Seizure defn epilepsy defn
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Seizure defn , epilepsy defn. Seizure: paroxysmal event due to abnormal, excessive, hypersynchronous discharges from an aggregate of the CNS neurons Epilepsy: recurrent seizures due to a chronic or underlying process. Classification of seizures.

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Seizure defn epilepsy defn

Seizure defn, epilepsy defn

  • Seizure: paroxysmal event due to abnormal, excessive, hypersynchronous discharges from an aggregate of the CNS neurons

  • Epilepsy: recurrent seizures due to a chronic or underlying process


Classification of seizures

Classification of seizures

  • Partial seizures – discrete regions of the brain

    • simple partial

    • complex partial

    • Partial seizures with secondary generalisation

  • Generalised seizures - diffuse

    • absent seizures (petit mal)

    • atypical absent seizures

    • generalised tonic clonic seizures (grand mal)

    • atonic seizures

    • myoclonic seizures

  • Unclassified seizures – neonates, infants


Partial seizures

Partial seizures

  • Discrete regions of the brain

  • Clinical manifestations can be simple/localised

  • If consciousness is impaired – complex symptoms

  • Partial seizures with secondary generation – begin discretely than spread diffusely


Simple partial seizures

Simple partial seizures

  • Motor, sensory, autonomic, psychic symptoms – no obvious alteration in consciousness

  • Partial motor seizures

    • Jacksonian march – seizure starts localised – then spreads to a larger portion of the extremity -> seizure activity is spreading over the cortex

    • Todd’s paralysis – localised paresis for minutes to hours in the region involved following the seizure

    • Epilepsiapartialis continua – seizure may continue for hours or days

  • Temporal or frontal cortex – alterations in hearing, olfaction, high cortical function


Complex partial seizures

Complex partial seizures

  • Focal seizure activity – along with transient impairment of consciousness

  • Unable to respond to visual or verbal commands during the seizure, impaired recollection of awareness

  • Frequently begins with an aura

  • Automatisms – involuntary, automatic behaviours that have a wide range of manifestations

  • Anterograde amnesia following seizure


Partial seizures with secondary generalisation

Partial seizures with secondary generalisation

  • Partial seizures can spread to both hemispheres causing a generalised seizure usually of the tonic clonic variety

  • Secondary generation frequently observed following simple partial seizures

  • Difficult to distinguish from other generalised seizures


Absent seizures petit mal

Absent seizures (petit mal)

  • Sudden brief lapses of consciousness without loss of postural control, typically lasting only seconds with nopostictal confusion

  • Usually begins 4-8 yrs old, or early adolescence

  • Can be provoked by hyperventilation

  • 60-70% have spontaneous remission during adolesence


Atypical absent seizures

Atypical absent seizures

  • Lapse of consciousness is of longer duration, less abrupt in onset and cessation, more obvious motor signs

  • Associated with diffuse or multifocal structural abnormalities of the brain – may be accompanied by mental retardation


Generalised tonic clonic seizures grand mal

Generalised tonic clonic seizures (grand mal)

  • Main type in 10% of epilepsy

  • Most common seizure resulting from metabolic derangements

  • Begins abruptly without warning, may report vague premonitory symptoms

  • Initial phase – tonic contraction of muscle throughout the body

    • Ictal cry – moan due to contraction of muscles of expiration and the larynx

    • Contraction of jaw muscles -> biting of the tongue

    • UP sympathetic tone -> UP HR, BP, papillary size

  • 10-20s tonic phase evolves into clonic phase – superimposition of periods of muscle relaxation on the tonic muscle contraction

  • Periods of relaxation increase until the end of the ictal phase which generally last 1 minute

  • Postictal phase – unresponsive, muscle flaccidity, excessive salivation, bladder or bowel incontinence – patient gradually regains consciousness, typically a period of confusion

  • Complains of headache, fatigue, muscle ache for many hours following the seizure


Atonic seizures

Atonic seizures

  • Sudden lost of postural muscle tone lasting 1-2 seconds

  • Consciousness briefly impaired, no postictal confusion

  • Very brief – quick head drop or nodding movement, if longer – collapse – substantial risk of head injury with the fall


Myoclonic seizures

Myoclonic seizures

  • Myoclonus – sudden and brief muscle contraction that may involve one part of the body or the entire body

  • Physiologically common – sudden jerking movement observed while falling asleep

  • Pathological – metabolic disorders, degenerative CNS diseases, anoxic brain injury


