Common Mechanisms of Brain Damage

LECTURE OUTLINE

Common mechanisms of brain damage

Acute hypoxic disorders

Cerebral haemorrhage

Head Injury

Direct blows to the head

Non-missile head injury

Acceleration

Deceleration

Rotation

Delayed complications

Late complications

Dementia

Alzheimers

Infections

Bacterial

Viral

Fungal

Protozoal

ACUTE HYPOXIC DISORDERS

NB: Arterial BP > 50mmHg

Brain has no reserves of O2 / glucose

ð must receive constant supply via arterial routes

Conditions that give rise either singly or in combination to cerebral hypoxia

CEREBRAL INFARCTION

Two main forms of stroke =

Cerebral infarction

Spontaneous intracerebral haemorrhage

NB – infarction is usually combination of occlusion + central circulatory deficiency

Lesion = liquefactive (distinctive) necrosis

LOCAL ARTERIAL DISEASE = most common cause

2. Arterial Stenosis – caused by atheroma

Mechanism – potentiates cerebral perfusion deficiency by

- redistribution of normal arterial flow

- favouring anastomses instead of the main routes

Again infarction is usually a result of a combination of reduced arterial perfusion as in sleep to shock / M.I. and the Atheromatous stenosis

Rare causes of arterials tenosis:

1. dissecting aneurysm

2. arteritis

3. arterial spasm

Sites:

1. Occlusion = internal structures supplied by “end” arterial branches (middle cerebellar artery)

2. Reduced arterial perfusion = boundary zones

CEREBRAL HAEMORRHAGE (in brain tissue)

Usually localized arterial disease aggravated by hypertension

Hypertensives (50yrs) – microaneurysms in small cerebral arteries – can rupture leading to intracerebral haemorrhage forming haematoma.

Common site = middle cerebral artery – basal ganglia + internal capsule

Progress:

Sudden onset with headache

Large haemorrhage

Associated raised ICP effects

Death

Apoplectic cyst = cystic space containing yellow-brown fluid / formed when bleeding is limited

SUBARACHNOID HAEMORRHAGE

· Usually rupture of berry aneurysm in Circle of Willis

· Congenital weakness of arterial wall elastic tissue

· Hypertension

Sites:

CSF findings:

1-24 HOURS = blood stained and constant in sequential samples

24 HOURS on = supernatant shows xanthochromia (yellow colour due to blood degradation products)

HEAD INJURY

Direct blow to head = missile head injury

Scalp – laceration +/-haematoma

Skull – comminuted fracture with depressed fragments

Brain – contusion, laceration or haematoma

Non-missile head injury

Skull fractures

Frontal & Temporal contusion (middle fossa & orbital plate)

Rotation = diffuse damage presents as minute haemorrhages & shearing injury to corpus callosum (axonal bulbs)

Delayed complications

1. extradural haematoma (direct blow)

2. subdural haematoma

3. intracerebral haematoma

4. cerebral edema

5. external leakage of CSF & blood from ear and nose

6. Local infection

Late complications:

1. epilepsy

2. chronic subdurla haematoma

DEMENTIA

DEF: an acquired progressive global impairment of intellect, memory and personality without impairment of consciousness.

5% > 65 years

20% > 80 years

Causes:

1. Alzheimers

2. Multi-infarct dementia

3. lew body dementia

ALZHEIMER’S DISEASE

INFECTIONS

NB - PIA protects so usually infection in either brain substance (encephalitis/abscess) or meninges (meningitis)

BACTERIAL INFECTIONS

PRION DISEASE

DEF: Transmissible and genetic neurodegenerative diseases of humans and animals caused by prions. The diseases are usually characterised by vacuolation in the gray matter and result in ataxia, motor disturbances, dementia, and progression to a fatal outcome. They include creutzfeldt-jakob syndrome, gerstmann-straussler syndrome, kuru, scrapie, fatal familial insomnia, bovine spongiform encephalopathy (encephalopathy, bovine spongiform), transmissible mink encephalopathy, and chronic wasting disease of mule deer and elk. The literature has sometimes referred to these as unconventional slow virus diseases.

