PATHOLOGY

Brain tumours
Remember that the skull is a rigid closed box. There are 3 compartments.
Two are above the tentorium cerebelli (divided by the falx cerebri) and 1 below.

- There are 3 things inside the head: Blood, brain and CSF
- Brain: mixture of glial cells and neurones (equal volumes)
- Relatively small amount of blood inside the brain at any one time.
- Small volume of CSF and extracellular fluid.
- Very little space inside the head, when there is an expanding mass inside the head (whether
this is tumour, haemorrhage, abscess or anything else)
- Pressure in adult is about 15mmHg. In newborn baby it is atmospheric pressure
(because it is in connection with the outside)
- You can measure the intracranial pressure by doing a lumbar puncture and attaching
a sphygmomanometer to it. Alternatively you can drill a small hole into the head and
attach a transducer.
- As the volume expands the pressure stays more or less the same (however
after a certain volume, the pressure expands rapidly). Eventually the pressure
inside the head exceeds the cerebral perfusion pressure and you become brain dead.
- Neurological intensive care units frequently measure the intracranial pressure.
- Important to recognise it early.
- As a mass expands (e.g above the tentorium cerebelli) then it initially squashes the ventricles.
Then it will eventually cause brain tissue to herniate to the other side.
- Finally, it will cause herniation of the brain stem (from one side to the other). This is important
because the brainstem is supplied by small branches from the basilar artery. The basilar artery itself
is anchored and can’t move. Therefore the vessels stretch and tear. This causes
secondary haemorrhages which will cause death.

Oedema and hydrocephalus

Oedema: excess water in the extracellular space
Hydrocephalus: excess water in the ventricular system
Oedema
Normally we don’t produce significant ECF in the brain because we don’t have lymphatics in
the brain (and thus we would have no way of removing it).
 Additionally, the blood vessels in the brain have tight junctions and unless there is a
pathological condition they do not allow fluid to getting across.
Thus if breakdown in BBB, fluid gets out into the extracellular space, it builds up (due to lack of
lymphatics)
There are 2 reasons that you can get cerebral oedema:
- Vasogenic: tight junctions open. This can be due to trauma or a tumour. This is the one that is
most amenable to treatment (putting patient on ventilator etc)
- Cytotoxic: Here there is a problem with the sodium potassium pump. This is dependent on
oxygen and glucose. If this pump fails then sodium cant be pumped out of the cell. Thus water
enters and it swells. This is seen in ischaemia. There is not much you can do in this situation.

Hydrocephalus
Causes:
Loss of brain tissue, as you can’t have a vacuum in your skull, so CSF fills up the space.
Commonest cause of this is Alzheimer’s where you have lost brain tissue. Termed
hydrocephalus ex vacuo.

Overproduction/blockage/reabsorption failure.
- Remember the anatomy of the ventricular system. You have the choroids plexus which produces
the CSF. This is present throughout the ventricular system. The CSF flows from the lateral
ventricles through the foramen of Monro to the third ventricle. It then flows via the cerebral
aqueduct to the fourth ventricle. Then it can flow down the spinal cord or through the foramen of
 Luschke and the foramen of Megendie. It then flows around the superior saggital sinus to be
reabsorbed by the arachnoid villi.
- This circulates about 3 times a day.
- You cannot stop CSF from being produced.
- Thus if there is a blockage then the pressure will rapidly rise and you will die from raised
intracranial pressure quickly.
- Can produce too much CSF – choroids plexus papilloma/carcinoma. Note how the ventricles are
equally enlarged (this is sign of papilloma/carcinoma)

Circulation blockage – need to think of the anatomy and find out where the blockage is. (below
scan does not show where the blockage is) (on right can see that there is blockage of the foramen of
monro)

Chiari malformation
Note that there is a congenital defect where you have a small posterior fossa which is not
large enough for the contents. You get these scan changes
- Treatment is with neurosurgery to decompress the area.
- Note that newborn infant is when there is the first presentation.
- Associated with spina bifida.
- Can also present in later life though (presenting with headaches, raised intracranial pressure etc)

Brain tumours
- Primary brain tumours are reasonably rare. 10X more common to have secondary brain tumours
(especially from lung, breast etc). This often occurs in the context of late stage disseminated
disease.
- However, there may be the presentation of a single brain tumour met as the first presentation.
- They are common in children (as common as childhood leukaemia)
- Survival not improved in 60 years.
- 1 year median survival.

Causes
- Not really known
- Maybe some familial, radiation, viral factors etc. (Most have no known cause)
- Some conditions have increased risk e.g neurofibromatosis, von-Hippel Lindau etc
- Not really any carcinoma sequence that we are aware of (e.g dysplasia, CIS etc).
- Don’t find incidental brain tumours (not known what the precancerous state is)

Clinical presentation
- Raised intracranial pressure e.g headache. Especially worse in morning (because when
lying down, venous drainage from head is not as good as when standing up), then it progresses to
persisting throughout the day. Eventually patient begins to vomit (remember this is a cardinal
feature of raised ICP). As vomiting persists the patient will begin to get drowsy (as the raised ICP is
having an effect on cerebral perfusion). Then only matter of hours before coma
- Behavioural change not as common presentation now because all psychiatric patients have
brain imaging.
- Seizure: first time patient has a seizure after the age of 4-5 then the patient has a brain tumour
until proven otherwise. (this is because seizures are common in childhood and vast majority are not
due to brain tumours – as child gets older and especially adult who gets this must get MRI – CT is
useless, not good resolution)
- Neurological deficit – (as opposed to stroke, the deficit comes on gradually over time –
as the tumour expands).
 Classification
- Tend not to use term benign or malignant.
- Unlike other tumours in the body, ALL brain tumours are potentially lethal (irrespective of type
and grade) due to raised ICP
- Major biological difference between infiltrating gliomas (these arise in the substance of the
brain. They infiltrate the brain by following line of least resistance). These will kill you within a
year.
- Tumours from the surface that push into the brain but don’t invade the brain tissue e.g pituitary
or meningeal tumours are a very different entity. Easily treated
- The first type is referred to as of glial origin.
- Remember that neurones are post mitotic cells and thus you cannot get neuronal tumours.

Glioma
- These tumours proliferate and invade adjacent brain tissue.
- They are capable of developing a new blood vessel for themselves.
- Astrocyte: scaffolding of the brain tissue, they support the brain. Also contribute to BBB
and provide nutrition to the brain. They turnover regularly
- Oligodendrocytes: lay down myelin over the axons.
- Note neural development. You have proliferation, differentiation (the cells are very
undifferentiated – can become astrocyte, oligodendrocyte or neurone). There is then migration to
the site of the developing cortex. First the astrocytes go up. Then the neurones move up and
they wrap themselves around the astrocytes (like a vine). Then they make connections to
other cells. The cells then begin apoptosis (if this doesn’t occur then half their brain will be
twice the size as the other)
- Sometimes there is arrested migration and you result in a double cortex

In brain tumours the opposite occurs

Glioma classification
- Astrocytoma,
- oligodendroglioma
- ependymoma (remember the ependymal cells are the cells which line the ventricles and
contribute to the choroids plexus)
 Key thing is to remember that these are highly malignant and will kill you (only matter of
time)

Astrocytoma
Two different groups: non-infiltrating and infiltrating
Non infiltrating are juvenile pilocystic, subependymal giant cell and subependynoma
Infiltrating include astrocytoma, anaplastic astrocytoma and glioblastoma multiforme. These
infiltrate surrounding brain, show progression to higher grade and very difficult to remove (as they
look like normal brain). Only on MRI is there a difference.
- Also problem as often presents late.
- The CT underestimates the tumour extent.
- The isolated tumour cells invade widely and it is impossible for the surgeon to remove it all
(need to add a couple of cm into the perimeter of the apparent tumour)
- They never metastastise because there are no lymphatics in the brain (additionally they lack
enzyme – metalloproteinase to invade blood vessels). However by contrast, secondaries can easily
metastasise to the brain because can spread by blood
- If they do reoccur then they do so in the same place (however still cannot be removed as it
invades the brain tissue)
- They are very leaky as they don’t have the normal tight junctions of normal brain. Thus they leak
fluid into the extracellular space and cause brain oedema and raised ICP (which is how they kill
you)

Grade:
Grade 1 = don’t progress to later grades and can often not present problems
Grade 2 = hypercellular
Grade 3 = has mitosis
Grade 4 = has necrosis and neovascularisation.

- Progression is inevitable (except grade 1).

- You try to delay progression with surgery/chemotherapy/radiotherapy but not
very effective.
- Can do surgery as below (you can use image guidance to locate the tumour amidst the
surrounding brain. It has not helped mortality but it has helped reduce morbidity.
 Extent of resection depends on the location (how much neurological deficit you will do by
performing the procedure)

Oligodendroglioma
- These are another form of glioma
- They have a unique genetic signature (1p 19q deletions). Those with this deletion respond
much better to chemotherapy.
- Either way, all the patients with these brain tumours will end up with a highly malignant
stage 4 glioma called a glioblastoma (most die within year).
- In summary, grade is very good predictor of survival.
- Additionally amount of neurological deficit is a good predictor.

Glioma treatments
- Removal
- Biopsy is not a treatment. Maximum safe debulking of the tumour.
- Can also do craniotomy (where a portion of the skull is removed) and decompression
- Radiation: Conventional external beam can be used. However, internal beams can also be used.
- Chemotherapy Can also be used.

Therapeutic resistance
- These tumours do so badly because radical resection is difficult (due to problem of
removing brain tissue and resulting in severe neurological deficit/death)
- Radiotherapy constraints
- Tumour heterogeneity (i.e multiple cell lines are involved and therefore as you kill off
one cell line, another takes its place)
- Blood tumour barrier (which makes it difficult for chemotherapy to act).

CHILD BRAIN TUMOURS

- These are as frequent as leukaemia but are more devastating.
- The impact of treatment on the developing nervous system is a problem.
- There are psychological and neurological effects of the treatment on it.
- There may be endocrine effects (e.g damage to the pituitary glands).
- If you e.g operate on a spinal cord in a child < 2 then they will not grow beyond that length.
- Most adult brain tumours occur above tentorium while most child ones occur below the
tentorium.

Cerebellar astrocytoma
- Cystic and it is easily resected.
- No other Treatment is necessary. There is excellent long term survival.

Brainstem astrocytoma
- Same tumour, same histology but different location. Now very different prognosis.
- Impossible to resect.
- There are major neurologic deficits.
- There is low grade histology but LOCATION and NOT the grade dictates the outcome.
- Only palliative care is possible.