Epilepsy syndromes

Epilepsy syndromes

  • Juvenile myoclonic epilepsy – appears early adolescnce, bilateral myoclonic jerks, most frequently in morning on awakening, provoked by sleep deprivation, may have generalised tonic-clonic, often FHx

  • Lennox-Gastaut syndrome

    • Occurs in children – following triad – multiple seizure types, EEG slow spike and wave discharge, impaired cognitive function

    • Associated with developmental abnormalities, perinatal hypoxia/ischaemia, trauma, infection etc

    • Poor prognosis – underlying CNS disease, uncontrolled epilepsy

  • Mesial temporal lobe epilepsy


Mesial temporal lobe epilepsy

Mesial temporal lobe epilepsy

  • Most common syndrome associated with complex partial seizures – symptomatic, partial epilepsy with distinctive clinical, electroencephalographic and pathologic features

  • Refractory to anticonvulsants, responds well to surgical intervention

  • History – febrile seizures, family history of epilepsy, seizures may remit and reappear, early onset, often intractable

  • Clinical observations – aura common, behavioural arrest/stare, compelx automatisms, unilaterial posturing, postictal disorientation, memory loss, dysphasia

  • Lab studies – unilateral or bilateral anterior temporal spikes on EEG, hypometabolism on interictal PET, hypoperfusion on interictal SPECT, material specific memory deficits on Wada test

  • MRI – small hippocampus with increased signal on T2-weighted sequences, small temporal lobe, enlarged temporal horn

  • Path – highly selective loss of specific cell populations within hippocampus in most cases


Causes of seizures and epilepsy

Causes of seizures and epilepsy

  • Seizures result from a dynamic interplay between endogenous factors, epileptogenic factors and precipitating factors

  • Causes according to age

    • Neonatal, infancy: hypoxic-ischemic encephalopathy, trauma, CNS infections, congenital, metabolic (B6), drug withdrawal

    • Late infancy, early childhood: febrile

    • Childhood: well-defined epilepsy syndromes present, mesial temporal lobe sclerosis, cortical dysgenesis, CNS infection, CNS tumor

    • Adolescence and early childhood: idiopathic or genetically based syndromes become less common, epilepsy secondary to acquired CNS lesions begins to predominate – head trauma, infection, tumors, drug use, alcohol withdrawal

    • Adolescents, adults: head trauma

    • Older adults: Cerebrovascular disease, trauma, CNS tumors, degenerative diseases


Basic mechanisms

Basic mechanisms

  • Mechanisms of seizure initiation and propagation

    • Partial – discrete region of the cortex and then spread

      • Separate initiation and propagation phases

    • Initiation – two events

      • High frequency bursts of APs

      • Hypersynchronization

    • Spread is usually prevented by

      • Intact hyperpolarisation and a region of surrounding inhibition created by inhibitory neurons

    • With sufficient activation surrounding neurons are recruited. Repetitive discharges lead to the following:

      • Increase in extracellular K which blunts hyperpolarisation and depolarizes neighbouring neurons

      • Accumulation of Ca in presynaptic terminals – enhanced neurotransmitter release

      • Depolarisation induced activation of the NMDA subtype of excitatory amino acrid receptor -> Ca influx -> neuronal activation

    • Mechanisms controlling neuronal excitability

      • Intrinsic: changes in conductance of ion channels, response characteristics of membrane receptors, cytoplasmic buffering, second-messenger systems, protein expression, posttranslation modification

      • Extrinsic: change in amount or type of neurotransmitter present in the synapse, modulation of receptors by extracellular ions and other molecules, and temporal and spatial properties of synaptic and nonsynaptic input


Mechanisms of action of anti epileptic drugs

Mechanisms of action of anti-epileptic drugs

  • Primarily act by blocking the initiation or spread of seizures

  • Inhibition of Na dependent action potentials in a frequency dependent manner – phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide

  • Inhibition of voltage gated Ca channels - phenytoin

  • Decrease of glutamate release – lamotrigine

  • Potentiation of GABA receptor function – benzodiazepines, barbiturates

  • Increase in the availability of GABA – valproic acid, gabapentin, tiagabine

  • Modulation of the release of synaptic vesicles – levetiracetam

  • Two most effect drugs for absence seizures – ethosuximide, valproic acid -> inhibit T type Ca channels in thalamic neurons


Hx and examination of pc of seizure

Hx and Examination of PC of seizure

  • History and examination

  • Is the event truly a seizure

    • Symptoms before, during and after the seizure – witnesses interviewed carefully