PRION = cell surface protein in brain cell membrane coded for by gene on chromosome 20

Normal = PrPc (PrP = prion prot.)

Abnormal = PrPsc (sc=scrapie)

PRION HYPOTHESIS = When abnormal PrPsc reaches normal PrPc in the brain it causes the PrPc to change its tertiary structure to an insoluble β-pleated (amyloid) plaque.

TYPES:

1. CJD (Creutzfeld-Jacob Disease) = can be (i) sporadic i.e. of unknown cause or (ii) acquired from infected corneal grafts / pituitary hormones or (iii) familial due to point mutation of PrPc gene.

2. New-variant CJD = younger patients / early psychiatric symptoms / longer clinical course. PrP strain is identical to bovine spongiform encephalopathy (BSE) is probably due to ingestion of products from infected cattle.

3. Other =

KURU (historical) / Ingestion of human brain
GERSTMANN-STRAUSSLER-SCHEINKER / Familial
BSE / Cattle
SCRAPIE / Sheep

PATHOLOGY

· Vacuoles around neurones & neuropil

· Immunohistochemistry uses Ab’s against PrPsc to detect fibrillary plaques

· Plaques are most numerous in occipital cortex of cerebellum

· Appearance = central core of amyloid surrounded by a halo of spongiform change

MISCELLANEOUS INFECTIONS & INFESTATIONS

FUNGAL

1. Meningitis – Crytpococcus neoformans shows neurotropism (healthy subjects)

2. Opportunistic infections – Candida / Aspergillus / Nocardia

Combination of several (typically three or four) antiretroviral drugs is known as Highly Active Anti-Retroviral Therapy (HAART).

PROTOZOAL

Cerebral Malaria – due to Plasmodium Falciparum

NB – Mechanism

· Massive parasitisation of erythrocytes

· Increased viscosity of blood with adherence of RBCs to cerebral capillary endothelium

· Sludging of blood

· Also acute haemolysis due to massive parasitisation

· Anaemia follows

· Both sludging and anaemia lead to SEVERE CEREBRAL HYPOXIA

· Coma

· Death

Toxoplasmosis

T. gondii in mother (congenital toxoplasmosis affects esp. brain & eye of fetus) =

1st trimester – abortion / still birth

2nd trimester – severe brain damage with secondary hydrocephalus

3rd trimester – moderate cerebral damage with chorioretinitis (Inflammation of the choroid and retina.)

T. gondii in immune compromised adults (opportunistic) =

Localized meningoencephalitis

Trypanosomiasis (African Sleeping Sickeness)

§ T. brucei from Tsetse fly in animal reservoirs

§ Nuerotropic causing meningoencephalitis

§ Histology: Cuffing infiltrate (i.e. luecocytes around / cuffing blood vessel) has many plasma cells

§ Congested cerebral capillaries

§ Mott cells = plasma cells distended by eosinophilic globules

MUTLIPLE SCLEROSIS (MS)

DEF: Neurodegenerative disease characterised by the gradual accumulation of focal plaques of demyelination particularly in the periventricular areas of the brain. Peripheral nerves are not affected. Onset usually in 3rd or 4th decade with intermittent progression over an extended period. Cause still uncertain.

Clinical Associations:

White Matter Signs – upper motor neuron weakness

Paralysis

Incoordination

Visual disturbances

Paraesthesia

Grey Matter signs are rare

Histology – No staining with Loyez stain in demyelinated areas

Lymphocytes in early stages

Axons remain

Glial fibers increase

Few oligodendrocytes

Demyelination Hypothesis:

· Latent viral infection + genetic predisposition (HLA A3/B7/DW2/DR2)

· Activation of CD4+ T cells

· Autoimmune attack on myelin

· Demyelination

PARKINSON’S DISEASE

DEF: A progressive, neurological disease first described in 1817 by James Parkinson.

The pathology is not completely understood, but there appears to be consistent changes in the melanin-containing nerve cells in the brainstem (substantia nigra, locus coeruleus), where there are varying degrees of nerve cell loss with reactive gliosis along with eosinophilic intracytoplasmic inclusions (Lewy bodies). Biochemical studies have shown below normal levels of dopamine in the caudate nucleus and putamen.