Medulloblastoma
This is a primitive neuroepidermal tumour (it is the equivalent of a nephroblastoma, retinoblastoma
etc)
Develops from the primitive developing cerebellum.
They spread down the spinal cord through the CSF.
There are small round cells (they look kind of like small cell carcinoma in the lungs)

Treatment in a child over 2: resection (as much as you can) and radiotherapy to the spinal
cord.
Treatment under 2: intrathecal chemotherapy (not as effective) and resection as much as
you can.
However there are devastating neurological affects as the effects on the developing nervous
system are extensive.

NON GLIAL TUMOURS

These arise from the structures that cover the brain (and structures around it)
 Meningioma.
This pushes into the brain tissue but does not invade (unlike a glioma).
Thus relatively easy to be removed.

Pituitary adenoma
- Can produce too much or too little hormone
- Can also compress surrounding structures e.g optic nerve – remember that patients often do
not notice visual field defects, cavernous sinus (remember, collection of veins), brainstem.

Schwannoma
- These are tumours of the cranial nerves (except II).
- Remember that the optic nerve is covered by oligodendrocytes (which is why it is the
only cranial nerve which is affected by MS).
- This is a schwannoma in the cerebello-pontine angle. Thus affecting 7th and 8th nerves.
Thus probably complaining of deafness. This is a difficult area to operate (and may be left
with a 7th nerve palsy afterwards)

Note that if you get it on both sides you almost definitely have type 2 neurofibromatosis.

Pinealoma
- Back of the brainstem is in a very inaccessible place of the brainstem, can press on back of
brainstem damaging nerves so cannot have vertical gaze, cannot move up or down.
- makes sense – arises posteriorly from the brainstem – supplies the superior oblique – which is
responsible for making the eye look down
- Also compresses the aqueduct of Sylvius – so patients get hydrocephalus.

Cerebral haemangioblastoma:
- This is a vascular tumour which arises from stem cells that produce blood vessels
- It is associated with von-Hippel Lindau disease. Remember this is a disease where there is
a mutation in a tumour suppressor gene – this causes them to be at increased risk of this as well as
phaochromocytoma but most importantly renal cell carcinoma.
- Since it is very vascular, it is prone to bleed.

Craniopharyngioma
- Benign tumour but due to where it is – right by the hypothalamus, it is very problematic
- Can be blind due to damage to pituitary stalk, they can have dwarfism due to damage to pituitary,
diabetes insipidus due to damage to posterior pituitary etc.
- 4 C’s Childhood, cystic, calcified and cholesterol in cyst.
- Microscopically composed of remnants of Rathke’s pouch.

Stroke
- is the rapidly developing loss of brain function due to disruption of the normal blood supply to
the brain
- You cannot manage a patient unless you can do a CT scan within 2 hours of the onset of
symptoms.
- Scan needs to tell you if you have a haemorrhage or an infarct (this is only thing you need to
initially know)
- Stroke units: need full work up within 3-4 hours
- Need early recognition with neuroimaging
- Early treatment with thrombolysis
- Need to have good prevention (with risk factor management).
- Remember that stroke risk is exactly the same as heart disease risk except heart disease is an
additional factor.
- Neurorehabilitation is essential. Recovery after stroke takes at least 2 years. Thus cant give up.
Need to make sure have access to speech therapy, physiotherapy etc. This makes a difference.
- Stroke is either an infarct or a haemorrhage.
- Infarct can be embolus or thrombus
- Haemorrhage can be intracerebral or subarachnoid. (you can get haemorrhages in other areas e.g
extradural haemorrhages in trauma)

Stroke incidence/mortality
- Declining mortality due to improved BP control (one of the main risk factors haemorrhagic
stroke) and other risk factor management.
- Case fatality is also declining due to improved acute stroke care.
- The stroke events are less severe and there is an increased dx of mild cases (i.e picked up earlier)
- Frequency of stroke type
- Infarction is most common (65%)
- Haemorrhage is about 1/10 (of which half are subarachnoid haemorrhage and half are
intracerebral haemorrhage). This is on the decline because of better BP control.
- TIA = 20%. (transient loss of unction within 20 mins. Platelets then break up and move on.
However, important thing is that high chance of then developing infarct. (i.e warning sign).
(traditional definition: <24 hours but most are within 20 mins.)

Risk factors
- Vessel wall risk factors: hypertension, smoking, atherosclerosis, hyperlipidaemia, diabetes
- Vessel lumen: Embolus: heart disease (impaired contraction means more likely to have
mural thrombus), CHF, A. Fib, Valvular disease, patent foramen ovale with DVT etc.
Thrombus as a result of hypercoagulable state (increased haematocrit etc)
- Other: family hx, oral contraceptives (these may increase venous thrombosis in the saggital
veins etc) and obesity.

Young stroke
Risk factors are very different
Large vessels: Vessel wall disease (non atherosclerotic)
- Dissecting aneurism (commonly due to trauma to the neck – common cause of stroke in young
people
- Migrane
Small vessels:
- Vasculitis - small vessels in the brain commonly supplies very important areas
Recreational drug abuse: such as amphetamine, methamphetamine etc is now a common
cause of stroke in a young person.
Other rare conditions e.g anti phospholipid syndrome
Heart disease:
- Congenital heart disease and complications
- E.g valve prolapse or patent foramen ovale.

Cerebral Auto-regulation
- Remember that over a wide variation in blood pressure the cerebral blood flow will stay the
same.
- However when mean arterial pressure goes above 150 or below 50 then it breaks down.
- Once electrical function has been compromised, then there is a very narrow window before
irreversible damage begins to occur.
- First there is electrical dysfunction
- Then there is complete electrical failure
- Afterwards, the Na+/K+ pump begins to fail. The Na+ floods into the cell and the cell begins to
swell and cell death occurs.
- Thus it is essential to restore blood supply to the area ASAP.

Reminder of anatomy
 Anterior cerebral artery
- goes along the midline of the cerebral hemispheres
- supplies middle inch of frontal and parietal lobes.
- Also supplies much of the inner aspect of the parietal lobe
- Thus occlusion causes contralateral loss of sensation and motor function in the lower limb and
perineum.
Middle cerebral artery
- supplies much of the lateral aspect of the cerebrum (i.e parietal lobe, bit of frontal and some
occipital).
- Thus occlusion leads to contralateral loss of sensation and motor function but with SPARING of
the FOOT and PERINEUM (as the anterior cerebral supplies this part of the motor/sensory
homunculus).
- Also damage to auditory and speech areas.
Posterior cerebral artery
- occlusion causes hemianopia with macular sparing (due to middle cerebral artery providing
blood supply to this area)
Dorsal columns: Proprioception, light touch and vibration
Spinothalamic: hard touch, pain and temperature (remember it a the more painful ones, hot,
painful punch. Hence why when you have thalamic problems you have incurable pain).
 Eye muscles: (easiest way to remember this is testing lateral is easy (medially is hard). Laterally
is lateral rectus, then superiorly and inferiorly is superior and inferior rectus respectively. However,
medially is counterintuitive. Not recta, but obliques and superior oblique moves it inferior and vice
versa.

- The boundaries of areas supplied by the different arteries is known as the watershed (because
there is relatively bad blood supply).
- The Circle of willis is highly variable. Some people have collateral circulation and this will
dictate what the outcome is.
- E.g some people have a collateral circulation going from the external to the internal carotid. Thus
these people can have a major carotid thrombosis and they do not have any affect, while others will
have a massive infarction.
- Note lower left – some collaterals, but not enough. Thus those areas of the brain that are furthest
away from the blood vessels (i.e watershed areas) become infarcted.

- Below: Note that there is an embolus that has been caught in the bifurcation (this is where most
emboli get lodged).
- Then the fibrillary system kicks in and dissolves the clot a little.
- Then it goes further. As a result, blood starts to enter the necrotic brain tissue. Therefore you can
have secondary haemorrhage.
- Thus in stroke you can have both an initial clot and then secondary haemorrhage (can occur up
to days later)
Possible origin of an embolus
 Remember that trauma to the neck can cause an arterial dissection which can then
thrombose and embolise to the brain. The same could happen with a piece of athersclerotic
plaque

- Mural thrombus
- DVT with patent foramen ovale: DVTs can then spread and cause a stroke.
- Note that we believe most emboli to the brain originate from the carotid bifurcation.

Brain imaging
Not really trying to dx infarction on a CT. Just trying to exclude haemorrhage (as obviously
will not want to do thrombolysis in this case)
Note that after a occlusion you can get cytotoxic oedema
(note the acute infarct below)

Subacute infarct appears as a hypodensity on a CT scan (Image A) obtained within 5-6 hours of onset and

as a region of hyperintensity on a T2-weighted MRI (Image B), on a fluid-attenuated inversion recovery

(FLAIR) MRI (Image C), and on a diffusion-weighted MRI (Image D).

The only thing that can help in such a situation is a craniectomy (to stop the resulting increase in
ICP herniating the brain stem etc and causing death). Eventually the brain swelling will settle and
you can the survive.
 However due to the infarction you will have a neurological deficit. (Note an older infarction
later). However, you can have rehabilitation up to 2 years later (because surrounding
brain tissue can take over the function of the lost tissue)

Image A) The CT scan shows a chronic infarct as a well-defined area of decreased attenuation equivalent

to that of the cerebrospinal fluid (CSF) in the ventricles. (Image B) On the T2-weighted MRI, a chronic

infarct has the signal intensity characteristics of CSF, whereas an acute infarct may be less intense than

CSF. (Image C)The diffusion-weighted MRI shows a chronic infarct as a region of hypointensity

Lacunar infarction
- This is infarction of the small end perorating arteries. They supply critical areas deep in the
brain.
- However, there is a design fault as although they are so important, there is no collateral supply.
- Additionally there is no pressure reduction system (i.e these come straight from the large
vessels)
- Unlike other strokes which mainly occur in the cerebrum, lacunar infarction affects the deep
vessels which supply parts of the brain such as the lentiform nucleus, internal capsule, caudate
nucleus and pons.)
- As a result they are particularly vulnerable to hypertension where they can form aneurisms and
rupture (Called Charcot Bouchard aneurisms) (although I believe these aneurisms can cause other
types of stroke as well)
- Additionally, atherosclerosis can also block off one of these small vessels.
- Since there is no collateral circulation, you result in a very small area of infarction.
- Since these areas of the brain are so critical, you end up with a severe stroke
- Note the picture of the lacunar infarction of the internal capsule. It is tiny but will be just as
devastating as an entire cerebral hemispheric infarction.
- Note also a rupture of a Charcot Bouchard aneurism.
- It is like a “bomb going off” (makes sense, they are under relatively high pressure) inside the
substance of the brain. There is very little that can be done and is very likely to be fatal.
- Patient would become unconscious immediately (cannot do neurosurgical procedure
because if you remove it then it will immediately re-accumulate)

- However there can sometimes be a small haemorrhage.