  • Predisposition to seizures: febrile seizures, auras, brief seizures

  • Exam – signs of infection or systemic illness

    • Skin – neurocutaneous disorders (neurofibromatosis, chronic liver or renal)

    • Organomegaly – metabolic storage disease

    • Head trauma, alcohol or illicit drugs

    • MSE


Investigations

Investigations

  • Labs

    • Bloods – common metabolic causes of seizures – electrolytes, glucose, calcium, Mg, hepatic or renal disease

    • Toxins – blood and urine is patient is in appropriate age groups

    • LP – meningitis or encephalitis – mandatory if HIV

  • Electrophysiologic studies

    • EEG for all patients with a possible seizure disorder

    • Portable EEG or continuous monitoring in hospital

    • MEG – magnetoencephalography – measures small magnetic fields that are generated by the electrical activity of the brain – can determine potential seizure foci

  • Brain imaging

    • All patients – determine if there is an underlying structural abnormality – only exception is children who have an unambiguous history and examination suggestive of a benign, generalised seizure disorder

  • MRI superior to CT


Important ddx s of seizures

Important DDx’s of seizures

  • Syncope – observations by patients and bystanders may help

    • Stereotypically transition into unconsciousness – tiredness, sweating, nausea, tunnelling of vision

    • Brief period of convulsive motor activity is frequently seen immediately at the onset of a syncopal episode – rarely a syncopal episode can induce a full tonic-clonic seizure

  • Psychogenic seizures

    • Nonepileptic behaviours that resemble seizures

    • Associated with: side to side turning of head, asymmetric and large amplitude shaking movements of the limbs, twitching of all four extremities without loss of consciousness, pelvic thrusting

    • Often last longer

    • Distinction difficult on clinical grounds alone

    • EEEG monitor


Treatment

Treatment

  • Underlying conditions

    • Metabolic – treat disorder, antiepileptic drugs usually unnecessary

    • Drug use – no need for antiepileptic meds

    • CNS lesion – treat lesion – risk seizure focus will remain – antiepileptic medication for at least 1 year, withdraw medications only if patient has been seizure free

  • Avoidance of precipitating factors

    • Some can identify particular situations, most can not

    • Alcohol intake and seizures, sleep deprivation, stress and seizures

  • Antiepileptic drug therapy

    • Risk factors associated with recurrent seizures

      • Abnormal neurologic exam

      • Status epilepticus

      • Postictal Todd’s paralysis

      • Strong family history

      • Abnormal EEG


Anti epileptic medication per seizure disorder

Anti-epileptic medication per seizure disorder

  • Primary generalised clonic tonic – valproic acid, lamotrigine, topiramate

  • Partial – carbamazepine, phenytoin, lamotrigine, oxcarbazepine, valproic acid

  • Absence – valproic acid, athosuximide

  • Atypical absence, myoclonic, atonic – valproic acid, lamotrigine, topiramate


Status epilepticus

Status epilepticus

  • Continuous seizures or repetitive discrete seizures with impaired consciousness in the interictal period

  • Numerous subtypes – generalised convulsive status epilepticus (GCSE), nonconvulsive status epilepticus

  • Duration to be status epilepticus – 15-30 minutes

  • GCSE – emergenry and most be treated immediately – common causes – anticonvulsant withdrawal, metabolic disturbances, drug toxicity, CNS infection, CNS tumors, refractory epilepsy, head trauma

  • Mangement of GCSE – attend to acute cardioresp problems or hyperthermia, brief medical and neuro exam, establish venous access, send sample for lab studies to identify metabolic abnormalities


Women and seizures

Women and seizures

  • Catamenial epilepsy – marked increase in seizure frequency around the time of menses – effects of oestrogen progesterone on neuronal excitability – acetazolamde – effective adjunctive therapy started 7-10 days prior to menses continue till bleeding stops

  • Pregnancy – most will have an uncomplication pregnancy. Seizure frequency may change due to endocrine effects on the CNS. Fetal abnormalities is 5-6% compared to 2-3%.

  • Contraception – some epilepsy meds can rapidly antagonize the effects of oral contraceptives

  • Breast feeding – antiepileptic medications are excreted in the breast milk to a variable degree. Should still be encouraged to breast feed. Stop if any evidence of drug effects on the infant.


