia” are not appropriate.

Progressive changes in behavior and gradual loss of language skills (frontotemporal dementia) are more commonly seen in the family of frontotemporal dementia with Pick’s disease as one of the prototype.

Association: Cortical degeneration may be combined with degeneration of other neuronal groups such as those in the basal ganglia. In these cases, a combination of deterioration in cognition and motor function will occur. One of the best examples is Parkinson’s disease combined with Alzheimer disease type changes.

A lzheimer’s disease : Top of the chapter

General: Diagnosis: Alzheimer’s disease is a clinical-pathologic diagnosis. The history of dementia must be

present for the pathologist to make a diagnosis of Alzheimer’s disease. Mechanism: Neuronal loss and destruction of neuronal connection. Incidence: The most common cause of dementia. Age: The age of onset of recognizable decline in interlectual ability is quite variable. In most cases,

deterioration starts after 60 years of age. However, early onset at the 4th to 5th decade can occur and are particularly common among familial cases.

Down’s syndrome: Patients that are over 40 years old invariably develop Alzheimer’s disease, both clinically and pathologically.

Clinical: Patients undergo steadily progressive intellectual deterioration, particularly memory loss and failure

to build new memory, without remission or plateau periods. The patients recognize their own defects at the beginning and get frustrated. In the terminal stage of the disease, the patient is generally bedridden and unable to attend to even

the most fundamental bodily processes, intellectual, and motor functions.

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Death generally occurs in 3 to 12 years. The level of care plays a critical role on the length of survival.

Genetics: Familialy history: A positive history is present in about 15% of patients. APP (amyloid precursor protein): Some mutations on amyloid precursor protein (APP) gene on

chromosome 21 are associated with about 10% of familial early-onset AD. Presenilin: Mutation on presenilin-1 (PS-1) gene on chromosome 14 and presenilin-2 (PS-2) on

chromosome 1 are found in autosomal dominant familial Alzheimer’s disease. ApoE: Patients with 4/4 has 19-fold increase in risk for developing Alzheimer’s disease, 3/4 is

4.5-fold, 2/3 is 2-fold increase. Very slightly reduced risk in subjects with 2/4.Gross Pathology:

Cerebral hemispheres: There is marked global atrophy, usually symmetrical, especially severe in the frontal and medial temporal regions, the brain may weigh less than 1000 grams. The atrophy is due to reduction in both grey and white matter volume.

Ventricle: Compensatory dilatation of ventricles (hydrocephalus ex vacuo) Lobes: The temporal pole is the most atrophic. The frontal lobe may have more atrophy than the

parietal lobe while the occipital lobe is usually unaffected. Hippocampus: The hippocampi and amygda are very atrophic. The under surface of the brain is

usually spared. In less severe case, there is always some degree of atrophy, especially in the medial temporal lobe.

Olfactory bulb and hypothalamus are atrophic. Locus coeruleus (in the pons) can be pale. The brainstem is otherwise within normal limit on gross

examination. Cerebellum and spinal cord are usually not affected.

Histopahtology: Method: The pathologic changes in Alzheimer’s disease are not obvious with routine hematoxylin-

eosin stain but they are well demonstrated by silver stains such as Bielschowsky stain or Gallya stain and immunohistochemistry.

Quantitative analysis: The presence of pathologic changes does not automatically qualify a diagnosis of Alzheimer’s disease. The amount, distribution, and correlation with age and clinical history must be taken in to account in order to make a diagnosis. A qualitive and semi-quantitative analysis of neurofibrillary tangles and senile plaques is important for the diagnosis.

Neurofibrillary tangles: 1. Histology: These are intracytoplasmic collections of filamentous substance that can be

well demonstrated by silver stains and by immunohistochemistry against tau protein (a high molecular weight microtubule associated protein).

2. EM: Ultrastructurally, they appear as paired helical filaments. 3. Distribution: Neurofibrillary tangles are found predominantly in projection neurons. They

are mainly found in hippocampal pyramidal neurons and neurons of the subiculunm, entorinal region and parahippocampal gyrus. The primary motor and sensory somatic cortical areas are scarely affected.

4. Density: The density of tangles is directly related to the severity of clinical manifestations.

Senile plaques:1. Histology: Plaques are extracellular deposition, 20 -150 m in diameter, featured by a

central amyloid core surrounded by blunt swollen neuritic processes. Like tangles, they are well demonstrated by silver stain, immunohistochemistry for tau and A amyloid (or beta-amyloid protein). Non-specific histochemical stains for amyloid protein such as Congo red and thioflavin S can also detect senile plaques.