- Then over following months it can be reabsorbed (macrophages remove blood clot).
- The axons in the brain tissue around the clot can actually recover function (unlike the infarct
where the neurons were actually killed, rather than just pushed aside)
- I.e small haemorrhage better prognosis than small infarct in this area.

Important intracerebral haemorrhage

Causes
- HYPERTENSION is BY FAR MOST IMPORTANT
- Small vascular malformations
- Sympathomimetic drugs such as cocaine and amphetamines.
- Amyloid angiopathy (stiffening of the blood vessels due to amyloid deposition. This occurs in
Alzheimer’s disease).
- Anticoagulants + other bleeding disorders (haemophilias etc)

Cerebellar haemorrhage
Same causes
Potential for neurosurgeon to remove haemorrhage (because can remove much of the
cerebellum and still recover fully)

Stroke Workup
- Need to do CT brain W/O contrast ASAP. Here you are just looking to see if the patient has a
haemorrhage.
- If you do not see a haemorrhage then you presume that it is an infarct.
- You need to check if the CT fits with the clinical findings of the patient.
- Then you do standard workup – CXR, ECG, FBC, ESR etc.
- Then decide if patient has embolus or thrombus (although in practice this is difficult, unless e.g
ECG picks up a. fib etc – due to lack of time)
- If CT is normal (note CT won’t show up an infarct until later in the stroke) then you may want to
do an MRI (this will show up infarcts that the CT misses).
- If the MRI is normal then by definition the patient has had a TIA.
- If haemorrhage (can be either into brain substance or SAH).
- If into the brain substance – check BP. It is very likely to be elevated. If not then need to look for
small vessel disease via angiography.
- If haemorrhage is in SAH – then have to find out where the haemorrhage is coming from.
- If both negative – then need to check for bleeding disorder – check INR etc.

In practice
- Since this is an emergency you don’t get time to do most of this.
- Thus when someone comes in with a suspected stroke all you have to do is a scan to check for
haemorrhage
- If haemorrhage is negative then only thing you need to decide is if they are suitable for
thrombolysis.
- Make sure platelet count is normal, make sure the patient is not too old, they don’t have severe
hypertension etc.
- Need to initiate therapy with thrombolytic therapy within 3.5 hours of symptoms.

Subarachnoid haemorrhage
- This commonly occurs due to berry aneurisms (associated with hypertension, smoking and
genetic conditions e.g polycystic kidneys).
- Since they follow La Places Law, once they form they are likely to expand and then rupture
(with fairly significant force)
- They feel a sudden “explosion” inside their head. (Feel worst headache of their life)
- Outcome could be death (straight away)
- Coma or alert but they can survive but rebleed (up to week later).
- Can sometimes have a small leak which is a warning of a massive SAH after.

Workup of suspected SAH

- Examine patient for neck stiffness etc. Either way, with such a history a CT scan is important
- Look for a bleed or other pathology
- If you find SAH then you need to do vessel imaging angiography to locate cause and then treat
by surgery or interventional radiology.
- If CT scan is negative then do a lumbar puncture (by colour of CSF can tell if there has been
SAH). Can be either blood stained or xanthochromia (yellow colouring). If positive then again do
vessel imaging/angiography etc
- If negative then DON’T SEND PATIENT HOME (with such a history). Need to admit and
observe. Do a repeat CT and consider angiography or non-invasive vessel imaging.
- I.e if patient has such a history (worst headache of my life) then make sure the patient does not
leave the hospital

I believe this is for final med but it seems important

General management measures
- Need to have early mobilization to prevent aspiration, pneumonia, DVT, PE ulcers etc.
- Need to give intermittent external compression stockings
- Antibiotics to treat the infectious complications of stroke (makes sense – increased risk of
aspiration pneumonia etc)
- Also need to treat any concurrent medical conditions (e.g heart disease)

Antiplatelet therapy
- Acute stroke – commence ASAP after ischaemic stroke
- Secondary prevention – after prior ischaemic stroke or TIA – give aspirin/clopidogrel or
dipyramidole.
 Anticoagulants
- Acute stroke – NO INDICATION (use physical methods for DVT)
- Secondary prevention – prior to TIA or ischaemic stroke + AFIF – then prescribe warfarin (2
weeks after)

Thrombolytic therapy
- In an ischaemic stroke within 6 hours (preferably within 3)
- Benefits: increased proportion of patients making good recovery (at 6 months)
- Risks: haemorrhage within 2 weeks.

Carotid surgery
- Good for stroke prevention in those with severe stenosis.
- However there is a high risk (e.g ulcerated plaques) – done at specialised centres.

Angioplasty: Carotid endarterectomy

- I believe that this is the same as carotid surgery.
- This is surgery to remove plaque from the carotid artery.
- When there is 70% + stenosis occlusion then it is most beneficial (remember that this is a
prophylactic procedure and thus it is essential to compare the risk benefits). Especially if there is a
healthy elderly patient, hemisphereic TIA’s and absent collaterals
- 50-69% occlusion = not known whether worth it
- <50% = no benefit.

Acute ischaemic stroke – clinical presentations

- Usually all SUDDEN IN ONSET.
- Altered consciousness, stupor/coma, confusion, seizures, dysarthia, facial weakness or
asymmetry, incoordination, weakness, ataxia, visual loss, vertigo, double vision etc (plus signs of
increased ICP – i.e nausea, vomiting etc)

Ischaemic stroke classification

- TACI – total anterior circulation infarction. Motor and sensory deficit, hemianopia (loss of half
field of vision), and disturbed higher cerebral function – not sure why, as posterior supplies
posterior lobe. Check
- PACI – partial anterior circulation infarct. Any 2 of the above or isolated disturbed cerebral
function
- POCI – posterior circulation infarction. Brain stem dysfunction or isolated hemianopia or ataxia
(I imagine this is referring to the blood supply from the basilar artery – which supplies the
cerebellum and posterior cerebral artery)
- LACI – lacunar infarction – pure motor stroke or pure sensory or mixed sensory or ataxic
hemiparesis.

Multiple sclerosis
- This is a common disease
- It can be included in the differential of pretty much any neurological symptoms or
sign.

Basic neuroanatomy
- Oligodendrocyte: this lays down myelin, the “plastic coating” that protects the axons. Consists of
compacted cell membrane
- One oligodendrocyte lays down myelin over a number of different axons.
- Myelin stretches from 1 node of Ranvier to the next.
- Without myelin conduction through the axons, conduction would be slower and of lowered
quality.
- In MS there is a immune attack on the myelin sheath, the myelin is stripped off the axon,
conduction velocity is reduced and the patient is left with a neurological deficit.
- There can be remyelination (in the early phases of the disease can get remyelination but with
subsequent attacks you get scarring and you cannot get full remyelination).
- This CHARACTERISES MS. You get an attack followed by recovery/remission followed by
another attack etc etc. Time between attacks get shorter and the attacks become more severe.

- Compare to the PNS where the Schwann cell is the cell that lays down the myelin (also this
only myelinates single cells)
- Although MS is the most important demyelinating disease, there are others.
- Can have other diseases that affect the oligodendrocyte. E.g Infection, the JC virus can cause
damage (can become activated in immune compromised patients – these patients die due to
lack of possible recovery). Other viruses and post vaccination can rarely result in this as well.
- Can have inherited defects in myelin synthesis as well (known as leukodystrophies)

Pathology of MS
- You get plaques (especially periventricularly)
- There are large numbers of macrophages (you can seem them engulfing the myelin)
- The target of the immune attack is myelin basic protein.
- They are recruited to the area by lymphocytes.
- So what you have are macrophages (the effector cell), the antigen = MBP.
- The process is complicated, a number of steps need to take place before effector

- The first thing that needs to occur is that lymphocytes (the cells which are recruiting the
macrophages) need to enter the CNS and this occurs through a deficiency in the BBB. Not
known why the BBB opens up and lets in these sensitised T cells (which were sensitised in a
different point in time)
- We think that the sensitisation of T lymphocytes occurs early on in life (e.g after
exposure to coxsacki virus, herpes simplex virus, echovirus etc).
- So it happens that the epitopes share molecular characteristics with MBP.
- Now have clone of T lymphocytes (do no harm until BBB breaks down for reasons
unknown)
- When they get in there, they recognise the MBP as foreign. They call in effector cells
(the macrophages) – which are recruited from within the brain. They then attack and strip
off the myelin (and you are left with a naked axon).
- The plaque is an area of demyelination: can be full of macrophages – in acute attack
or they may be scarring – if it is chronic
- There is an attempt for remyelination but eventually with subsequent attacks there is no
remyelination and then the axons are lost (in which case there is no potential for recovery).
- Remember this attack can happen anywhere in the CNS (NOT the PNS).
- Also note that it does NOT affect the cranial nerves (except II) – remember that the optic
nerve is an extension of the brain substance.
- Note the plaques.
 Note one of the biggest developments in MS is MRI (as you can see the white matter – which
you cant see on CT.)

Treatment
Based on removing the T lymphocyte clone (which is attacking the MBP).
However, controversial as this results in immunosupression and some patients have died from
infections e.g reactivation of JC virus.

- Note that we don’t think that the B lymphocytes have a big role to play.
- The break in the BBB is best seen using a chemical called gadolinium. This will pass into the
brain and can be picked up by MRI if there is a break in the BBB (will light up areas on the brain in
which the BBB is deficient)
- The glial cells are activated – (microglial cells form the foamy macrophages
(remember that microglia is the name for macrophages that are found within the CNS – i.e the T
lymphocytes enter from outside the CNS due to breakdown in the BBB however the microglia are
already present and they attack if there is recognition by the T cells of the MBP)
- Note that people think that the astrocyte is involved in antigen presentation (but are not
sure.)
- This process is repeated over and over again with MS.
- The problem is that these plaques become chronic (remyelination is then not very good,
there is scarring and then the axons begin to die.)
- It starts off as chronic active plaque, then chronic inactive and then end stage.
- Depending on where the plaques are located, this dictates the symptoms and signs.

Axonal loss
- We think that this actually happens early on in the disease.
- This is the best predictor of long term morbidity in MS.
- However don’t have good way of measuring axonal loss early on in the disease.
- Can measure transverse diameter of spinal cord, volume of lateral ventricles = crude ways of
measuring axonal loss.
- It is irreversible

Clinical
- MS is a immune mediated demyelinating disease of the CNS almost certainly triggered by an
environmental factor (probably an infection) – in a genetically susceptible individual.
- Disease has attacks and remissions. It is a relapsing/remitting clinical course.
- Some people eventually go on to a progressive phase (secondary progressive)
- Small group of people that have a primary progressive disease (they get progressive disease right
from the beginning). Often associated with spinal cord disease (attacks in the spinal cord will cause
disability more quickly than in the cerebral hemispheres (makes sense – the spinal cord is a kind of
“choke point” where all the fibres run through)
- Some people also have a “benign” course (where they have one attack and then many years later
they may have another attack) e.g optic neuritis – painful inflammation of the optic nerve –
remember the optic nerve is the only place where you can directly see the myelin
- However difficult to predict which course they will take.