Cns tumours

CNS tumours


Diffuse atrocytoma morphology

Diffuse atrocytoma - morphology

  • Diffuse astrocytoma

    • Gross – poorly defined, gray, infiltrative mass – expands and distorts the invaded brain

    • Tumour may be centimetres or take up an entire hemisphere

    • Cut surface – firm, or soft and gelatinous, cystic degeneration may be seen

    • Micro: mild to moderate increase in glialcellularity, variable nuclear pleomorphism, intervening feltwork of fine GFAP-positive astrocytic processes that give the background a fibrillary appearance

    • Transition between neoplastic and normal tissue is indistinct


Glioblastoma multiforme morphology

Glioblastoma (multiforme)- morphology

  • Tumour varies in gross appearance from region to region

    • Some white and firm, others soft and yellow due to necrosis, others show cystic degeneration and hemorrhage

    • Histo: same as anaplasticastrocytoma plus necrosis and vascular or endothelial cell proliferation (malignant astrocytes produce VEGF)

    • Tumour signs along the edge of necrosis produce a pattern called pseudopalisading

    • Vascular cell proliferation – tufts of piled up cells that bulge into the lumen, minimal criteria – double layer

      • Marked vascular proliferation tuft forms a ball-like structure – the glomeruloid body


Infiltrating astrocytomas genetics clinical features

Infiltrating astrocytomas – genetics, clinical features

  • Molecular genetics

    • Low grade - P53, overexpression of PDGF and its receptor

    • High grade – RB, p16.CDKNaA, unknown tumour suppressor on 19q

    • Glioblastoma

      • Adults – new onset – primary glioblastoma – MDM2 (code inhibitor for p53), EGRF

      • Younger – Hx of low grade astrocytoma – secondary glioblastoma – p53, PDGF-A receptor

      • Same pathways but different mutations – RAS, PI-3 kinase

      • P53, RB present in 80-90% of primary glioblastomas

  • Clinical features

    • Symptoms depend on location and growth rate of the tumour

    • High grade astrocytomas – abnormal vessels that are leaky – demonstrate contrast enhanacement

    • Glioblastoma – prognosis is very poor

      • Treat: tyrosine kinase inhibitors that target EGFR -> encouraging

      • Mean length of survival after diagnosis – 15 months


Pilocytic astrocytoma

Pilocyticastrocytoma

  • Grade I/IV – relatively benign

  • Typically occur in childhood and young adults

  • Located cerebellum, also in floor and walls of the third ventricle, optic nerves, cerebral hemispheres

  • Morphology

    • Macro: cystic, often well circumscribed, less frequently infiltrative

    • Micro: bipolar cells with long thin hairlike processes that are GFAP positive and form dense fibrillarymeshworks; rosenthal fibres and eosinophilic granular bodies often present

    • Tumour often biphasic, loose microcystic pattern in addition to fibrillary areas.

    • Increase in number of blood vessels, often with thickened walls is seen

  • Tumours grow slowly, can often be resected (particularly in the cerebellum)

  • Symptomatic resurgence associated with cyst enlargement rather than recurrence

  • If extends into hypothalamic region – more ominous clinical course


Pleomorphic xanthoastrocytoma

Pleomorphicxanthoastrocytoma

  • Most often temporal lobe of children and young adults – history of seizures

  • Consists of neoplastic occasionally bizarre astrocytes, sometimes lipidised – often express neuronal and glial markers, degree of nuclear atypia may be extreme, presence of abundant reticulindepositis, relative circumscription, chronic inflammatory cell infiltrates, absence of necrosis and mitotic activity

  • Low grade tumour – WHO II/IV, 5 year surivival 80%


Oligodrendroglioma morphology

Oligodrendroglioma - morphology

  • 5-15% of all gliomas, most common in the fourth and fifth decade

  • Patients may have several years of neuro complaints – seizures

  • Cerebral hemisphere, predilection for white matter

  • Morphology

    • Gross – well circumscribed, gelatinous, gray masses, cysts, focal haemorrhage, calcification

    • Micro – sheets of regular cells with spherical nuclei containing finely granular chromatin surrounded by a clear halo of cytoplasm, tumor contains a delicate network of anastomosing capillaries

    • Calcification – present in 90%, ranges from microscopic to massive deposits

    • Perineuronalsatellitosis – as tumour cells infiltrate cerebral cortex there is formation of secondary structures with tumour cells arrayed around neurons

    • WHO II/IV

    • Anaplasticoligodendrogliomas

      • WHO grade III/IV – increased cell density, nuclear anaplasia, increased mitotic activity, necrosis

      • Can often be found in nodule within an otherwise grade II/IV oligodendroglioma

      • Also often present – discrete round cells, cytoplasmic GFAP and nuclei that resemble the other elements of the tumor – microgemistocytes – lack abundant processes