Disease of the extrapyramidal system.

Important neurotransmitters are DOPAMINE & γ-AMINOBUTYRIC ACID (GABA)

Aetiology:

Idiopathic = elderly population over 50 years (1% of over 60s)

Secondary = postencephalitic

Drug induced

Arteriopathy

Heavy metal poisoning

Clinical features are classical extrapyramidal damage:

o Mask-like expressionless face

o Drooling

o Bent posture

o “pill-rolling” tremor of hands

o Stiff shuffling gait

Histology = degenerative changes in extrapyramidal

nuclei

Depigmentation of substantia nigra

Reduced dopamine in affected nuclei

Loss of neurons

Lewy body inclusions in remaining neurones

DISORDERS OF MOTOR PATHWAYS

UPPER MOTOR NEURONS / LOW MOTOR NEURONS
STROKE
MS / POLIOMYELITIS
PERIPHERAL NEUROPATHY
TENDON REFLEXES INCREASED
PLANTAR REFLEX IS EXTENSOR / REFLEXES ABSENT
MUSCLE ATROPHY

SENSORY DISORDERS

· Tabes Dorsalis: tertiary manifestation of syphilis

§ Degeneration of the post. Nerve

§ roots of the lumbar cord

§ loss of vibration sense & reflexes

§ Ataxia (Failure of muscular coordination, irregularity of muscular action. Origin: Gr. Taxis = order)

§ Trophic skin ulcers

§ Severe joint pathology (Charcot’s joint see p 617)

PERIPHERAL NUEROPATHY

Mononeuropathy – compression of median nerve = carpal tunnel syndrome

Polyneuropathy – Toxic degeneration = diphtheria

Vit B def. = beri-beru

Inflammatory / immunological =

Guillain-Barre syndrome

Bell’s Palsy

o Def: unilateral facial weakness of sudden onset

o Inflammation and swelling with compression of facial nerve

o As nerve travels along bone adjacent to internal auditory meatus

o Recovery in 4-8 weeks

o Drooping & loss of facial expression on paralysed side

o Innervated muscles pull mouth across mid line

HYDROCEPHALUS

DEF:A condition marked by dilatation of the cerebral ventricles, most often occurring secondarily to obstruction of the cerebrospinal fluid pathways and accompanied by an accumulation of cerebrospinal fluid within the skull, the fluid is usually under increased pressure, but occasionally may be normal or nearly so. It is typically characterised by enlargement of the head, prominence of the forehead, brain atrophy, mental deterioration and convulsions, may be congenital or acquired and may be of sudden onset (acute h.) or be slowly progressive (chronic or primary b.).

1. Obstruction to flow of CSF

intracerebral flow = lat. Ventricle – via foramen of munro – third ventricle – via aqueduct of sylvius – fourth ventricle – via foramina magendie & luschka – subarachnoid space

extracerebral flow = subarachnoid space around cerebrum

Areas prone to obstruction:

§ Aqueduct of sylvius

§ Foramina of magendie & luschka

§ Subarachnoid space @ the interposition of tentorium cerebelli

If obstruction prevents CSF from reaching subarachnoid space = NON-COMMUNICATING hydrocephalus

When obstruction is in subarachnoid space = COMMUNICATING hydrocephalus

CAUSES:

Congenital (developmental) abnormalities

Arnold-chiari malformation

Congenital stenosis (Narrowing or stricture of a duct or canal. Origin: Gr. Stenosis) / atresia (Absence or closure of a natural passage or channel of the body; imperforation.) of aqueduct of Sylvius

Atresia of foramina of Magendie and Luschka

Acquired hydrocephalus

Cerebral tumour

Scarring following meningitis

EFFECTS:

Infant:

Great enlargement of the head

Prominent scalp veins

Forehead overhanging eyes

Fontanel remains open

Massive dilatation of ventricles

Thinning & stretching of the brain

Convolutons flattened

Older child / adult:

Dilatation of ventricles only because cranium

can’t expand

↑ICP

DEVELOPMENTAL ABNORMALITIES

Neural Tube defects

Spina Bifida – vertebral arch and meninges deficient

Meningocele – thin skin

rounded sac containing CSF

Meningomyelocele – skin defective

cord discplaced into sac

serious leg and bladder nerve deficit

infection through broken skin = complications

Diagnosis = α-fetoprotein leaks through defective skin covering with increased amounts in amniotic fluid

Complication= hydrocephalus

NON-SPECIFIC CLINICOPATHOLOGIC EFFECTS OF CEREBRAL TUMOURS

1. Local compression

2. Local atrophy

3. Atrophy and destruction of cerebral tissue

4. Signs of neuronal and tract deficit

5. Increasing occupation of limited space

6. ↑ ICP

7. Headache / vomiting / raised BP / slow pulse / papilloedema

8. Stupor (The partial or nearly complete unconsciousness, manifested by the subject's responding only to vigorous stimulation.)

9. Coma (A deep prolonged unconsciousness where the patient cannot be aroused. This is usually as the result of a head injury, neurological disease, acute hydrocephaly, intoxication or metabolic derangement. )

10. Death

TUMOUR CLASSIFICATION

SECONDARY

Multiple

Well delineated spherical nodules

Random distribution

Meningeal carcinomatosis = permeation of subarachnoid space by malignant cells

Primary sites

Prostate

Cervix

Lung

Breast

Kidney

Name / Cell of origin/histology / Population / Other
Astrocytoma / Astrocyte / Young adults / Low grade
Glioblastoma / Pleomorphic / mitoses / angiogenesis / NA / Highly malignant
Oligodendroglioma / Oligodendroglia / Cerebrum of adults / Shows calcification
Edpendymoma / Ependyma of ventricles & central spinal cord / Rare / Cause hydrocephalus
Medulloblastoma / Primitive nerve precursors (blast cells) / Infancy & childhood / In cerebellum
Retinoblastoma / Primitive nerve precursors (blast cells) / In children under three / In retina
Neuroblastoma / Precursor cells of autonomic system large soft haemorrhagic, necrotic / Infancy & childhood / Metastasis early to LNs / liver / bones
Meningiomas / Arachnoid granulations nearvenous sinuses / 15-20% of intracranial tumours / smooth firm lobulated / arises from broad base adjacent to the sagittal sinus
Hamartoma / Tumour like but non-neoplastic overgrowth of tissue that is disordered in structure.
Tumours of peripheral nerves
Acoustic neuroma / CN VIII in cerebellopontine angle / Compresses CN VIII causing tinnitus / deafness / Also compresses IV ventricle causing hydrocephalus
Neurofibromas / Solitary / multiple = neurofibromatosis / Rounded or fusiform swellings

CEREBROSPINAL FLUID

Normal Values

· The presence of any neutrophils in the CSF is unusual in normal children and should raise concern about bacterial meningitis

· Meningitis can occur in children with normal CSF microscopy. If it is clinically indicated, children who have a ‘normal’ CSF should still be treated with IV antibiotics pending cultures.

· CSF white cell count and protein level are higher at birth than in later infancy and fall fairly rapidly in the first 2 weeks of life. In the first week, 90% of normal neonates have a white cell count less than 18, and a protein level < 1.3 g/L.

Interpretation of abnormal results

White cell count / Biochemistry
Neutrophils
(x 106 /L) / Lymphocytes
(x 106/L) / Protein
(g/L) / Glucose
(CSF:blood ratio)
Normal
(>1 month of age) / 0 / 5 / < 0.4 / 0.6 (or 2.5mmol/L)
Normal term
neonate / 0 / 11 / <1.0 / 0.6 (or 2.1mmol/L)
Bacterial meningitis / 100-10,000
(but may be normal) / Usually < 100 / > 1.0
(but may be normal) / < 0.4
(but may be normal)
Viral meningitis / Usually <100 / 10-1000
(but may be normal) / 0.4-1
(but may be normal) / Usually normal

· Gram stain may be negative in up to 60% of cases of bacterial meningitis even without prior antibiotics.