2. Distribution: They are generally distributed throughout the neocortex of the frontal, temporal and parietal lobe. In contrast to neurofibrillary tangles, they are relatively less common in hippocampus. They are also found in some nuclei, particularly the amygdala, and also the caudate and putamen.

3. A amyloid: The amyloid protein is about 28-43 amino acid in length. It is derived from proteolytic cleavage of a large transmembrane glycoprotein, amyloid precursor protein (APP). Amyloid protein is toxic to neurons.

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4. Density: The density is not directly related to the clinical severity. Other histologic findings: These histologic changes are commonly seen in Alzheimer’s

disease: Granulovacuolar degeneration: Cytoplasmic vacuoles (3-5 m) containing small round

dense bodies (1-2 m). They are largely but not exclusively confined to the cytoplasm of the hippocampal pyramidal neurons, especially CA1 and subiculum). Most often seen in AD and Pick’s disease but has also be described in many other conditions including normal aging.

Amyloid angiopathy: Deposition of A amyloid in blood vessels is a common finding in Alzheimer’s disease.

Hirano bodies: Brightly eosinophilic rod-shaped or elliptical cytoplasmic inclusions that may appear to overlap the edge of a neuron. They are most numerous in the CA1 region of the hippocampus. Increase in number of Hirano bodies is seen in Alzheimer’s disease, Pick’s disease, and Guam parkinsonism-dementia complex.

F rontotemporal dementia (FTD) : Top of the chapter

General: Confusion with other disorders: Frontotemporal dementia is one of the neurodegenerative

disorders commonly mistaken for Alzheime’s disease in older patients and primary psychiatric disorder in middle aged patients. Pick disease can be considered the prototype of frontotemporal dementia. A clear-cut, positive family history is present in about 20-40% of patients.

Age and sex: 35-75 years, both sexes are equally affected. It is rare to have onset after 75 years of age.

Clinical feature: Progressive and gradual changes in behavior or language dysfunction. Behavial presentation: Early change in social and personal conduct that is often associated with a

lack of inhibition, resulting in impulsive or inappropriate behavior, inappropriate sexual behavior, overeating, lack of personal hygiene, and lack of insight. At the extreme, these impulsive actions can be self destructive. Although they may have memory abnormalities on formal testing, they do not have a true amnestic syndrome. They are able to keep track of day-to-day events and to be oriented.

Language presentation: The other cognitive functions such as memory are preserved but there is progress deterioration of language functions. The first subgroup (primary progressive aphasia) present have troubles in the expression of language, the second group (semantic dementia) has severe problems naming and understanding word meaning. The language abnormalities may be the initial presentation but behavioral changes may occur later.

P ick’s disease : Top of the chapter

General: Arnold Pick first characterized this cognitive disorder with aphasia, apraxia, and agnosia. The

clinical onset in most cases suggests the beginnings of frontal lobe damage. Language problem is particularly severe in cases when temporal lobe is severely affected.

Mistaken for Alzheimer’s disease: It is questionable whether Pick’s disease can be diagnosed on pure clinical ground. Some of the patients are clinically indistinguishable from AD.

Length of illness varies greatly but is seldom less than a year, or more than 10 years. Incidence: They account for less than 2% of all dementia cases. The incidence is rare when

compared to Alzheimer's disease. Genetics: 80% are sporadiac, 20% are clearly inherited.

Gross pathology: Extreme atrophy of the brain. Brain weight can be less than 1000 g. Circumscribed atrophy: The typical cases show extreme shrinkage of relatively circumscribed parts

of both cerebral hemispheres, particularly parts of the brain in and around anterior temporal lobes. The atrophic cortex is extremely thin “Knife blade” atrophy or “walnut”. The atrophy is typically asymmetrical and has left side dominance. The hippocampus and entorhinal cortex are always involved. However, the characteristic gross picture may not be fully developed in all cases.

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Sparing: The posterior 2/3 of the superior temporal gyrus and the precentral gyrus are typically spared.

Ventricular dilataion is always present.Histopathology:

Neuronal loss in cortex and deep nuclei: Intense cortical neurona loss in the affected areas. The cortical architecture can be completely lost. In less severely affected, neuronal loss and gliosis is most severe in lamina III and V. Intense neuronal loss may also be seen in the caudate and amygdala; thalamus in about half of the cases; substantia nigra in about 10% of the cases.