      • May appear similar to glioblastoma


Oligodendroglioma genetics clinical

Oligodendroglioma – genetics, clinical

  • Molecular genetics

    • Loss of heterozygosity for 1p and 19q – 80% of cases

    • Tumour suppressor genes involved remain unknown

  • Clinical features

    • Better prognosis than astrocytoma

    • Average survival 5-10 years

    • Progression from low to high grade occurs over 6 years


Ependymoma morphology

Ependymoma - morphology

  • Most often arise next to the ependymal lined ventricular system

  • First two decades of life – near fourth ventricle – 5-10% of primary brain tumours

  • Adults – spinal cord, frequently in the setting of neurofibromatosis type 2

  • Morphology

    • Fourth ventricle – solid or papillary masses extending from the floor of the ventricle – total removal is not feasible due to proximity to other areas of the brain

    • Intra-spinal tumours – sharp demarctation – total removal feasible

    • Micro – cells with regular, round to oval nuclei with abundant granular chromatin, variably dense fibrillary background between the nuclei

      • Tumour cells may form glandlike round or elongated structures (rosettes, canals) resemble the embryologic ependymal canal

      • Perivascularpseudorosettes – tumor cells are arranged around vessels with an intervening zone consisting of thin ependymal processes directed toward the wall of the vessel

    • Anaplasticependymomas – III/IV – reveal increased cell density, high mitotic rates, areas of necrosis, less evident ependymal differentiation

    • Myxopapillaryependymomas

      • Occur in the filumterminale of the pinal cord and contain papillary elements in a myxoid background, admixed with ependymoma like cells

      • Cuboidal cells – clear cytoplasm, arranged around papillary cores containg connective tissue and blood vessels


Ependyoma genetics clinical

Ependyoma – genetics, clinical

  • Molecular genetics

    • NF2 gene on 22 for ependymomas on spinal cord

    • Chromosome 9 for others

  • Clinical features

    • Posterior fossa – hydrocephalus secondary to progressive obstruction of the 4th ventricle rather than invasion of the pons or medulla

      • Worst clinical outcome – 5 year survival 50%


Other paraventricular mass lesions

Other paraventricular mass lesions

  • Subependymomas

    • Solid, sometimes calcified, slow growing nodules attached to the ventricular lining

    • usually asymptomatic, if sufficiently large may cause hydrocephalus

    • most often in lateral or 4th ventricle

    • micro: clumps of ependymal appearing nuclei scattered in a dense, fine, glialfibrillar background

  • Choroid plexus papillomas

    • Anywhere in the choroid plexus, common in children, usually found in the lateral ventricle, adults – 4th ventricle

    • Almost exactly recapitulate the structure of the normal choroid plexus

    • Hydrocephalus (obstruction) , or overproduction of CSF

    • Choroid plexus carcinoma (far rarer) – adenocarcinoma – children

  • Colloid cyst of the third ventricle

    • Non-neoplastic, occurs in young adults

    • Attached to the roof of the third ventricle, obstruct one or both of the foramina of Monro -> noncommmunicating hydrocephalus – rapidly fatal

    • Positional headache

    • Cyst – thin, fibrous capsule, lining of low to flat cuboidal epithelium – contains gelatinous, proteinaceous material


Medulloblastoma clinical genetic

Medulloblastoma – clinical, genetic

  • Children, exclusively in the cerebellum

  • Neuronal and glial markers may be expressed, often largely undifferentiated

  • Molecular genetics

    • Loss of material from 17p, MYC amplification -> more aggressive

    • Hedgehog pathway, NWT, Notch

  • Clinical

    • Highly malignant, prognosis for untreated patients is dismal

    • With total excision and irradiation – 5 year survival 75%


Medulloblastoma morphology

Medulloblastoma - morphology

  • Morphology

    • Children – located in the midline of the cerebellum, lateral locations more often in adults

    • Rapid growth – csf occlusion – hydrocephalus

    • Tumour well circumscribed, gray, friable, may extend to the surface of the cerebellar folia and involve the leptopmeninges

    • Micro – extremely cellular, sheets of anaplastic cells, tumor cells are small, scant cytoplasm, hyperchromatic nuclei, frequently elongated or crescent shaped, mitoses are abundant

    • Tumour may express neurosecretory granules (Homer Wright rosettes) as occur in neuroblastomanadglial phenotypes

    • Desmoplastic variant – areas of stromal response, marked by collagen and reticulin deposition, nodules of cells forming pale islands – more neuropil, greater expression of neuronal markers