Epidemiology
- The prevalence of the disease varies around the world.
- Common in English speaking countries and Europe (North America, Europe, Australia, new
Zealand etc).
- However not known why.
- The idea is that there is molecular mimicry – i.e there is some virus with similar epitope to MBP
which when combined with a particular HLA (genetic susceptibility) results in sensitisation to the
MBP.
- Twin studies have shown that there is a greatly increased disease incidence in monozygotic twins
– with one having MS (while dizigotic twins had same incidence). I.e this proves there is a genetic
factor. (however it is not known what it is).
- Complicated – genes involved in BBB, antigen presentation etc, not known what the genetic link
is.

Clinical

Any neurological sign/symptom can occur (depends on distribution of the plaques – and this
distribution is entirely random)

Symptoms/signs from most common to least:

- Balance problems (spinal cord)
- Altered sensation (spinal cord
- Paraparesis (spinal cord)
- Micturition problems (spinal cord)
- Optic neuritis (optic nerve)
- Monoparesis, diplopia, hemiparesis, facial palsy, seizures, deafness, trigeminal neuralgia (less
common)

Two cardinal symptoms/signs in MS: UHTOFF’S and L’HERMITTE’s

L’hermitte’s symptom: when bends neck forwards then they get electrical shocks down the
arms (not specific for MS but means there is pathology high in spinal cord)
Uhtoff’s: relates to the effect of temperature on the conduction velocity of an axon that has been
demyelinated. IMPORTANT.
- Patients with MS should not be allowed to have a bath without leaving the door open.
- There is deterioration of the symptoms with heat.
- This is because the temperature of the water can trigger problems. The hot water slows the
conduction velocity (resulting in potentially not being able to move in the bath).
- Often occurs after using hairdryer etc – worsening of symptoms
- (makes sense – heat increases resistance in conducting systems)

Optic neuritis
This is one of the commonest presentations.
Pain and inflammation in the optic nerve head.
There is reduced visual acuity, it is painful to turn the eye.
On examination – see that optic nerve is swollen, vessels are enlarged and over time this
may resolve or may end up with optic atrophy (loss of visual acuity)

Optic Neuritis

Optic Atrophy

Internuclear ophthalmoplegia
- Remember that if you want to look right – the right 6th nerve and the left 3rd nerve need to work
together. (makes sense – 6th moves the abducens to abduct right eye and 3rd acts on the left eye to
move it medially)
- They need to move synchronously to project the image properly.
- Patient gets double vision
- There is a small amount of white matter that joins the right 6th nerve and the left 3rd nerve.
(Remember 3rd nerve is higher up in brain stem than the 6th nerve)
- This is called the MLF (medial longitudinal fasciculus. (remember that this is a branch of white
matter that goes from the nuclei of III, IV and VI – i.e eye movement nerves).
- This allows the two of them to work together.
- If you tell patient to look right – the right lateral rectus can move, but the left medial rectus cant.
- Look left – the left lateral rectus can work but the right medial cannot.
- I.e there is a problem with adduction in both eyes.
- Note that you also get nystagmus in the eye which is abducted.
- Thus get diplopia

http://www.youtube.com/watch?v=6KL-AAkFYEE

Investigations
- HISTORY: most important. Try to make a diagnosis of disease that is dissociated with time and
space. Time: have you ever had weakness/numbness in your arms/legs before etc. Space: see that
different parts of CNS are involved, can’t be explained on basis of stroke etc)
- MRI: good at picking up asymptomatic plaques. Can see myelin breakdown and can give the
patient gadolinium (to see inflammation and breakdown in the BBB)
- Evoked responses (using EEG): look for loss of function (e.g if think that there is plaque in
optic nerve then flash light in the eye and record over occipital cortex to see how long it takes to
activate (compare with normal response). Can do same for auditory evoked response
- CSF: can examine for lymphocytes present in the spinal fluid (can tell that there is inflammatory
process going on in the brain)

MRI
- Can show areas of inflammation, demyelination and remyelination.
- It is not good for showing areas of axonal loss
- Can also show areas that are about to lose white matter.
- Can also show atrophy.

First attack
- It is difficult to know what disease course it will take.
- Can do MRI and do evoked responses to check extent of disease.
- Can also give gadolinium to check for inflammation of CSF.
- If all negative then don’t have MS but can’t say what will happen in 20 years time etc.

Treatment
Designed to make patient feel better but also reduce frequency and severity of attacks.
Also try and delay progressive phase of the disease.
This is hard.

Acute attack
Give IV methyl-prednisolone (a variant of prednisolone). Helps to shorten attack but does not
modify natural history of disease

Modify natural history

- Big drug: Antegren (natalizumab, Tysavri) believed to work by preventing migration of the
T cells through the BBB. However many ADE including PML (progressive multifocal
leukoencephalopathy – caused by reactivation of JC virus)
- Interferons: used for all patients with secondary progressive MS
- Glatiramer (thought to induce Th2 response so reducing attack. Not known mechanism
though)
- Can also used immunoglobulins
All in all, they are not very effective at modifying the natural history of the disease.

Symptomatic treatment
- Spasticity: treat with Baclofen a GABA agonist that does not seem to induce tolerance but has
same risks as benzodiazepines e.g withdrawal syndrome
- Urinary symptoms: incomplete emptying, detrusor instability
- Seizures: need managing (not sure how, probably just similar treatment as with epilepsy)
- Fatigue: (big problem in MS – unknown mechanism – treatment involves putting patient on
exercise machine – paradoxically seems to help)
- Tremor: beta blockers etc.

Neurorehabilitation: VERY IMPORTANT

PML – PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY

- This is caused by the JC virus.
- We all are infected with it but it becomes reactivated after immune suppression.
- Seen in patients treated for MS with immunosupressants
- It attacks the myelin and there is no possibility for recovery (die in a few months)

RAISED ICP
- ICP is normally 7–15 mm Hg; at 20–25 mm Hg, the upper limit of normal, treatment to reduce
ICP is needed.
- Most cases are due to a mass effect, either diffuse (as in brain edema) or focal (as with tumours,
abscesses or haemorrhages)
- There are a number of compensatory mechanisms which can help if you have a slowly evolving
lesion.
- The compensatory mechanisms do not help in the acute situation and even in chronic they
become limited: they are displacement of blood, displacement of CSF and loss of brain tissue.

Effects
Compression of the brain
Stretching of the IIIrd nerve. Hence need to look at the side of the dilated pupil. (makes
sense, the 3rd nerve supplies the parasympathetic supply to the pupil, hence if it is damaged it will
cause dilation of the pupil)
Stretching of the posterior cerebral artery.
Hernitaion

Herniation
The cranial vault is subdivided by rigid dural folds. These are the falx and the tentorium. A
focal expansion of the brain causes it to be siplaced in relation to these partitions. If the
expansion is sufficiently severe, then a herniation will occur.
Remember there is a double fold of of dura matter called the falx cerebri (running sagitally)
(side note remember saggital view = you would see the ventricles, coronal view = going from
superficial to deep of the brain while transverse would be going from frontal to occipital lobe)
Subfalcine herniation = occurs when unilateral expansion of the cerebral hemisphere
displaces the cingulated
d gyrus (part of the limbic system deep in the brain) under the falx cerebri. Is associated with
compression of the anterior cerebral artery

Transtentorial herniation – occurs when the medial aspect of the temporal lobe is
compressed against the free margin of the tentorium cerebelli. (remember the tentorium
cerebelli is travelling transversly)
Tonsillar herniation refers to displacement of the cerebellar tonsils through the
foramen magnum. Life threatening because it causes brainstem compression and
compromises the respiratory and cardiac centers in the medulla oblongata. This is also
referred to as coning.
Note that if the lesion is above the tentorial membrane (another name of the tentorium
cerebelli) then you can ONLY get transtentorial or subfalcine herniation while if it is
below then you can ONLY get tonsillar herniation.
Remember that in such a lesion the ipsilateral ventricle is compressed and the
contralateral is dilated.
Symptoms/signs of raised ICP
KNOW THIS!
Headache, vomiting and papilloedema.
DANGER of lumbar puncture
IMPACT INJURIES
Acceleration/deceleration injuries
Subdural haemorrhage and dfuse axonal injury are risks.
Scalp injuries
Abrasions, contusions and lacerations (with or without avulsion) (avulsion is pulling off
tissue from the bone)
There is a risk of haemorrhage (remember the scalp is very vascular) and infection
Skull fractures
Skull fractures do NOT always correlate with brain injury. There may be a skull
fracture W/O significant brain injury and vica versa.
May involve calvaria or base.
Can be a “deformed hoop” injury. (think of bending a hula hoop) where you have cracking
of the outer table in the opposite end and cracking of the inner table in the inner area
High velocity impact produces penetrating or depressed fractures while flat
impacts produce linear, non displaced fractures.
Probability of skull fracture depends on severity of blow, age of victim (elasticity,
brittleneess) and other factors.
Types of fracture
Linear fracture – tends to follow lines of force (course modified by suture lines and
convolution of the skull)
Depressed = localised impacts causes intrusion of bone (may injure underlying brain)
Ring fracture - when someone falls onto feet from a height. The cervical spine drives
up into the skull.
Complication of skull fractures
Possible brain damage, intrusion of the bone fragments and epilepsy (either in the
acute phase or the late phase).
Extradural haemorrhage
There is a potential space between the inner skull and the dura.
90% have skull fracture (squamous portion of the temporal bone).
There is a lacerated middle meningeal artery and it is unilateral (usually due to the coup
injury, rarely contracoup).
1/3 have immediate loss of consciousness.
However classic scenario is that after injury you have a concussion (mild TBI where you
have transient mild symptoms of headache etc) then you feel better and then later you start to feel
nauseated, somnolent etc. You go to bed and the next morning you are found dead
Death occurs due to displacement and herniation of the brain.
Sub-dural haemorrhage
Actual space between the brain and the dura.
Due to acceleration/deceleration injuries with tearing/shearing forces affecting the
para-sagittal bridging veins.
Can be ipsilateral, contralateral or bilateral
May or may not be accompanied by cerebral injuries.
Especially common in the elderly and alcoholics due to brain atrophy. Common in falls and
assaults.
Remember that they can be acute (within 72 hours), subacute (3 days to 2-3 weeks) or
chronic (>3 weeks)
Reabsorption is possible but it may rebleed
Subarachnoid haemorrhage
Natural. 95% = berry aneurysms (5% are arteriovenous malformations)
(important side note, don’t think AVF’s were explained elsewhere. They are
abnormal connections between arteries and veins. Since they don’t have
capillaries in between as normally, there is ischaemia of areas. This is usually
congenital. Additionally since the blood is going into the veins at a high
pressure, they are prone to bleed)
Trauma: (much less commonly) is due to the lateral neck with resulting damage to the
vertebral artery. (this makes sense, the vertebasilar system/Circle of willis is in the
subarachnoid space). This is because the basilar artery is the most firmly anchored. This is the
reason why when you get trauma, you commonly get teaing of the basilar artery at the base
of the neck. (also a rotational blow to the head/ear can cause this)
Contusions
Deep contusions = to the deep structures of the brain (thalamus/globus palladis).
Gliding contusions = in periventricular white matter (towards the midline) They are
significant because they are often associated with diffuse axonal injury.
Cerebral contusions are produced as the brain moves and impacts with the bony
Herniation contusions = see above.
Fracure contusions = from overlying fracture
Irregularities at these sites: Coup (point of impact) and contre-coup (diametrically
opposite of the site of primary impact – more common than coup lesions). Commonest example
is fall on back of head (with frontal and temporal contusions.
Fresh contusions = haemorrhage and necrosis while old = depressed
haemosiderin stained (golden brown).
Lacerations of the brain
Skull fractures or gunshot wounds
Diffuse axonal injury
Remember that hypoxic encephalopathy and DAI are the commonest causes for the
persistent vegetative state.
They are due to acceleration/deceleration forces and stretching/shearing of the nerve
fibres. There is neuronal dysfunction.
There is coma with no lucid interval.
Note that even though you get some clues, it can only be seen on histology.
Brain swelling
May occur as complication of blunt force trauma. Can be diffuse or focal.
May be diffuse or focal. Maybe adjacent to the specific area of injuray
Can also occur following evacuation of a subdural or extra dural haemorrhage. (The
brain will swell in order to fill the space. )
Can be due to vasodilation (increased intravascular volume).
It has effects on cerebral perfusion and can cause herniation. It may be delayed –
especially in children.
Alcohol and head injuries
Many accidents/assaults occur in setting of excessive alcohol intake.
Intoxication causes a worse outcome – even with relatively minor degrees of head
trauma.
There is muscle laxicity and they are unprotected when they fall. Additionally the period of
post injury apnoea is lengthened by alcohol intoxication.
Brain swelling
Sometimes after evacuating a haematoma, the brain will swell in order to fill up the space.

