CNS Pathology - III Motor Neuron Diseasespau.lf1.cuni.cz/file/6420/cns-iii-mndtu.pdf · CNS Pathology - III Motor Neuron Diseases ... (esp. in children) –clouding of consciousness,

CNS Pathology - III

Motor Neuron Diseases

Jaroslava Dušková

Inst. Pathol. 1st. Med. Fac. Charles University, Prague

Intracranial Tumours

ALS

Axon

terminals

Node of

Ranvier

Schwann

cellMyelin sheet

Dendrites

Nucleus

Cell

body

NEURON

Motor Neuron Damage

Axonopathies

toxic

toxoinfectious

metabolic (drugs!)

avitaminoses

traumatic (shearing injury)

malignancy associated

Motor Neuron Diseases

Neuronopathies

Poliomyelitis anterior acuta

Poliomyelitis anterior chronica

Sclerosis amyotrophica lateralis ALS

Paralysis progressiva bulbaris

Tractus corticospinalis

Motor Neuron Diseases

1. paralysis spastica spinalis

2. paralysis progressiva bulbaris C

m. Aran - Duchenne T(poliomyelitis ant. chronica)

m. Werdnig Hoffmann Lmyatonia (amyotonia) congenita Oppenheim

1. + 2. ALS

1.

2.

SMA –Spinal

Muscular

Atrophy

Classification of Disorders Affecting

Motor Neurons

Primary

– idiopathic (ALS)

– inherited (SMA)

Secondary

– infective :acute poliomyelitis, HIV, syphilis, prions

– metabolic: hyper/hypo thyr, hyperparathyr…

– immune. paraproteinemia

– Environmental/toxic: Pb, Sb, Cd…neurolathyrism

– vascular

– paraneoplastic: nHML, MLH

Multisystem neurodeg. diseases affecting motor neurons

– Western Pacific ALS /Parkinson/dementia complex

– spinocerebellar degeneration

– Huntington´s disease

– prionoses

genus Lathyrus sweat pea

β-ODAP

= 3-N-oxalyl-L-2,3diaminopropionic acid

The level of this compound in the dry

seeds varies depending on genetic

factors and environmental conditions.

Neurolathyrism

is a neurological

disease of

humans and

domestic

animals, caused

by eating certain

legumes of the

genus Lathyrus

sweat pea

motor neurons

Spinal Muscular Atrophy -Type I - m. Werdning- Hoffman – autosomal rec. – floppy baby-

survival not beyond 3 years of age

Amyotrophic Lateral Sclerosis

Def.

motor neuron disease affecting

both 1st and 2nd neuron of pyramidal

tract

5-10% familiar, autosomal dominant SOD I

(SuperOxidDismutase) gene on chromosome 21

Amyotrophic Lateral Sclerosis

Clinical features

start: 10 – 60 yrs

palsies spastic/ feeble

neurogenous hand muscle atrophy

„simian hand“

bulbar disturbances

death in several years (aspir. bpn.)

Amyotrophic Lateral Sclerosis

Etiopathogenesis

(Greenfield´s Neuropathology 9th ed., 2015)

„IDIOPATHIC“

genetic factors (9, 18, 21…ALS 1…ALS5 types)

mostly sporadic forms

5-10% autosom. dom. familial form – starts 10 years

earlier

autosomal recessive described as well

environmental factors – toxic, infectious

autoimmune

Amyotrophic Lateral Sclerosis

Morphology

macro:

micro:

atrophy of gyrus praecentralis

atrophy of ventral roots

atrophy of muscles („simian“ hand)

loss of neurons (GPC, ant. horns)

funicular demyelinisation

atrophy (denervation type)

Atrophia musculorum interossearum manus neurogenes ALS

A

L

S

ALS

ALS

anterior

roots

atrophy

ALS – medulla oblongata

ALS – medulla oblongata

ALS

MS

ALS - tractus corticospinalis anterior

ALS - tractus corticospinalis lateralis

palor

A

L

S

ALS - tractus corticospinalis lateralis

PPB ALS

Paralysis progressiva bulbaris

Clinical features

fonation and deglution disturbancestachycardia, dyspnoe (insuff. n. X)

Morphology

neuronal atrophy nn. IX, X, XI, XII.

chewing muscles, tongue

Prognosis fatal (aspir. bpn.)

Neurological control of normal speech

Corticobulbar tracts from both of the motor cortices send signals down to the nuclei of the following nerves:

Vagal nerve

Facial nerve

Hypoglossal neve

Phrenic nerve

The motor aspects of speech influenced by the extrapyramidal system via the basal ganglia and the cerebellum.