    • At the edge of tumor – linear chains of cells infiltrating through the cerebrellar cortex to aggregate beneth the pai, penetrate the pia, and sed into the subarachnoid space – dissemination through the CSF is a common complication – metastases to the caudaequina – drop metastases


Atypical teratoid rhabdoid tumor

Atypical teratoid/rhabdoidtumor

  • Highly malignant tumor of young children occurs in the posterior fossa and supratentorial compartments

  • Presence of rhabdoid cells – resembling those of a rhabdomyosarcoma is the defining characteristic of this lesion

  • Morphology

    • Large, soft consistency, spread along the surface of the brain

    • Rhabdoid cells – eosinophilic cytoplasm, sharp cell broders, eccentrically located nuclei – if smaller cell mimicksrhabdomyosarcoma

    • Prominent mitotic activity

  • Molecular genetics – chromosome 22

  • Clinical

    • Highly aggressive, nearly all before the age of 5, patients live less than a year after diagnosis


Primary cns lymphoma

Primary CNS lymphoma

  • 2% of extranodal lymphomas, 1% of intra-cranial tumors

  • Most common CNS neoplasm in immunosuppressed patients

  • Non-immunosuppressed – frequency increases after the age of 60

  • Often multifocal within the brain parenchyma, involvement outside the CNS is a rare and late complication

  • Most B cell, possible association with EBV

  • Morphology

    • Lesions frequently multiple, involve deep gray matter as well as white matter and cortex

    • Periventricular spread is common

    • Tumors well defined but not as discrete as metastases, often show extensive areas of central necrosis

    • Diffuse large B cell – most common histological group

    • Tumor cells infiltrate parenchyma accumulate around blood vessels

    • Reticulin stains – infiltrating cells are separated for one another by silver-staining material – referred to as hooping – characteristic of primary brain lymphoma

    • Cells express B cell markers, BCL-6, markers of EBV infection

  • Intravascular lymphoma

    • Tumor cells grow intraluminally within small vessels, often involves the brain

    • Occlusion of vessels by malignant cells can result in widespread microscopic infarcts

    • Affected individuals will present with evidence of multifocal lesions, DDx – vasculitis, showers of emboli


Pineal parenchymal tumours

Pineal parenchymal tumours

  • Arise from specialised cells of the pineal gland – features of neuronal differentiation

  • Range form well differentiated lesions (pineocytomas – neuropil, small round nuclei, no evidence of mitoses or necrosis) to high grade tumors (pineoblastomas, little evidence of neuronal differentiation, densely packed small cells with necrosis, frequent mitotic figures).

  • High grade – children, low grade – adults

  • Pineoblastoma commonly spreads through the CSF

  • Associated with retinoblastoma mutation


Meningiomas genetics clinical

Meningiomas – genetics, clinical

  • Benign tumors of adults, usually attached to the dura – arise from the meningothelial cell of the arachnoid

  • May be found along any of the external surfaces of the brain as well as within the ventricular system

  • Prior radiation therapy, typically decades earlier is a risk factor

  • Other metastases may grow as dural-based masses

  • Molecular genetics – loss of chromosome 22 (NF2 gene)

  • Clinical features

    • Usually slow growing present with vague nonlocalizing symptoms, or with focal findings referable to compression of underlying brain

    • Common sites of involvement – parasagittal aspect of brain convexity, dura over lateral convexity, wing of the sphenoid, olfactory groove, sellaturcica, formaen magnum

    • Uncommon in children, 3:2 female predominance (10:1 for spinal)

    • Often express progesterone receptors – may grow more rapidly during pregnancy


Meningioma morphology

Meningioma - morphology

  • Rounded masses with well-defined dural bases that compress the underlying brain but are easily separated from it

  • Surface of the mass is encapsulated with thin, fibrous tissue nad may well have a bosselated or polypoid appearance

  • May also grow en-plaque – tumor spreads in a sheet like fashion along the surface of the dura – associated with hyperostotic reactive changes in the overlying bone

  • Lesions range from firm and fibrous to finely gritty, may contain numerous calcified psammoma bodies, gross evidence of necrosis or extensive haemorrhage is not present

  • Low risk of recurrence or aggressive growth – I/IV

  • Various histo patterns

    • Syncytial – whorled clusters of cells that sit in tight groups without visible cell membranes