Traumatic brain injury

These are very common – need to know if it is serious or trivial.
Need to remember that when someone gets blow to the head, a series of events can be initiated
which can cause death (within 24 hours etc). Essential to differentiate between serious and not.
(Although usually not such a thing as not serious bang to the head. We don’t know what cumulative
effect of repetitive bangs to the head are – may result in dementia etc.
Remember that trauma can cause raised ICP - thus transtentorial herniation, pushing the
brainstem across and down (causing stretching of perforating vessels that supply the
basilar artery – thus secondary brainstem haemorrhages – pushing the brainstem)
Same sequence for haemorrhage, head injury large infarct. (Outcome will be the
same without treatment)
Head injuries have huge economic impact (survivor of TBI costs $4million per person).
People that don’t die often don’t return to former occupation. Can result in
Cause depends on social situations (e.g crashes, firearms – during war etc, falls – alcohol.
Commonest in Ireland)
20% all head injuries require hospitalization. However, not all need neurosurgical intervention.
Often patient will be drunk etc, so difficult to take history. Need to make sure that you don’t send a
patient home who will then die in the next couple of hours.
Clinical points
What you see on the outside bears LITTLE relationship to the pathology inside the head.
E.g can have massive scalp lacerations that may occur in absence of brain injury (which
may kill patient due to blood loss, but no brain lesions).
On the other side, may have little external pathology (may not even have bruises, may have
just sustained a shake to the head etc, and may be harbouring changes in the head which will kill
them)
Remember that LOW BLOOD PRESSURE IS NOT A FEATURE OF BRAIN INJURY. (I.e if
they have hypotension, there must be pathology elsewhere. I.e they may have brain injury, but
something else is causing the hypotension – e.g hidden haemorrhage etc).
All the time with head injuries, need to avoid making the situation worse. Thus need to avoid
hypotension, low O2, low haemoglobin etc.
Need to avoid this by ABC rescusiation (protect airway from aspiration, protect against
hypotension etc)
TBI – rules
Often patients have polytrauma (i.e injury as well as head injury – don’t be only distracted by the
head injury)
ABC rescuscitation to prevent further brain injury. Maintain BP, PO2 and
haemoglobin.
Trivial injury may initiate events which may be fatal. (if patient abusive and wants to go to
sleep, may be sign of serious events to follow)
ALWAYS assume that patient has spinal injury until proven otherwise. (Need to take
Xray to check spinal alignment). (1/3 of patients with TBI have spinal injury)
Glasgow coma scale
Need to assess level of consciousness (see other lecture of Glasgow coma scale). Remember
that level of consciousness isn’t directly related to level of injury.
Most importantly need to look out for a change in level of consiousness (e.g not responding
with voice, then not responding to pain etc = bad sign)
Eye response (no eye = 1, eye to pain = 2, eye to verbal = 3, eyes open spontaneously = 4)
Best verbal response. None = 1, grunting/incomprehensible wounds = 2, inappropriate words e.g
abusive etc = 3, confused = 4, orientated = 5
Best motor response. None = 1, extension to pain = 2, flexion to pain = 3, withdrawal to pain (just
pulling away from area of pain) = 4, localising pain (eyes closed etc, but if cause pain, hand comes
up to move yours away) = 5, obeying commands = 6.
Often in emergency will assess every 15 minutes. If it starts to deteriorate then this is sign of
emergency. It is an indication of ICP.
Missile injury
Note forensic medicine.
However have to take into account calibre of bullet, position etc
The bullet is presceded by compressed air (in front of the bullet), once inside the skull, the
compressed air dissipates inside (so bullet can take any track inside the skull, fragment inside
etc
Bullet can come out anywhere (e.g lung, arm etc)
Penetrating TBI
Can sometimes walk into A and E. This is because head is stationary during the trauma (big
difference between stationary and mobile head)
(Cant just take it out as wont be able to achieve vascular control).
Repetitive non-coma producing TBI
Repeated non coma producing TBI e.g in rugby/boxing etc can cause progressive damage to the
brain (e.g ending up with parkinsonism etc)
Acceleration/deceleration
When a person like this falls backwards, the rate of acceleration is greater than gravity.

This is because there is a rotational force (you pivot like a pendulum).

Thus the skull hits. This is protected by the cushion of CSF. However, the front of the
brain is more likely to be damaged (this is because of the rest of the brain following with
gravity then rebounding off the inner frontal bones).
Crucial point – you often get most damage to the opposite side that is impacted.
TBI –
Different types - remember that often you get multiple of these though.
Focal: Scalp laceration, skull fracture, haematoma (extradural, subdural or
intracerebral) and contusions.
Diffuse: Oedema (most common complication), hypoxia (avoidable injury), axonal injury
etc.
FOCAL
Scalp/facial lacerations
Can die from scalp lacerations. Remember that the scalp is extremely vascular.
Rarely get post operative wound infections because of how fantastic the blood supply is.

Tx = put pressure and get sutures in ASAP.

Avulsion (avulsion means forcible detachment of body tissue) injury (machines, getting hair
caught in etc) – dead in few minutes due to blood loss
Facial injury – Big problem is scarring – psychological impact etc
Skull fracture
20% of patients with TBI do NOT have a skull fracture (so no reassurance that they will be ok)
However if do find need to consider if it is open (i.e skin also torn over the fracture). This is a
massive risk for meningitis
May also be open to the sinuses (where bacteria can infect to cause meningitis)
Linear fracture = usually ok unless it causes injury to an artery/nerves.
Comminuted fracture (shattered bone e.g after hammer blow – need reconstructive surgery
afterwords)
Depressed fracture – this is where a piece of bone is depressed into the brain (causing
scarring of the brain and raises ICP. Emergency and needs to have neurosurgery to elevate it)
Most skull fractures don’t cause significant impairment. However can damage meningeal
artery, can damage cranial nerves (e.g can become deaf after), can get scarring of the brain
and epilepsy as a result. Fracture may also extend into nasopharynx and may get salty drip
(CSF) in nose/mouth (thus will get meningitis).
Extradural haemorrhage
E.g damage to middle meningeal artery.
Known as “talk and die”. I.e initially no loss in consciousness (as brain is not injured),
however blood accumulates and may die later.
Tx = Burr hole to drain out blood.
If any suspicion, observe patient for 24hrs.
Contusions
Note pic of massive areas of bruising. – where the brain impacted against the periosteum –
pia surface is torn and blood oozes out into subdural space.
Not much you can do as if you take blood out it will reaccumulate.
Patient probable fell on left side but most damage is on right side.

Most common pathology that you see in significant head injury.

Not much you can do, often die. Even if they survive, will get significant neurological deficit
and highly likely to get epilepsy.
Acute subdural haematoma
Left lateral ventricle is reduced in size, right is increased. Midline shift
This is caused by the contusions leaking into the subdural space (note that this is different to
the vein damage as seen below)
Note that if you drain this then it will just refill with blood.
Tend NOT to “talk and die” as there is brain injury. I.e they come in unconscious and tend to
die afterwards.
Not much that you can do.
Chronic subdural haematoma
Develops slowly over period of weeks to months.
Brain is not bruised.
This is common in elderly the brain gets smaller. Thus the bridging veins that run to the dura
– the bridging veins will tear and the blood will gradually accumulate.
Can present with minor neurological signs.(Often only had recent minor head injury, may not
remember)
Traumatic intracerebral haemorrhage
RARE
Much more likely to be a stroke (e.g on ladder, have a stroke first and then fall due to that rather
than vica versa).
Not much you can do about this either.
DIFFUSE
Oedema
Any trauma will produce oedema
If it is vasogenic then it should respond to steroids and mannitol. Howeve3r it is often
cytogenic in which case not much can be done.
Hypoxia
Common
Always secondary and always avoidable.
Most people that die with TBI have hyoxic brain injury.
Usually due to avoidable events – fall of pO2 or low BP.
Remember that to perfuse the brain you have a mean arterial pressure and an
intracranial pressure. Cerebral perfusion pressure = MAP – intracranial pressure.
Thus if the intracranial pressure rises then you need a greater MAP to adequately
perfuse the brain.
Thus Cushings reponse = normal response to keep the brain perfused (rise in BP after
TBI – due to raised ICP) – helps keep perfusion to the brain.
pO2 and haemoglobin also is important to make sure they are not low – Treat this ASAP
Note below – someone that was hypoxic and infracted the watershed area of the brain (the
part of the brain with less blood suplply – boundary between the different vessels that supply the
brain.)
Diffuse axonal injury

Commonest cause of long term morbidty in TBI.