Phonation: the production of sounds, a result of the vocal cords in the larynx.

Articulation: contractions of the muscles of the various other structures involved in speech, ie the pharynx, palate, tongue and lips. These muscle contractions change the vocal sounds from the larynx, thus resulting in noises recognised as words.

Case Report ALSman 52 yrs (driver) *1943 †1999

July 1991

physical exercise (mountain bike trip)first symptoms

Disturbance of

pronounciationtransient , later standing expressive aphasia

swallowing

central hemiparesis dx., later sin.

Progression during 4 years death from bronchopneumonia

Guerreiro R et al.:

SnapShot: Genetics of ALS and

FTD.Cell. 2015 Feb 12;160(4):798

Frontotemporal dementia (FTD) and amyotrophic lateral

sclerosis (ALS) are considered to be part of a spectrum.

Clinically, FTD patients present with dementia frequently

characterized by behavioral and speech problems. ALS patients

exhibit alterations of voluntary movements caused by

degeneration of motor neurons. Both syndromes can be present

within the same family or even in the same person. The genetic

findings for both diseases also support the existence of a

continuum, with mutations in the same genes being found in

patients with FTD, ALS, or FTD/ALS.

CNS neoplasms

primary CNS neo:

– approx. 2% of all cancers

– approx. 20% of cancers in children under 15

secondary

– 25-50% (lung, breast, kidney, melanoma)

fewer than 5% associated with hereditary syndromes

(NF1,NF2, tuberous sclerosis, von Hippel-Lindau,

…MEN I)

CNS Neoplasms - Manifestation

epilepsy

focal deficits –palsies

raised intracranial pressure

– headache

– vomiting (esp. in children)

– clouding of consciousness, coma

– papiledema

hydrocephalus

Ellison & Love.

NEUROPATHOLOGYA reference texts of CNS pathology.

Mosby 2004

Common

locations of

various

neuroepithelial

neoplasms

Ellison & Love.

NEUROPATHOLOGY

A reference texts of CNS pathology.

Mosby 2004

The mass effect of a cerebral neoplasm

Epilepsy – Epileptic Syndromes

an „umbrella diagnosis“ for a broad

family of neurologic disorders

characterized by seizures of different

quality

after stroke the commonest neurological

disorder

up to 2% of population worldwide

Epilepsy – Epileptic Syndromes

Primary

– genetic disorders of ion channels, brain

neuronal architecture – many different genes

involved

Secondary

– brain malformations, metabolic diseases

– glioses (postinfectious, posttraumatic,

postnecrotic…)

– neurodegenerations ( m. Alzheimer, m.

Huntington…)

– NEOPLASMS

Epilepsy – Epileptic Syndromes

Morphology – not always provable

– dysgenetic foci of cortex

– hippocampal sclerosis

– secondary causative pathologies

– secondary posttraumatic lesions caused by

seizures

WHO – CNS – 2016 – revised 4th edition

117 contributors from

20 countries revised

the 2007 classification.

Three-day Consensus

conference by a

Working group of 35

neuropathologists.

Molecular parameters

incorporated into the

classification

WHO Classifications

of Tumours of the CNS

1979, 1993, 2000, 2007,

- 134 nosology units

revised 4th 2016

- 154 nosology units

WHO Grading of Tumours of the

Nervous System (2016)

G I - well circumscribed, slowly progressing,

cured by resection

G II – infiltrative, low proliferation, a higher

likelihood of recurrence

G III – histologically malignant, require more

aggressive adjuvant therapy

G IV – highly malignant, rapidly fatal

WHO - CNS - 2016

154 nosology units

(WHO 2007 134 nosology units)

WHO Classification of Tumours of the Central Nervous System 2016 – selection 1/6

Gliomas

diffuse astrocytic and oligodendroglial – GII –IV

other astrocytic – e.g. pilocytic, subependymal GI-III

ependymal tumours GI-III

other gliomas - angiocentric, astroblastoma GI-III

tumours of the choroidal plexus – papilloma, atypical

papilloma, papillocarcinoma GI-III

(cont.)

WHO Classification of Tumours of the Central Nervous System 2016 – selection 2/6

Neuronal and mixed glioneuronal (epilepsy

associated)

ganglioglioma GI

ganglioglioma GII

anaplastic ganglioglioma GIII

Tumours of the pineal gland

pineocytoma GI

pinealoblastoma GIV

(cont.)