Pick’s cell: Characteristic ballooned cells with their nuclei pushed to the margin by poorly stained cytoplasm that is almost devoid of Nissl substance. These cells are filled with neurofilaments and re positive for silver stains; they are positive for phosphorylated neurofilament proteins, tau, ubiquitin and B crystalline. They may or may not contain Pick’s body.

Pick’s body: Pick’s bodies are seen in only about 20% of the cases with typical macroscopical pathology. They are well demarcated, amorphous, slightly basophilic and argentophilic spherical cytoplasmic inclusions that may also be oblong, falciform and irregular in shape. They are immunopositive for tau, ubiquitin and other proteins. EM: They appear as accumulations of filamentous material with interspersed osmiophilic granular and vesicular structures. No limiting membrane is present.

Gliosis: There is marked pancortical gliosis in the atrophic cortical and subcortical areas. The cortex may develop a spongy appearance.

Granulovacuolar degeneration: Frequent, mainly in the pyramidal cells of the hippocampus.

B asal ganglia degeneration : Top of the chapter

General: Neurodegenerative disorders of this category often produce movement disorders. It may be an

akinetic-rigid disorder (e.g., Parkinson’s disease) or hyperkinetic disorder (e.g. Huntington’s disease). Overlaping symdromes can occur. The most common is Parkinson’s disease and Alzeheimer’s

disease, and less commonly Hungting’s disease and Alzheimer’s disease. Some entities that are included in this category include:

1. Huntington’s disease2. Parkinson’s disease (idiopathic)3. Postencephalitic parkinsonism4. MPTP parkinsonism5. Progressive supranuclear palsy6. Cortical basal degeneration

P arkinson’s disease : Top of the chapter

Summary: Characteristics: Parkinson’s disease is a neurodegenerative disease that is clinically characterized

by the development of extrapyramidal movement disturbance; the diagnosis is based on the presence of two out of the three following clinical features: bradykinesia, resting tremor and rigidity. Pathologically, Parkinson’s disease is featured by degenerative changes of substantia nigra and accumulation of Lewy bodies.

Overlap: it is common to have combined features of Alzheimer’s disease. The clinical and pathologic features also overlap with diffuse Lewy body disease.

Clinical subtypes: Classic: Onset in the 7th decade (With Lewy body pathology). Autosomal recessive juvenile Parkinson’s disease: Onset under 21 years. Young-onset: Onset between 21 and 40 years old (With Lewy body pathology).

Neurochemical defects: Parkinson’s disease is resulted from a primary defect in dopaminergic projections to the

striatum due to degeneration of neuromelanin-containing dopaminergic neurons in the substantia nigra; this defect can be partially corrected by L-DOPA.

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Other populations of neuromelanin and non-neuromelanin containing neurons in the brain stem and basal forebrain also degenerate and accumulate Lewy bodies.

Genetics: Most cases are sporadic, a small proportion of cases are familial. Some of the known genetic

alternations are as follows:1. Mutations in -synuclein gene 2. Mutation in ubiquitin carboxy-terminal hydrolase L1.3. Parkin gene and autosomal recessive juvenile parkinsonism.

Gross Pathology: Loss of pigmentation in substantia nigra and locus coeruleus and other pigmented nuclei of

the brain stem. The caudate, putamen, and globus pallidus has to be normal in appearance.Histopathology:

Region-specific neuronal loss in substantia nigra: The pattern of cell lost is opposite to that due to normal aging. Cell lost is greatest in the ventrolateral groups of neurons.

Lewy bodies:1. If Lewy body is not identified, the diagnosis of Parkinson’s disease is highly unlikely.2. Morphology: Intraneuronal, spherical (8-30 m), eosinophilic inclusion with a hyaline core

and a pale staining peripheral halo. Multiple inclusions may be present in one neuron but this is uncommon.

3. Biochemical component: Lewy bodies are positive for -synuclein, neurofilament proteins and ubiquitin (only detected in the halo of Lewy bodies). It is very likely that -synuclein is the building blocks for the fibrillary structure of Lewy bodies.

4. EM: The halo is composed of radially arranged 7-20 nm intermediate filaments associated with a granular electron-dense coating material and vesicular structures; the core is composed of densely packed filaments associated with dense granular material.