    • Fibroblastic – elongated cells, abundant collagen deposition between them

    • Transitional – shares features of syncytial and fibroblastic

    • Psammomatous – psammoma bodies – formed from calcification of syncytial nests

    • Secretory – with PAS positive intracytoplasimc droplets

    • Microcystic – loose, spongy appearance

  • Atypical meningiomas (II/IV)

    • Higher rate of recurrence, more aggressive local growth – radiation in addition to surgery

    • Distinguished by mitotic index of 4 or more per 10 power fields or at least three atypical features

  • Anaplasticmeningioma (III/IV)

    • Highly aggressive tumor, appearance of a high-grade sarcoma

    • Mitotic rates are extremely high >20

    • Papillary meningioma – pleomorphic cells arranged around fibrovascular cores

    • Rhabdoidmeningioma – sheets of tumor cells with hyaline eosinophilic cytoplasm containing intermediate filaments

    • Papillary and rhabdoidmeningioma – III/IV

  • Some meningiomas will infiltrate the brain


Metastatic tumours in the cns

Metastatic tumours in the CNS

  • ¼ to ½ of intra-cranial tumors in hospitalised patients

  • Five most common primary sites – lung, breast, skin, kidney, GIT

  • Choriocarcinoma has a high likelihood of metastasising

  • Present clinically as mass lesions

  • Morphology

    • Intraparenchymal metastases – sharply demarcated masses, junction of gray and white matter, usually surrounded by a zone of oedema

    • Boundary is well deifned

    • Meningealcarcinomatosis – carincoma of lung and breast


Paraneoplastic syndromes of cns tumours

Paraneoplastic syndromes of CNS tumours

  • Main mechanism appears to be a immune response against tumour antigens

  • Well recognised syndromes- patterns of encephalomyelitis

    • Subacute cerebellar degeneration – destruction of purkinje cells, gliosis, mild inflammatory infiltrate may be present

    • Limbic encephalitis – subacute dementia, pervascular inflammatory cuffs, microglial nodules, some neuronal loss, gliosis – anterior, medial portions of temporal lobe

    • Eye movement disorders – opsoclonus, in associated with other evidence of cerebellar and brainstem dysfunction. IN children assoc w neuroblastoma, myoclonus also found

  • Peripheral NS

    • Subacute sensory neuropathy – loss of sensory neurons from dorsal root ganglia, in association with lymphocytic infiltration

    • Lambert-Eaton myasthenic syndrome


Schwannoma

Schwannoma

  • Benign tumours from neural crest-derived Schwann cells

  • Component of NF2 – inactivating mutation of NF2 gene (product Merlin – normally restricts EFGR)

  • Morphology

    • Well-circumscribed encapsulated gray masses, may be separated from the nerve

    • May have cystic and xathomatous change

    • Micro

      • Antoni A pattern of growth – elongated cells with cytoplasmic processes arragned in fasciles in areas of moderate to high cellularity

      • Nuclear free zones of processes that lie between the regions of nuclear palisading are termed Verocay bodies

      • Antoni B – less cellular, loose meshwork of cells, microcysts and myxoidstroma

      • Silver stains demonstrate axons are largely excluded from the tumour

    • Malignant change extremely rare, but local recurrence can follow incomplete resection

  • Clinical features

    • Most schwannomas occur at the cerebellopontineangile -> attached to vestibular branch of the 8th nerve

    • Present – tinnitus, hearing loss -> acoustic neuroma (although it is vestibular)

    • Extradural – associated with large nerve trunks


Neurofibroma

Neurofibroma

  • Can present as discrete localised masses

    • Cutaneousneurofibroma – present in dermis and sub cut fat, skin lesions, nodules, overlying hyerpigmentation

    • Solitary neurofirboma - in a peripheral nerve

    • Plexiformneurofibroma – growing within and expanding a peripheral nerve – may result in severe neuro deficits – significant potential for malignant transformation

    • Suggests diagnosis of NF-1

  • Morphology

    • Cutaneousneurofibroma – composed of spindle cells, straom is highly collagenised, little myxoid

    • Plexiformneurofibroma – large nerve trunks most commonly affected

      • Frequrently multiple

      • Affected nerve – irregularly expanded, not possible to separate from tumour

      • Micro – loose myxoid background, low cellularity

      • Several cell types present – Schwann cells – elongated nuclei, larger multipolar fibroblastic cells, sprinkling of inflammatory cells

      • Shred carrot appearance – areas of dense collagen bundles

    • NF-1 – produces neurofibromin – stimulates activity of GTPase that inhibits RAS activity