It is not avoidable. Occurs at moment of impact.
 You get tearing of the nerve fibres (especially in kinetic impacts, moving brain e.g in RTA.
You get rotational forces in the head and can get tearing of the axons).
Cortex is still intact, but because of white matter damage you get no information going in/out.
Cannot see on MRI/CT but will be able to see at pathology.

Neurodegenerative disorders
- All show common features of it being relentlessly progressive, fatal and treatment does not arrest
disease progression – can only improve the symptoms.
- They cause system degenerations – one part of the CNS dies before the other
Examples
Parkinson’s: pathology mainly in the substantia nigra
Motor neuron disease; mainly in the anterior horn cells of the spinal cord.
Huntington's; caudate nucleus
- In all there is loss of nerve cells.
- Also get scarring (known as gliosis of the brain)
- Note that during studies of the pathology of these diseases, a number of inclusion bodies
were identified (abnormal)
Alzheimer’s Disease markers: plaques and tangles.
Parkinson’s disease markers: Lewy bodies

Motor neuron disease: swellings of axons

Huntington's: we thought nothing to see for long time, but recently found inclusions in the
caudate nucleus
 Note that these diseases are known as protein aggregation diseases where they become
insoluble and become toxic. All of these “grave stones” are due to polymerisation of
previously soluble proteins.

Alzheimer's DISEASE
- Most common cause of dementia
- Dementia: neurologic disease characterized by loss of mental ability severe enough to
interfere with normal activities of daily living, lasting at least six months, and not present from birth
(as opposed to delirium).
- Affects two or more cognitive domains (e.g if just had memory loss, would have amnesia
not dementia). Eg language, memory, visuospatial etc.
- Remember symptoms often start with initiative/interest decline, forgetfulness (e.g
grandchildren’s names), then start getting distracted.
- There is emotional instability (e.g outbursts, crying for no reason etc), social graces
diminished (e.g not using cutlery to eat, not washing etc), then motor system begins to go
(get incontinence, don’t get out of bed) etc until death.
- However although this is classical picture, it is NOT NECESSARILY SEQUENTIAL (e.g can
start off with any of these)
- Note that apraxia: an inability to carry out a previously learned skilled movement in spite of
adequate understanding of the task and absence of weakness.
- (E.g can ask patient to cut paper with scissors, they understand what you are asking, but are
unable to do so). Thus have problems with e.g dressing, gait etc. This is feature of dementia as it
progresses.

Causes of dementia
Divide into 3 categories
- Dementia with other disease
 HIV, B12 deficiency, hypothyroidism, mercury poisoning, copper poisoning etc can result in
dementia
- Dementia with other neurologic signs
Multiple strokes is commonest (resulted in significant loss of brain tissue), CJD, Parkinson's,
hydrocephalous, brain tumours etc.
- Dementia alone
Alzheimer's, Frontotemporal dementia (where frontal and temporal lobe are primarily involved.
Used to be called picks disease) and lewy body dementia. Usually some degree of Parkinson's but
also dementia and die with lewy bodies all over brain – makes sense since lewy bodies are found in
Parkinson's disease. Remember that brain atrophy is found in the illness but this does not occur
until very late into the process (lost lots of nerves when brain begins to shrink)

AD clues - APP
- Downs syndrome – trisomy 21 . They get Alzheimer's at a very early stage. Thus gave clue to
find that problem was with a gene in chromosome 21. This is called APP gene – amyloid precursor
protein.
- These were younger people (familial AD – however indistinguishable from sporadic AD)
- APP is a transmembrane protein. It spans the nerve cell.
- Normally it is broken down by alpha and beta secretase. It is then cleared and no damage occurs.
- For some reason, a third enzyme is active. This is called gamma secretase. This cuts the
molecule at a different site. Thus it generates 3 fragments (amino fragment, carboxy fragment) and
Beta amyloid. This is highly toxic (one of most neurotoxic molecules known to man)
Can use antibody to show up the amyloid plaques.
- The extent of the plaque distribution shows the extent of the disease.
- Usually you find plaques in the temporal lobe, frontal lobe and occipital lobe.
- Not known why don’t see much clinical correlation for the pathology in the occipital lobe –
maybe there is recognition problem in visual cortex but not seen.
- NOT much in the motor strip and not much in the brainstem/cerebellum). This is why patients
can keep walking the whole way through the disease, but they can fall, get hit by cars etc (makes
sense, that’s why sometimes you treat with low dose haloperidol etc)
Remember that the amyloid also develops in the blood vessels. Thus the blood vessels are brittle
and can get haemorrhage into the brain. (Termed amyloid angiopathy)
- The plaques are highly insoluble material. However they do NOT cause the disease (the disease
has been caused before this accumulated).
- Instead it appears to be a highly soluble form of Beta amyloid which is able to diffuse through
the brain and cause destruction as it moves through – before accumulating as an insoluble plaque
- Lots of theories as to why this occurs – e.g mutation in APP gene, change in pH in the brain etc.
Not known for certain. Just known that there is stage where there are highly soluble molecules
which cause the damage within the brain. (Cannot measure the soluble beta amyloid yet)

Tau
- The cause of the neurofibrillary tangles.
- Cannot pathologically diagnose Alzheimer's unless you see abnormal Tau and beta amyloid.
- Also seen in frontotemporal dementia. Here you get substantial behavioural change and can get
Parkinsonian features. The brains show lobar atrophy (frontal and temporal lobe specifically show
atrophy). See big blobs of Tau.
- Tau: microtubule associated protein
- When it accumulates it is abnormally phosphorylated. It accumulates inside the nerve cells as
tangles and threads.
- Normally Tau stabilises microtubules (binds all the microtubules together, like an elastic band
over asparagus). It is essential for normal growth and development of nerve cells (e.g if you inject
tau into epithelial cells, they will start behaving like nerve cells).
- It is essential for maintaining integrity of nerve cells. If you do not have tau then the nerve cells
will die.
- If this happens by itself then you get frontotemporal dementia but if you get both this and beta
amyloid you get Alzheimer's disease. (Not known why both get problems at the same time)

Huntington's disease
- This is a very rare genetic condition. It is very dramatic.
- AD – gene on chromosome 4.
- There is expansion of a triplet.
- Can see it in the caudate nucleus as an inclusion body (we don’t know how it causes damage
though)
- The caudate nucleus is atrophic.
- Very obvious clinical findings. Have continuous purposeless activity (all the time unless asleep)
– This is called chorea. They never stop. Every part of the body
- Symptoms/signs don’t manifest until 20’s
- Also dementia
- No real treatment.

Motor Neuron Disease

- Known in the states as ALS – Amyotropic, lateral sclerosis – (because the lateral columns of the
spinal cords which contain the corticospinal tracts degenerate as well)
- This is the worst of the neurological diseases.
- Often occurs in sports people (for reasons unknown)
- Starts off with insidious onset (slight weakness, especially in area that is used most often)
- It is invariably fatal – (within 2 years)
- The anterior horn cell dies (and as a result the muscle atrophies and dies)
- Additionally the corticospinal tract dies
- It is characterised by BOTH lower motor AND upper motor signs
- As anterior horn cell degenerates, the muscle cells begin to degenerate
- Neurofilament appears just after the anterior horn cell.
- Characteristic feature of motor neuron disease is presence of fasciculations (these are the visible
contractions of an enlarged motor unit (the motor unit tries to enlarge to compensate for the death of
the other muscle fibres)
- although may be benign fasciculations seen by lots of people, however, their presence frequently
shows damage to the anterior horn cell
- Also can have upper motor signs (due to involvement of corticospinal tract) – so can have
spasticity, weakness etc
- Sometimes have lower motor signs, sometimes upper while others then both.
- Inevitably it involves the respiratory muscles (and patient dies)
- No treatment, relentlessly progressive.
- Management = very difficult (e.g putting patient of ventilator etc – need to make decision as
patient is cognitively fine)
Causes: Not known
There are theories:
- Genetic – (e.g superoxide dismotase)
- Toxic – possibly some occupational/environmental hazards
- Metabolic – final common pathway probably due to damage to mitochondria etc causing death
of the cells (but this doesn’t explain why it happens)
- Can say this for any neurodegenerative disease – i.e lots of theories, but nobody really knows.

Parkinson's disease
- Asymmetrical at first resting tremor – described as pill rolling. It is a coarse tremor
- Rigidity – Often have a flexed posture
- Bradykinesia: Have poverty of movement. Have very narrow based gait so can easily fall
- Often have mask like facies, hypomimia
- It is a clinical diagnosis based on those findings.
- Down microscope – in substantia nigra (loss of nerve cells, get accumulation of Lewy bodies.
Not just present in substantia nigra, also in other areas.
- Remember that Parkinson's is NOT JUST a movement disorder. Also get systemic problems:
- Get autonomic involvement. Get dysregulation of cardiac control, constipation (major problem)
- Drugs can help the movement disorder symptoms, but will not effect the disease process.
- Side note – difference between Parkinsonism and chorea.

The striatum produces ACh and this is excitatory.

The substantia nigra is inhibitory – and this produces dopamine
When you have ACh excess OR dopamine depletion you get Parkinsonism
When you get ACh depletion OR dopamine excess you get chorea – makes sense, as you get excess
movement rather than bradykinesia.

Clinical diagnosis
- You get a metabolic and essential tremor absent at rest.
- You have spasticity which is felt towards the end of movement.
- You get gait disturbance of normal pressure hydrocephalus.

Parkinsonism
- Can be idiopathic
- Symptomatic secondary – normal pressure hydrocephalus, vascular or trauma
- Can be post infectious
- Due to drugs (e.g antipsychotics, which are anti-dopamine drugs)
- Parkinson’s plus – e.g diffuse lewy body disease (dementia plus parkinsonian features)
- Other hereditary degenerative disorders – e.g frontotemporal dementia, dopa responsive
dystonia, Wilson’s, Hallervorden-Spatz and juvenile Parkinson's autosomal recessive.

Causes: Note – just like before – Toxic, metabolic final common pathway of oxidative stress on
the mitochondria etc.
Features of Parkinson's
- Pale substantia nigra
- Lewy bodies
- Alpha – S nuclein accumulation – check what this is.