.

H untington’s disease : Top of the chapter

General: Summary: First complete description by George Huntington in 1872. Autosomal dominant. Classic

clinical manifestations are chorea, rigidity, and mental deterioration leading to dementia, with onset in middle or late life. Genetically it is linked to abnormal expansion of CAG trinucleotide repeats. Huntingtin gene is on chromosome 4 (4p16.3). Pathologically characterized by degeneration of caudate nuclei.

Pathophysiology: destruction of the basal ganglia lead to a disinhibition of the thalamus and causes chorea. Chorea in HD is caused by diminished striatal inhibition of neurons in the lateral globus pallidus, reducing activity of the subthalamic nucleus, and releasing thalamic neurons to excite the cortex.

Prevalence: 5-10/100,000. Highest in Western Europe and lowest in Africa and Asia. Age: mean age of onset is 40 years old but may have onset as early as 10 years old.

1. Juvenile-onset (4-19 years of age)- 10% of cases2. Early-onset (20-34 years of age)3. Midlife-onset (35-49 years of age)4. Late-onset (over 50 years of age)- 25% of cases

Genetics: Autosomal dominant. Huntingtin gene is on chromosome 4 (4p16.3). Unstable expansion of CAG (trinucleotide) repeats

within the coding region of the gene coding for the protein huntingtin on chromosome 4 (4p16.3). The mutation in huntington gene produce an expanded stretch of glutamine residues attached to its amino-terminal.

Normal individual has an average of 19 CAG repeats with a range from 9 to 37. Patients have 36-40 trinucleotide repeats may or may not develop the disease, and those with >40 will develop the disease. Those with adult-onset have repeats ranging 40-55, those with early-onset have repeats >70.

Size of repeats: The larger the number of repeats the earlier the onset.

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Genetic Anticipation: The disease exhibits the phenomenon of anticipitation. Recent generations are affected at an earlier age and more severely than older generations within the same family (e.g., the son has earlier onset than the mother).

Gross pathology: Bilateral symmetric atrophy of striatum in 95% of cases. Nonstriatal regions show atrophy of variable

severity or have normal appearance. There may be atrophy of the cerebral cortex, thalamus, caudate nucleus, and putamen. The atrophy of the caudate is most striking.

Histopathology: The striatum is the only site where neuronal loss is associated with "active" reactive, fibrillary

astrocytosis. An increased density of oligodendrocytes, up to twice that of control, is observed in the anterior neostriatum. Cell lost is more prominent in the caudate.

Abnormal neurites may be demonstrated by immunostaining for ubiquitin.

T rinucleotide disease : Top of the chapter

General: A family of human disorders are characterized by abnormal expansions in the gene, most commonly

abnormal of trinucleotide repeats. Huntington disease is a prototype. It is very interesting that all nucleotide repeats in the coding regions are CAG (glutamine repeats).

Nucleotide repeats in the non-coding regions are diversified. Also, diseases with CAG repeats affect the basal ganglia, brain stem, cerebellum and spinal cord. The following is a list of these diseases.

Disorder Inheritance Repeat Gene

Expansions in noncoding regions:

Fragile X syndrome XD CGG (untranslated region) FMR-1

Myotonic dystrophy AD CTG (untranslated region) Myotonin protein kinase

Spinocerebellar ataxia type VIII (SCA-8) AD CTG (untranslated region) Not named yet

Friedreich ataxia AR GAA (intron) Frataxin

Unverricht-Lundborg disease AR GC rich 12 nucleotide repeats (promoter region)

Cytostatin B

Expansions in coding regions:

Kennedy disease XR CAG (first exon) Androgen receptor

Huntington disease AD CAG Hungtintin

Dentorubropallidoluysian atrophy (DRPLA)

AR CAG Atrophin

Spinocerebellar ataxia type I (SCA-1) AD CAG Ataxin-1

Spinocerebellar ataxia type II (SCA-2) AD CAG Ataxin-2

Spinocerebellar ataxia type III (SCA-3) AD CAG Ataxin-3

Spinocerebellar ataxia type VI (SCA-6) AD CAG 1A voltage-dependent calcium channel subunit (CACNL1A4)

Spinocerebellar ataxia type VII (SCA-7) AD CAG Not named yet

Oculopharyngeal muscular dystrophy AD and AR GCG PABN1 gene.