Malignant peripheral nerve sheath tumour

Malignant peripheral nerve sheath tumour

  • Locally invasive, frequently with multiple recurrences, and eventual metastatic spread

  • 50% arise in setting of NF-1 – transformation of plexiform or radiation therapy

  • Alterations – p53, RB dependent pathways

  • Morphology

    • Poorly defined masses, infiltrate along axis of parent nerve, invade adjacent tissue

    • Micro – wide range

      • Patterns like fibrosarcoma or pelomorphic sarcoma

      • Tumour cells resembling Schwann cells

      • Mitoses, necrosis, extreme nuclear anaplasia are common

    • Immunoreactive for S-100 protein

    • Triton tumour – rhabdomyoblastic differentiation

    • Epithelioid malignant schwannomas – aggressive variant, tumour cells with visible cell borders that grow in nests, S-100, but not keratin


Familial tumour syndromes

Familial tumour syndromes

  • Syndromes which include CNS tumours, but bulk of disease lies elsewhere

    • Cowden syndrome – dysplastic ganglioglicytoma of the cerebellum – AKT, mTOR

    • Li-Fraumeni syndrome – medulloblastomas – p53

    • Turcot syndrome – medulloblastoma or glioblastoma – APC, mismatch repair genes

    • Gorlin syndrome – medulloblastoma – PTCH – sonic hedgehog


Neurofibromatosis type i

Neurofibromatosis type I

  • Autosomal dominant, 1 in 3000

  • Characterised by

    • Neurofibromas – plexiform, solitary

    • Gliomas of the optic nerve

    • Pigmented nodules of the iris – Lisch nodules

    • Cutaneoushyperpigmentedmacules – Café’ au lait spots

  • Increased propentsity for plexiformneurofibromas to undergo malignant change

  • NF-1 – 17q11.2, codes neurofibromin – GTP-ase activating domain that inhibits RAS

  • Course of disease is highly variable


Neurofibromatosis type ii

Neurofibromatosis type II

  • Autosomal dominant disorder resulting a range of tumours

    • Bilateral 8th nerve schwannomas

    • Multiple meningiomas

    • Gliomas – typically ependyomomas of the spinal cord

  • Many have non-neoplastic lesions

    • Nodular ingrowth of schwanna cells – schwanosis

    • Meningoangiomatosis – proliferation of meningeal cells and blood vessels that grow into the brain

  • Less common than NF-1 frequency of 1 in 40,000 to 50,000

  • NF2 gene, chromosome 22q12, merlin – regular membrane receptor signalling – contact growth factor inhibition


Tuberous sclerosis complex

Tuberous sclerosis complex

  • Autosomal dominant syndrome – frequency 1 in 6000 births

  • Characterised – hamartomas and benign neoplasms involving the brain and other tissues

  • CNS

    • Cortical tubers (epileptogenic) and subqpendymal nodules, subependymal giant-cell astrocytomas

  • Elsewhere

    • Renal angiomyolipomas, retinal glialhamartomas, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas

  • Cysts found at various sites – liver, kidney, pancreas

  • Cutaneous lesions – angiofibromas, localised leathery thickenings(shagreen patches), hypopigmented areas (ash-leaf patches)

  • TSC1 – 9q34, encodes protein – hamartin

  • More common TSC2 – 16p13.3 – encodes protein tuberin

  • Tuberin and hamartin – form a complex inhibits mTOR- control cell size

  • Treatment – symptomatic

  • Morphology

    • Cortical hamartomas – firm areas of cortex – likened to potatoes – tubers

    • Candle guttering – multiple droplike masses that buldge into the ventricular system


Von hippel lindau disease

Von Hippel-Lindau disease

  • Autosomal dominant disease

  • Develop hemaingionblastomas and cysts involving the pancreas, liver, kidneys

  • Propensity to renal cell carcinomas, pheochromocytoma

  • Hemangioblastomas – cerebellum and retina

  • Frequency 1 in 30,000 to 40,000

  • VHL 3p25-p26, codes component that down regulaes hypoxia induced factor HIF-1 – involved regulating expression of vascular endothelial growth factors, EPO other factors

  • Morphology

    • Hemangioblastomas – highly vascular neoplasms – mural nodules associated with a large fluid-filled cyst

    • Micro – variable proportions of capillary size or somewhat larger thin walled vessels, intervening stromal cells – vacuolated lightly PAS-positive, lipid rich cytoplasm

  • Therapy – symptomatic neoplasms, resection of the cerebellarhemangioblastomas, laser therapy for retinal hemangioblastomas


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