Bone pathology
The musculoskeletal system provides mechanical support, it protects the organs, allows for efficient
movement, stores salts and other materials needed for metabolism and produces haematopoietic
elements (bone marrow)

Normal bone
- Organic matrix is made up of type 1 collagen and proteoglycan
- Inorganic component is made up of calcium hydroxyapatite.
- Cellular component is osteoprogenitor cells (the stem cells I believe – they produce osteoblasts),
osteoblasts (lay down the bone – they produce osteoid – the type 1 collagen), osteocytes (these are
the osteoblasts that have become trapped in the osteoid). Osteoclasts (break down the bone)

Osteoid
Two types
 1. Woven bone
- This is laid down quickly and as such is laid in a haphazard fashion.
- It is seen physiologically in foetal skeleton
- It is always pathologic state in adults
2. Lamellar bone
- Seen physiologically in adult skeleton.
- Two types: compact (called cortical bone – seen in the periphery) and cancellous (called
trabecular bone– seen in centre).
- Between compact and trabecular will see bone marrow eminence.

Tissues of the bone

- At outer surface you have connective tissue called periosteum (a fibrous tissue)
- Underneath you have compact cortical bone (a hard and dense bone that forms the outer layer)
- Spongy (cancellous) bone (inside – this is a lighter bone which is commonly found in the ends
and inner portions of long bones.
- Medullary cavity (located in the shaft of a long bone and surrounded by compact bone) (I think
this is the same as bone marrow)
- Cartilage – a connective tissue that provides a smooth articulation surface for the other bones.

Structure of lone bone

- Diaphysis: main shaft of the bone
- Epiphysis: end of long bone
- In between the diaphysis and epiphysis you have the metaphysis.
- Metaphysis: where the growth plate is present.
- Inside you have medullary canal – which contains bone marrow.

Bone growth and development: two types

1. Endochrondral ossification
- The bone is formed from cartilage
- See it during foetal development (the bones are composed of cartilage and become ossified to
produce the bone).
- Also see in epiphysis of long bone.
- This is how long bones grow
- Epiphysis is made up of cartilage (which becomes ossified – which allows growth in length)
 2. Membranous ossification
- Here the bone is formed from the connective tissue (from the periosteum).
- Have fibroblasts in periosteum which differentiate to form osteoblasts (and they lay down
osteoid)
- You see this in cranial bones and in bones that grow in width (i.e bones grow in length by
endochrondral ossification and in width by membranous ossification).
- This makes sense, the long bones can increase in length this way because the epiphyseal plates
are making the bone while the increase in width comes from the fibrous covering of periosteum
over the bone.

Formation of bone
- Production of osteoid
- Mineralization of osteoid (I think this means with the inorganic material – i.e hydroxyapatite)
- Remodeling by resorption and reformation of the bone.
- There are several factors which are involved in bone remodeling – including exercise, hormones,
vitamins, growth factors and cytokines.
- Vitamin D: an important bone remodeler.

Functions of vitamin D
- Get this from the sun or diet (fish is good source).
- It has to be activated.
- Two steps: first occurs in liver (25 hydroxy vitamin D) and second occurs in kidney (1,25
dihydroxy vitamin D – active vitamin D).
- It increases absorption of calcium from the bowel.
- It increases resorption of calcium from the urine.
- Causes mineralization of bone (in normal doses)
- However large doses of vitamin D causes release of calcium from the bone by stimulating
osteoclastic activity. Thus net effect is an increase in calcium level.

Parathyroid hormone
- Also important for bone remodeling
- It acts on osteoclastic bone resorption
- Increases renal tubular reabsorption of calcium
- Increases 1,25 vitamin D production
- Increases urinary phosphate excretion (makes sense, phosphate binds with calcium reducing free
calcium)
- Increases GI calcium absorption

Calcitonin
- The production of this is stimulated by high calcium levels.
- Produced by parafollicular cells.
- It reduces bone resorption by suppressing osteoclast activity (remember that high levels are not
normally a problem I think)

CONGENITAL BONE DISORDERS

Achondroplasia
- It is a reduction in chondrocyte proliferation in the growth plate with premature ossification.
Thus dwarfism.
- It is the commonest cause for dwarfism
- Note that unlike e.g growth hormone deficiency where substituting GH will work, in
achondroplasia it will not
- It is hereditary and is autosomal dominant.
- However may be spontaneous (apparently that is the most common reason)
- Homozygotes: usually die shortly after birth (due to multiple fractures)
- Heterozygotes: have normal longevity.
- Features of achondroplasia
- Shortening of long bones. This is because this is a disease of chondrocyte proliferation –
remember this is endochondral ossification (which generates length of long bones – from growth
plates)
- Normal skull – Makes sense - because it is membranous ossification (not by endochondral –
which is affected by the disease)
- Can also get severe spinal canal stenosis with severe pain.

Osteogenesis imperfecta
- This is a disorder of type 1 collagen (the most common collagen which is present in scar tissue,
tendons and organic part of bone)
- Genetic basis for the different types: the key point is completely knocked out gene is in this case
better than partially knocked out gene.
- Normal collagen is a triple helix formed from two col1A1 proteins and one colA2 protein.
- Type 1 OI: AD resulting in one of the Col1 A1 genes (from one of the chromosomes) being
inactivated. Therefore only half the Col1 A1 is produced.
- Thus therefore only half the procollagen 1 is produced and the remaining excess of the Col1 A2
is degraded.
- Since you normally need twice as much col1 A1 as col1 A2, now they are produced in the same
amount so only half is made – the A1 is in limited supply and the excess A2 is degraded).
- Therefore you get frequent fractures among other symptoms.
- Type 2/3/4: mutant (NOT INACTIVATED) Col1 A1.
- Therefore you have half normal A1, half mutated A1 and normal A2.
- Thus by random combination you get 4 different possibilities. 2 normal A1 + 1 normal A2, 2
abnormal A1 + 1 normal A1 and 2 lots of 1 abnormal A1, 1 abnormal A1 and 1 normal A2.
- Thus you get ¼ normal procollagen and ¾ abnormal procollagen.
- Now you can get differing severities in the abnormal procollagen depending on how early the
mutation is.
- Small effect = early mutation (near N terminal), large effect = late mutation (near C terminal).
- Thus type 2 is most severe form and it is perinatally fatal (thus most are new mutations since
offspring don’t reach sexual maturity).
- It is mostly AD and can occur in either alpha1 or alpha 2. Thus 75% collagen = abnormal and is
degraded therefore extreme bone fragility.
- Type 3/4 = less severe

It is hereditary. Most are AD (although may get spontaneous mutations.

There are several forms (I-IV). Some are fatal but some are compatible with life.
Associated with fractures, blue sclera (because collagen type 1 is usually in sclera – and
since abnormal then it becomes translucent), dental abnormalities and hearing loss.
 Osteopetrosis (also known as marble bones)
- This is a disorder of osteoclasts.
- There is failure of bone resorption. Thus there is increase in bone mass
- Thus you get sclerosis (hardening) and bone fractures.
- Also get hydrocephalus (because compresses some of the structures in the head) and cranial
nerve palsies
- Bone also fills the medullary cavity – thus get anaemia and neutropenia (resulting in infections)
- Also get hepatosplenomegaly due to extramedullary haematopoiesis (again makes sense – not
producing in bone marrow due to blockage of medullary cavity.)
- Treat with bone marrow transplant (makes sense – since the osteoclasts originate from
monocytes/macrophages – which come from the bone marrow)
- This is kind of like the opposite of osteoporosis – you are getting increased bone density – rather
than decreased.

METABOLIC BONE DISEASES

- Osteoporosis,
- Osteomalacia,
- Paget’s disease,
- Hyperparathyroidism
- Renal Osteodystrophy.

Diagnosis: Need careful history, physical exam, radiographic exam, lab tests (and rarely bone
biopsy)

Osteoporosis
- Very common.
- Get progressive reduction in bone mass.
- However mineralization is normal.
- Get reduction in osteoid formation but calcium deposition is normal.
- Can be localised (affecting single bones) or generalised (affecting multiple bones)

Causes
Primary:
- Senile, especially post menopausal female. Females lose 1% of bone mass a year after 30 until
menopause. Then starts rapidly decreasing (7% of bone mass). This is due to reduction in oestrogen
(hence increase in Il-1, Il-6 and TNF-alpha. These cytokines induce osteoclastic activity hence
increased bone resorption)
- Genetic factors (e.g vitamin D receptors polymorphism)
- Idiopathic
 Secondary:
- Due to immobility (e.g after fractures – being in plaster – can get localised osteoporosis)
- Insufficient Ca intake
- Hormones (e.g steroids)
- Drugs
- Neoplasia.

Pathogenesis
- It is due to an increase in resorption by osteoclasts and a decrease in new bone formation by
osteoblasts.
- Thus there is thinning and increased porosity of the cortical and trabecular bone.

Complications
- Bone pain
- Bone fracture (makes sense)
- Loss of height (reason why lots of elderly – especially women - are short – due to compression
fractures of the spinal cord.
- Can also predispose to deformity (e.g scoliosis, kyphosis etc)

Diagnosis
- Imaging techniques that measure bone density.
- X-ray does NOT dx osteoporosis until very late disease. (very severe bone loss)

Treatment
- Exercise
- Oral calcium and vitamin D
- HRT (for post menopausal women)
- Calcitonin
- Bisphosphonates (this is just the term for the drugs which act to reduce bone breakdown by
inhibiting or killing osteoclasts)

Rickets and osteomalacia

- Here there is inadequate mineralization of bone and osteoid production is normal.
- opposite to osteoporosis.
- Rickets: if disease is in children (as you get skeletal deformities)
- Osteomalacia: disease of adults (associated with fractures)

Causes
It is due to deficiency of vitamin D and thus increase PTH.
- Dietary lack
- Malabsorption (e.g celiac disease or Crohn’s disease)
- Chronic renal failure (as involved in activation of vitamin D)
- Liver diseases (same reason)
- Inadequate exposure to sunlight
- End organ vitamin D resistance
- Drugs

Rickets
- This is disease of children.
- You get inadequate mineralisation of the epiphyseal cartilage and get lack of osteoid
mineralization
 Deformities:
- Get deformity of the skull (craniotabes) – thus frontal bossing and squared appearance of the
head
- Thickening of the knees/wrists (as you are not getting mineralization so the cartilage keeps
growing)
- Enlargement of costochondral junction (same reason)
- Can get protrusion of the sternum (pectus carinatum)
- Retraction of softened rib (Harrison's groove)
- Lumbar lordosis
- Bowing of the long bones of the legs.