AD: Autosomal dominant, AR: Autosomal recessive, XD: X-linked dominant, XR: X-linked recessive.

A myotrophic lateral sclerosis (ALS) : Top of the chapter

General:

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Motor neuron diseases: The pathologic features of motor neuron diseases are remarkablely similar. They are featured by degeneration and loss of upper motor neurons (neurons in the motor cortex) or lower motor neurons (neurons of the cranial nerve nuclei and anterior horn cells of the spinal cord) or a combination of both over months to years.

Amyotrophic lateral sclerosis is featured by atrophy and loss of both upper and lower motor neurons.

Clinical: Initially, the symptoms may be asymmetrical. There is relentless progress with eventual loss of all

voluntary movement with the exception generally of extrocular motility. Patients usually die of respiratory failure and other complications that are common in prolonged bed

ridden patients. Lower motor neuron loss: Weakness, atrophy of muscle, fasciculation of muscle. Upper motor neuron loss: weakness and spasticity. Since only motor neurons are affected, the patients have normal cognition and intellect.

Pathology: Atrophy of nerve root and tracts: The lateral corticospinal tract is atrophic (lateral sclerosis). The

anterior spinal nerve roots are small and atrophic when compared with the dorsal nerve roots. The muscle intervated by the affected nerve roots are atrophic (amyotrophic).

Biochemistry: Superoxide dismutase: Mutation in superoxide dismutase has been described in familial ALS

cases.

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Chapter 9

Peripheral Nerve and Muscle Table of Content

Overview Pathologic changes in peripheral nerves General considerations of muscle disorders Inflammatory myopathies Dernatomyositis Dystrophic myopathies Dystrophinopathies (Duchenne & Becker muscular dystrophy) Metabolic and mitochondrial myopathy Myopathy, encephalopathy, lactic-acidosis, and stroke like episodes (MELAS) McArdle’s disease

Overview: Top of the chapter

The peripheral nerve is responsible in carrying an electrical signal to and from the target organs. The neuronal body, the axon, and the neuromuscular junction provide a mechanism for the transduction. The myelin sheath allows rapid transduction of action potential. Pathologic changes in any of these components will lead to a reduction of either the amplitude or speed of transduction. Clinical manifestations include weakness, numbness, burning sensation, tingling, and others.

In the case of motor function, the electrical signal will be converted into a chemical signal that would be conducted through the synapse. The chemical signal will illicit an action potential in the muscle that lead to opening of the voltage gate and eventually lead to contraction of muscle. Therefore, clinical manifestations of skeletal muscle can be caused by abnormalities up to the point of signal transduction at the neuromuscular junction (neurologic etiology) or resulted from intrinsic abnormalities of the skeletal muscle (myogenic etiology).

Electrical studies such as nerve conduction study and electromyogram (EMG) are important tools for the study of disorder of the neuromuscular system.

Pathologic changes in peripheral nerve : Top of the chapter

General: Axonal neuropathy: Destruction of the axons. Microscopically, the axon is destroyed and has

degenerative myelin beads. Demyelinating neuropathy: There are features for lost of myelin. In the acute phase, there is

phagocytosis of the myelin with preservation of axons. In chronic phase, there is thinning of myelin, segmental demyelination, and elongation of internodal distance.

General considerations of muscle disorders: Top of the chapter

General: Goal: Pathology of the peripheral nerve and muscle is a vast field. Only some distinct examples are

illustrated here. Communication: The peripheral nerve and muscle have only a very limited way to manifest their

abnormalities at the histologic level. Disorders of diverse etiology may produce comparable clinical manifestations and similar pathologic findings. Clinical-pathologic correlation is of great importance in understanding and accurately diagnosing muscle disorders. Communication between the pathologist and neurologist is important.

Systemic and medication: Many manifestations of muscle are caused by a systemic disorder such as hypothyroidism, systemic infection such as HIV, and medications such as the use of HMG-CoA reductase inhibitors.

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Associated life threatening conditions: Some disorders of the skeletal muscle are associated with some life threatening conditions. It is important to recognize these muscle disorders. Some examples are as follows:

Myotonic dystrophy: Cardiac arrhythmia and sudden death.Emery-Dreifuss muscular dystrophy: Cardiac arrhythmia and sudden death.Central core myopathy: Increased risk to develop malignant hyperthermia with anesthesia.Dermatomyositis in adults: Internal malignancy.

General histological consideration: Please review your histology.