WHO Classification of Tumours of the Central Nervous System 2016 – selection 3/6

Embryonal tumours (GIV)

Meduloblastomas genetically defined (WNT, SHH)

Meduloblastomas histologically defined

Embryonal tumours

Tumours of the cranial and paraspinal nerves schwannoma, neurofibroma, perineurioma, GI

MPNST GIII

(cont.)

WHO Classification of Tumours of the Central Nervous System 2016 – selection 4/6

Meningeal tumours

meningioma GI, atypical GII, anaplastic GIII

Mesenchymal non-meningotelial tumours

Solitary fibrous tumour GI-III

Hemangioblastoma, hemangioma, hemangioendotelioma,

angiosarcoma, Kaposi sarcoma, Ewing/PNET, lipoma,

liposarcoma, leiomyomas, rhabdomyoma, chondroma,

osteoma, and sarcomas GI-III

(cont.)

WHO Classification of Tumours of the Central Nervous System 2016 – selection 5/6

Melanocytic tumours

meningeal melanocytosis, m. melanocytoma, m. melanoma,

m. melanomatosis

Lymphomas

DLBCL, immunodef. associated, AIDS, EBV..low grade, T

cell, Anaplastic Alk +/Alk -, MALT…

Histiocytární tumory

Langerhans cell histiocytosis, Erdheim-Chester disease,

Rosai Dorfmann disease, histiocytic sarcoma

(cont.)

WHO Classification of Tumours of the Central Nervous System 2016 – selection 6/6

Germ cell tumours

germinoma

embryonal carcinoma

yolc sac tumour

choriocarcinoma

teratoma (mature, immature)

Tumours of the sellar region

craniopharyngeoma

pituicytoma

spindle cell oncocytoma

granular cell tumour of the sellar region

METASTATIC TUMOURS

WHO Classification of Tumours of the Central Nervous System 2016 – selection 4/6

Meningeal tumours

meningioma GI, atypical GII, anaplastic GIII

Mesenchymal non-meningotelial tumours

Solitary fibrous tumour GI-III

Hemangioblastoma, hemangioma, hemangioendotelioma,

angiosarcoma, Kaposi sarcoma, Ewing/PNET, lipoma,

liposarcoma, leiomyomas, rhabdomyoma, chondroma,

osteoma, and sarcomas GI-III

(cont.)

Meningeoma

Meningeoma – multiple – brain impression

Topic frequency of MENINGEOMA ICD-O 9530/0

convexity8561

parasagital

fossa cerebri ant

media

post

24

os sphenoides

medulla

other

multiple

falx

n. olfactorius

sella

n. opticus

tentorium

45

27

35

19

12

33

2

14

8

15

30

• middle aged, elderly

• risk fc. :irradiation

• mutation of NF2 (22q)

• mostly G 1

Meningeoma GI

ICD-O 9530/0

G I- benign

G II- atypical

G III – anaplastic

(malignant)

G IV - exceptionally

Meningeoma – Age & Sex Distribution

Meningeoma

fibrosum

Meningeoma

meningoteliomatosum

Meningeoma

psammomatosum

Meningeoma

transitorium

Angioma racemosum cerebri et

meningum

Hemangioma cavernosum ICD-O 9121/0

Types of CNS vascular malformations

arteriovenous

capillary teleangiectasia

cavernous hemangioma

venous angioma

Hemangioma – malformatio arteriovenosa

Chordoma ICD-O 9370/3

• remnants of notochord

• sacral 60%

• sphenooccipital 25%

• cervical 10%

• thoracolumbal 5%

WHO Classification of Tumours of the Central Nervous System 2016 – selection 1/6

Gliomas

diffuse astrocytic and oligodendroglial – GII –IV

other astrocytic – e.g. pilocytic, subependymal GI-III

ependymal tumours GI-III

other gliomas - angiocentric, astroblastoma GI-III

tumours of the choroidal plexus – papilloma, atypical

papilloma, papillocarcinoma GI-III

(cont.)

Astrocytic tumours

• difuse – G2

• anaplastic - G3

• glioblastoma – G4

DIFUSELY INFILTRATING ASTROCYTOMAS

PILOCYTIC

ASTROCYTOMA –

BRAF(V600E)

mutation,

Age Distribution

IDH1 -

immunocytochemistry

Astrocytoma diffusum

Astrocytoma fibrillare

Astrocytoma

A. protoplasmicum

A. anaplasticum (GIII)

Astroblastoma (GIII)

Astrocytoma pilocyticum (juvenile) –ICD-O 9421/1

WHO G I• Does not share genetic

abnormalities of astrocytoma.

• Better prognosis.