Serum creatine kinase: The level of serum creatine kinase reflects the extent of muscle destruction and often provides a

rough hint on the underlying pathologic process. A normal or low level of elevation (5 to 10 times of normal) is seen in neurogenic atrophy and many

congenital myopathies. A medium level of elevation (20 to 50 times of normal) is often seen in inflammatory myopathies. A high level of elevation (above 20 to 50 times of normal) is often seen in dystrophic myopathies.

Methods of muscle biopsy: The qualitative and quantitative aspects are evaluated. These evaluation focus on the morphology at

light and electron microscopic levels, presence of abnormal components (histochemistry), enzyme histochemistry, presence and absence of certain molecules (immunohistochemistry), biochemical and genetic analysis. Not all these modalities have to be employed make the final diagnosis in many cases.

Morphology at light electron microscopy level: The most commonly used stains are hematoxylin-eosin stain, modified Gomori’s trichrome stain. This is particularly helpful in identification of inflammation in inflammatory myopathies and in vasculitis.

Enzyme histochemistry: Fresh frozen tissue is required (frozen sections). These preparation detects the presence or absence of an enzyme through a color generating reaction. The enzymatic reactions include ATPase, nicotinamide adenine dinucleotide- tetrazonium reductase (NADH-TR), succinate dehydrogenase (SDH), cytochrome oxidase (COX), myophosphorylase, adenylate deaminase, esterase, acid phosphatase, and others.

Histochemistry: These stains are basically performing a chemical reaction on the tissue section to detect the presence or absence of a particular component. The best example is the use of periodic acid Schiff stain to demonstrate the presence of excessive glycogen in glycogen storage diseases (the glycogen will turn purple red).

Immunohistochemistry: This allows detection of a particular protein in tissue sections. A large variety of molecules can be detected and some of the more commonly used ones in myopathology include dystrophin, merosin, and desmin.

Electron microscopy: Electron microscopy is a useful adjunct that is best used as a tool to confirm the light microscopic diagnosis.

Biochemistry: This is particularly useful in confirming enzyme deficiencies such as McArdle disease (myophosphorylase deficiency or glycogen storage disease type V) and mitochondrial disorders.

Genetic analysis: Some disorders of the skeletal muscle are associated with deletions or mutations of a particular gene.

Classification of muscle disorders: Top of the chapter

Morphologic analysis allows us to segregate the pathologic process into three major histopathologic types. Additional

Necrotizing myopathies: They are featured by necrotic fibers, regenerating fibers and interstitial fibrosis as their salient pathologic features. The classic examples are muscular dystrophies such as Duchenne and Becker muscular dystrophy.

Inflammatory myopathies: They are featured by chronic inflammation as the salient pathologic features. The classic examples are the dermatomyositis, polymyositis, and inclusion body

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myositis. It should be noted that many dystrophic myopathies such as fascioscapulohumeral dystrophy and merosin deficient type of congenital muscular dystrophy also possess a variable and sometimes impressive degree if chronic inflammation.

Non-destructive, non-inflammatory myopathies: They lack both necrotic fibers and inflammatory changes as their major pathologic features. The classic examples include a variety of congenital myopathies such as myotubular myopathies, nemaline myopathies, and central core disease.

Pathologic classification: Disorders of the skeletal muscles can be classified by the pathologic features. Some examples are listed here:

Inflammatory myopathies: dermatomyositis, polymyositis, inclusion body myositis, etc. Dystrophic myopathies: Dystrophinopathies (Duchenne and Becker muscular dystrophy),

Emery-Dreifuss muscular dystrophyies (X-linked and autosomal dominant type). congenital muscular dystrophy of the merosin (laminin 2) deficient type, etc.

Congenital myopathies: X-linked myotubular myopathy, nemaline myopathy, central core myopathy, etc.

Metabolic and mitochondrial myopathies: Pompe disease (fetal type of glycogen storage disease type II), McArdle disease (glycogen storage disease type V), myopathy, encephalopathy, lactic-acidosis, and stroke like episodes (MELAS), etc.

Etiologic classification: Disorders of skeletal muscles can also be classified according to their etiology. Unfortunately, the etiology of many disorders of the skeletal muscle are unclear and cannot be accurately classified in this manner. Some examples include:

Inflammatory myopathies: dermatomyositis, polymyositis, inclusion body myositis, etc. Developmental disorders: X-linked myotubular myopathy, central nuclear myopathy, congenital

fiber disproportion. Defects of extracellular matrix and sarcolemma: Dystrophinopathies (Duchenne and Becker

muscular dystrophy), congenital muscular dystrophy of the merosin (laminin 2) deficient type, etc.

Nuclear envelopathies: Emery-Dreifuss muscular dystrophy, X-linked type (emerin), Emery-Dreifuss muscular dystrophy, autosomal dominant type (Lamins A/C), etc.

Iatrogenic myopathies: Cochicine myopathy, acute quadriplegic myopathy (myosin heavy chain depletion syndrome, critical care myopathy, chronic steroid myopathy, etc.

Inflammatory myopathies : Top of the chapter

General: Inflammatory myopathies refer to a family of myopathies with inflammation as their salient

pathologic features. Dermatomyositis, polymyositis, and inclusion body myositis are the more common entities. The

diagnosis of dermatomyositis and polymyositis always require clinical-pathologic correlation and pathologic examionation alone is not sufficient to make the diagnosis.

It is very important to note that the presence of inflammatory cell infiltration is not an unequivocal signature for inflammatory myopathies but can also be seen in other myopathies particularly some of the dystrophic myopathies.

Dermatomyositis is taken as an example to illustrate features of inflammatory myopathies.

Dermatomyositis: Top of the chapter

General information on inflammatory myopathies Inflammatory myopathies refer to a family of myopathies with inflammation as their salient pathologic

features. Dermatomyositis, polymyositis, and inclusion body myositis are the more common entities. The

diagnosis of dermatomyositis and polymyositis always require clinical-pathologic correlation and pathologic examionation alone is not sufficient to make the diagnosis.

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It is very important to note that the presence of inflammatory cell infiltration is not an unequivocal signature for inflammatory myopathies but can also be seen in other myopathies particularly some of the dystrophic myopathies.

Dermatomyositis is taken as an example to illustrate features of inflammatory myopathies.Clinical Features:

The three cardinal features are muscle weakness and pain, skin rash, and constitutional symptoms such as fever and malise.

More common in woman. Pediatric type is not associated with internal malignancy, peak incidence around 10 years of age. Adult type is often associated with a malignant neoplasm in the internal organs. The peak incidence

is 40-70 years of age. Pathology:

Inflammatory infiltration in muscle. Perifascicular atrophy of muscle. Deposition of complement complex in capillaries. Ultrastructural evidence of endothelial damage.

Polymyositis: In contrast to dermatomyositis, polymyositis do not have skin rash, is essentially unknown in

children, and is not associated with internal malignancy.

Dystrophic myopathies : Top of the chapter

General: In general, muscular dystrophies comprise a group of genetically determined, destructive muscle

disorders with progressive necrotizing myopathy as the salient feature with dystrophinopathies as the prototypes.

The histologic changes revolve around the central theme of fiber necrosis, regeneration, and fibrosis. The severity of muscle destruction, however, is highly variable among different types.

A very high serum creatine kinase level is typical for many types of dystrophic myopathies Many dystrophic myopathies are caused by malfunctioning of components on the glycoprotein

complex that link the myofibrils through the cytoplasmic membrane (sarcolemmal membrane) and in tern to the extracellular matrix.

Dystrophinopathies is being used here to illustrate the general features of dystrophic myopathies.

Dystrophinopathies (Duchenne & Becker muscular dystrophy) : Top of the chapter

General: A progressive X-linked recessive dystrophic myopathy. Dystrophin gene is the largest known human gene and is on chromosome X21.2. Dystrophin is a component of the Dystrophin-glycoprotein complex which is a transmembrane

complex that links the contractile filaments to the extracellular matrix through laminins.Clinical:

Muscle weakness is the cardinal problem and is usually not recognized by the parents until the baby starts to walk.

The clinical course is progressive. Initial onset is usually before 3 years of age, lost of ambulation usually occurs at 7-11 years of age and death at around 20 years of age. With sophisticated care, the tragic outcomes can be delayed but not overcome.

Serum creatine kinase level is very high. Gower’s maneuver. The child will take more then 2 seconds to rise from a sitting position on the floor

(normal is 1 second).Pathology:

Necrotic fiber, regenerating fiber, interstitial fibrosis (fibrosis around individual muscle fiber). In advanced stage, the bulk of the muscle is replaced by mature adipose tissue and fibrous tissue

which is the basis for pseudohypertrophy.