• Associated with

neurofibromatosis type I.

• Children & young adults.

• Often cystic, better

circumscribed

BRAF(V600E)

mutation

Pilocytic Astrocytoma

Pilocytic

Astrocytoma

Pilocytic Astrocytoma - syringomyelia

Pilocytic Astrocytoma

Oligodendroglioma ICD-O 9450/3 GII-III

del 1p, 19q

Oligodendroglioma

Oligoastrocytoma

ICD-O 9382/3

Glioblastoma (multiforme) ICD-O 9440/3

WHO – G IV

Glioblastoma multiforme ICD-O 9440/3

Glioblastoma

multiforme

Ependymoma

ICD-O 9391/3

associated

frequently with

NF 2

Ependymoma

Ependymoma ICD-O 9391/3

Ependymoma

Ependymoma

sacrale

WHO Classification of Tumours of the Central Nervous System 2016 – selection 2/6

Neuronal and mixed glioneuronal (epilepsy

associated)

ganglioglioma GI

ganglioglioma GII

anaplastic ganglioglioma GIII

Tumours of the pineal gland

pineocytoma GI

pinealoblastoma G IV

(cont.)

Pineocytoma ICD-O 9361/1 G I

Pineocytoma ICD-O 9361/1 G I

WHO Classification of Tumours of the Central Nervous System 2016 – selection 6/6

Germ cell tumours

germinoma

embryonal carcinoma

yolc sac tumour

choriocarcinoma

teratoma (mature, immature)

Tumours of the sellar region

craniopharyngeoma

pituicytoma

spindle cell oncocytoma

granular cell tumour of the sellar region

METASTATIC TUMOURS

WHO Histological Typing

of Tumours of the CNS

TUMOURS OF THE SELLAR REGION

craniopharyngeoma, pituitary tumours

Craniopharyngeoma

Craniopharyngeoma

WHO Classification of Tumours of the Central Nervous System 2016 – selection 3/6

Embryonal tumours (GIV)

Meduloblastomas genetically defined (WNT, SHH)

Meduloblastomas histologically defined

Embryonal tumours

Tumours of the cranial and paraspinal nerves schwannoma, neurofibroma, perineurioma, GI

MPNST GIII

(cont.)

Medulloblastoma ICD-O 9470/3

G IV

Medulloblastoma

cerebelli

Isochromosom 17q

WHO Classification of Tumours of the Central Nervous System 2016 – selection 3/6

Embryonal tumours (GIV)

Meduloblastomas genetically defined (WNT, SHH)

Meduloblastomas histologically defined

Embryonal tumours

Tumours of the cranial and paraspinal nerves schwannoma, neurofibroma, perineurioma, GI

MPNST GIII

(cont.)

Neurilemmoma ICD-O 9560/0

Neurofibroma

WHO Classification of Tumours of the Central Nervous System 2016 – selection 5/6

Melanocytic tumours

meningeal melanocytosis, m. melanocytoma, m. melanoma,

m. melanomatosis

Lymphomas

DLBCL, immunodef. associated, AIDS, EBV..low grade, T

cell, Anaplastic Alk +/Alk -, MALT…

Histiocytic tumours

Langerhans cell histiocytosis, Erdheim-Chester disease,

Rosai Dorfmann disease, histiocytic sarcoma

(cont.)

Lymphoma malignum

Lymphoma malignum (prim. cerebri)

WHO Classification of Tumours of the Central Nervous System 2016 – selection 6/6

Germ cell tumours

germinoma

embryonal carcinoma

yolc sac tumour

choriocarcinoma

teratoma (mature, immature)

Tumours of the sellar region

craniopharyngeoma

pituicytoma

spindle cell oncocytoma

granular cell tumour of the sellar region

METASTATIC TUMOURS

„Pinealoma anisomorphe“ – seminoma

Cystis dermoides

Pseudotumours (diff. dg.!)

Cysts

– Rathke´s cyst

– epidermoid cyst

– dermoid cyst

– colloidal cyst of the 3rd ventrikle…

VASCULAR MALFORMATIONS

– capillary teleangiectasia

– a.– v. malformation

WHO Histological Typing

of Tumours of the CNS

METASTATIC TUMORS

mostly carcinomas !!!

…… melanoma…..

Metastases adenocarcinomatis meningum et cerebri

Carcinosis meningum

Carcinoma diffusum ventriculi (ad meningos metastaticum)

M57. History of melanoma.Melan A

M73. History of bronchogenic carcinoma

MGG

MGG

TTF1

TTF1 -control

Hippocampus