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Immunofluoresence will show a complete absence of dystrophin in Duchenne muscular dystrophy and partial absence in Becker muscular dystrophy.

Metabolic and mitochondrial myopathy : Top of the chapter

General: Skeletal muscle is a highly metabolic active organ. As a result, there is a large family of primary

myopathies that are produced by disturbed energy metabolism at different levels. Metabolic and mitochondrial disorders are systemic disorders. Organs other then the muscle,

particularly the brain and liver, are often also affected. Abnormal metabolism resulted from insufficient supply of energy may lead to ischemic changes at

the cellular level and breakdown of muscle fibers. Therefore, necrotic fibers and regenerating fibers are not uncommon in this category of myopathies. We will take myopathy, encephalopathy, lactic-acidosis, and stroke like episodes (MELAS) and McArdle’s disease (aka. glycogen storage disease type V, myophosphorylase deficiency) as examples to illustrate the principles.

The three most common groups are mitochondrial myopathies, glycogenosis and myopathies associated with abnormal lipid metabolism.

Glucose, glycogen, and fatty acid are the three major source of energy for muscle and their relationship is interlinked as illustrated below:

Myopathy , encephalopathy, lactic-acidosis, and stroke like episodes (MELAS): Top of the chapter

General: CNS: The brain and the skeletal muscles are predominantly involved. MELAS is characterized by

periodic stroke like episodes beginning before age 40, usually before age 15, seizures and progressive encephalopathy leading to dementia and progressive deterioration in motor functions.

In contrast to stroke, the infracted areas do not follow a vascular territory. Patients with full expression often die before 20 years of age.

Muscle: There is also exercise intolerance and episodic lactic acidosis. Endocrine dysfunction resulting in poor growth, infertility, and diabetes melitis may occur.

Genetics: Often associated with specific point mutations of mitochondrial DNA. Substitution of an A3243G

mutation in the tRNALeu gene is present in over 80% of the cases.Muscle pathology:

The muscle pathology is not specific for MELAS and is shared by a variety of mitochondrial myopathies.

Ragged fiber is a common finding and is best demonstrated by modified Gomori’s modified trichrome stain. The red, irregular, subsarcolemmal depositions are resulted from accumulation of abnormal mitochondria.

GlucoseGlycolysis & oxidative phosphorylation

(cytosol & mitochondria)

Glycogen(cytosol)

Fatty acid-oxidation

(mitochondria)

ATP

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Neuropathology Lecture 2005-2006 KM Fung Page 78

Succinate dehydrogenase and cytochrome C oxidase negative fibers are also common. Abnormal mitochondrial can be seen under electron microscopy. Necrotic fibers and regenerating fibers are common.

McArdle’s disease (aka. glycogen storage disease type V, glycogenosis type V, myophosphorylase deficiency): Top of the chapter

General: McArdle’s disease is a disorder characterized by abnormal glycogen metabolism. These disorders

are collectively known as glycogenosis or glycogen storage disease. Although glycogen storage is common among these disorders, excessive glycogen storage is not

always and the abnormal storage is not always chemically normal glycogen but abnormal polysaccharides. These disorders are therefore better termed glycogenosis.

Deficiency of a specific enzyme involved in the metabolism of glycogen is involved in glycogenosis. In McArdle’s disease, there is a deficiency of the muscle isoform of phosphorylase (myophosphorylase). The clinical manifestation is therefore limited to the skeletal muscle. Other entities such as the type II glycogenosis may involve muscle, liver, kidney, and CNS.

Clinical: McArdle’s disease is compatible with prolonged survival. Clinical manifestations are that of a “metabolic myopathy” featured by muscle fatigue, cramps and

pain after exercise, exercise intolerance. Patients that are subjected to strenuous exercise may develop rhabdomyolysis and myoglobinuria

(tea colored urine). Myoglobinuria, when severe, may lead to renal failure.Pathology:

The pathology is variable. In the mild form, there are no significant morphologic changes on biopsy material. In the more severe form, there are many necrotic fibers and regenerating fibers.

On histochemistry, there is a total absence of myophosphorylase. Increase in glycogen storage can be detected by periodic acid Schiff (PAS) reaction. The glycogen can be digested by diastase on sections. Glycogen can also be detected on electron microscopy.

On biochemical analysis, the myophosphorylase level is usually under 10% of normal. There is also increase in glycogen content.

-The End-