Clinical features of osteomalacia

Bone pain and microfractures (called Looser’s zone fractures)
Treatment: vitamin D

Hyperparathyroidism
Can be primary or secondary.
- Primary: due to a thyroid adenoma or hyperplasia. It is associated with high calcium levels.
- Secondary: get it when you get prolonged hypocalcaemia due to low calcium (hence
increased PTH production). Thus can have normal calcium as well I believe – as the parathyroid
hormone has acted to normalise the levels

Effects of hyperparathyroidism on bone

- It induces osteoclast activity thus you get cavities in the bone.
- This is associated with fibrosis and microfractures (which themselves are associated with
haemorrhage)
- The disease seen in bone in association with hyperparathyroidism is osteitis fibrosa cystica (as it
is associated with cavities (cystica) and fibrosis (fibrosa).
- They are also called brown “tumours”. Called brown because associated with haemorrhage. Also
known Von Reckilinghausen disease of bone.
- Changes rare now due to diagnosis of hyperparathyroidism and the changes regress after
treatment

RENAL OSTEODYSTROPHY
This is a combination of bone diseases secondary to renal failure.
4 types
- Osteitis fibrosa cystica
- Osteomalacia
- Osteosclerosis (don’t worry about osteosclerosis for now)
- Osteoporosis.

Pathogenesis
Osteitis fibrosa cystica
- Chronic renal failure -> hypocalcaemia (lack of Vitamin D) and phosphate retention (decrease in
reabsorption)
- Thus secondary hyperparathyroidism and thus osteitis fibrosa cystica.
Osteomalacia
- Due to less activation of vitamin D (I believe thus calcium decrease), Thus reduction in
mineralization of bone
- Another cause is dialysis units which contain aluminum (bind osteoid and inhibit mineralization
of bone)
- Can also be due to metabolic acidosis – get bone resorption and release of hydroxyapatite from
the bone. (i.e you are releasing Ca2+ - another positive ion being exchanged for hydrogen, from the
bone)
Osteoporosis
- Usually due to steroid therapy (given to those with renal failure, especially those with
glomerulonephritis)

Osteitis fibrosa cystica:

- Due to hypocalcaemia/phosphate retention and thus increased parathyroidism.
- Can also get amyloid deposition (B2 microglobulin) – associated with dialysis

Paget’s disease (osteitis deformans)

Epidemiology
- Can effect one bone but much more commonly it affects multiple bones.
- You get “collagen matrix madness”
- You have initial osteolytic phase (hence reduction in bone formation)
- Mixed phase: get both osteolytic and osteoblastic. However this is haphazardly laid down (which
means that this is woven bone – see above)
- Osteoblastic activity prevails: thus you get gain in bone mass. Thus fibrosis of bone marrow and
thickening of bone trabeculae (osteosclerotic phase – thus get mosaic pattern)

Pathogenesis
- Unknown cause
- More common in whites
- Slow virus: paramyxovirus potentially implicated.
- Also genetic predisposition (18q is locus implicated in Paget’s disease)

Morphology
At late phase get sclerosis, thickening of bone mass. Especially affects skull and long bones

Complications of Paget’s disease

- Fractures (because even though increase in bone mass, it is laid down quickly and haphazardly)
- Bone pain (due to fractures)
- Deformity (due to increased bone mass)
- Nerve or cord compression
- Deafness (due to compression of nerves)
- Osteoarthritis
- Heart failure (because have increase in vascularity of the bone – resulting in shunts)
- Rarely – can have malignant transformation (to osteosarcoma – makes sense, increase in
proliferation)

SUMMARY
Abnormal matrix/osteoid: osteogenesis imperfecta (inherited) or acquired (osteoporosis)
Abnormal mineralization: rickets/osteomalacia or renal osteodystrophy (I believe this is the main
one, even though other 2 also)
Abnormal parathyroid: osteitis fibrosa cystica
Abnormal osteoclastic function: Paget’s disease or osteopetrosis (these 2 seem very similar, just
seems to me like Paget’s difference is that the osteoblastic activity comes at the end rather than
primarily)

AVASCULAR NECROSIS (OSTEONECROSIS)

This is due to infarction of bone and bone marrow.
Due to ischaemia:
(Can be vascular injury – usually tauma)
thrombosis
Steroids
Radiation
Alcoholism
Idiopathic
Major sites
Head of femur and scaphoid bone.
May be asymptomatic or associated with pain.
If not treated then can predispose to severe osteoarthritis.

Fractures/Tumours
Fractures can be complete (where you get 2 fragments of bone) or incomplete (also called
greenstick fractures. This is where the bone is cracked but not brocken into two
pieces)*
Often seen in young, immature bone (this is common in children)
Theycan also be simple or compound.
Simple = closed – the surrounding skin is intact

Compound = open, the skin is broken and the bone may protrude through (thus risk of
infection)

They can be comminuted – where the bone is splintered into multiple bone fragments.
They can be displaced – where the ends of the bone are not aligned

.
Spiral fracture = seen in twisting injury (common in dancers)

Complicated = when there is injury to adjacent tissues (e.g blood vessels and nerves)
Depressed fracture = commonly seen in the skull (where the fractures can compress
underlying tissue – with risk of damaging the brain)

Stress fracture (bone fracture after repetitive stress). E.g tibia, fibula and metatarsals
(e.g athletes, dancers and army recruits)
Pathologic fractures = fracture of a bone that has been damaged by disease.
Pathological fracture
Any condition that affects the bone, weakening it can result in this.
Osteoporosis
Osteomalacia
Pagets disease
Tumours (both primary or secondary)
Congenial bone disorders e.g osteogenesis imperfecta.
Fractures cont
Incomplete simple fractures heal the most quickly.
Communitated fractures are characterized by multiple fragments and so it will delay
healing.
Compound fractures communicate with the overlying skin and thus are more likely to become
infected.
Healing of bone
You injure the blood vessels and thus you get haematoma formation (collection of blood)
Then you get inflammatory phase (get neutrophils, then macrophages and then granulation
tissue formation). This is called procallus (remember this is fibroblasts and blood vessels)
(formation of granulation tissue at the site of the fracture)
Osteoprogenitor cells give rise to osteoblasts which migrate to the site of the
granulation tissue. They proliferate and produce osteoid.
You get external callus bridges at the fracture site and outside of bone, internal callus
bridges the fracture in he medullary cavity.
You get ossification (need it to make the bone strong)
This bone is formed quickly and thus it is woven bone. Therefore you need to replace it with
lamellar bone. This is called remodeling.
Factors that affect healing of bone fracture
Type – e.g simple heals more quickly than comminuted and compound
Alignment (if not aligned then impaired healing)
Degree of immobilization – need it for callous formation (excessive movement stops this
– this is why we use plaster of paris in fractures)
Interposition of soft tissue
Blood supply – because inflammatory phase involves tiny blood vessels.
Steroids (because they are anti inflammatory – remember all healing is reduced with
steroids)
DM (due to lack of poor blood supply, poor function of macrophages and prone to
infection)
Nutrition – D for calcium deposition, C for function of fibroblasts.
Infection
Age – due to poor blood supply.
Malignancy.
Complications of fracture
Delayed union
Malunion
Fibrous union (where you have fibrous tissue instead
Non union (failure of 2 ends to meet)
Aseptic necrosis (infarction of bone and bone marrow)
Osteomyelitis (infection of bone and bone marrow)
Treatment of fracture
Immobilization (either internal fixation – plates/screws)
External – plaster of paris.

OSTEOMYELITIS
This is inflammation of bone and marrow due to infection.
Bacterial infection = most common cause.
Mycobacteria (Tb), fungi, viruses and parasites
Pathology
Can spread from bloodstream to extra-osseus site
Direct extension from neighbouring site
Direct inoculation (e.g traumatic or surgical)
Most common cause = staph aureus.
E.coli, pseudomonas and klebsiella can occur in patients with GU infection and drug
abusers.
Patient with sicke cell disease are also prone to osteomyelitis – commonly due to
salmonella.
Strep B = most common in neonates. (Makes sense – just like it can cause neonatal
meningitis)
Many of the non haematogenous cases are caused by mixed flora and/or anaerobes.
(Again, makes sense – spreading straight from outside world)
The initial focus of inflammation (in children) is in the metaphysic (as this is the best
vascularised part of the bone in children). Overall osteomyelitis is most common in
children
Most common (in adults) = vertebrae.
When you have osteomyelitis you have necrosis of the bone (necrotic bony fragment is called
sequestrum)
Reactive bone formation
The adjacent bone is trying to heal itself (termed involucrum)
Clinical features
Often a child (more common)
Fever, malaise, bone pain and tenderness. Also reduced movement of limb.
Dx
Blood culture = best test
Blood tests: increased WCC, ESR and C-reactive protein
Radiography (can see lytic lesions but it takes time – changes are late)
Either ultrasound or MRI = best dx
Bone scan hot spot is useful and bone scintigraphy for difficult cases.
Complications of ostemyletitis
Abscess formation (called Brodie’s abscess)
Continuous bone formation – (called Garres sclerosing osteomyelitis)
Sinus tract formation –
Can get chronic osteomyelitis
Can get pathological fractures
Can get amyloidosis (in the chronic condition)
Bacteraemia.
Tx of osteomyelitis
Antibiotics and then PO
May also need to do surgical drainage.
Tuberculous ostemoyelitis
It is rare in developed country.
Occurs by haematogenous seeding from extra osseous sites.
Most common site is the spine (Potts disease)
Get granulomatous inflammation of affected bone (just like any Tb infection)
Very difficult to tx.
BONE TUMOURS
Classification:
Benign
Malignant (primary or secondary)
Most common tumour in tumours/young adults are primary benign bone tumours
Most common in older adults = multiple myeloma and mets from other sites
Metastatic tumours
Common ones are carcinoma of breast, prostate, renal or bronchogenic lung
carcinoma.
The can be either osteolytic (bone destruction – either due to direct bone erosion or due
to stimulation of osteoclasts by cytokines or osteosclerotic (e.g prostatic
adenocarcinoma – can cause bone formation)
Complications
Pain
Pathological fracture
Replacement of bone marrow (can get anaemia, infection, bleeding etc)
Hypercalcaemia (I imagine due to resorption of bone???)
Nerve and spinal compression
Myeloma
There is primary malignant proliferation of plasma cells in the marrow. (see other
lecture)
Primary bone tumours
Primary benign tumours = more common in children and young adults.
Primary malignant tumours = more common in elderly.
Accurate dx depends on clinical, radiologic and pathologic examination of lesion.
Classification
Can be bone-producing or cartilage producing (As well as others)
Bone forming tumours
Can be benign, malignant or locally aggressive (in between)
Benign – can be osteoma or osteoid osteoma
Locally aggressive (can be osteoblastoma)
Malignant (ostesarcoma)
Osteoma
This is a benign bone forming tumour.
Usually seen in craniofacial location.
Probably a harmatoma (some people believe)
Multiple association are associated with Gardners syndrome (type of FAP)
Osteoid osteoma
This is a benign bone forming tumour.
Seen in young.
(More prevelant in men)
Painful (due to production of prostaglandin).
Characteristically relieved by aspirin.
Commonest in femur or tibia.
Charectirsed by a nidus (small focus of blood vessel proliferation). In this site the cells produce
prostaglandin (hence can be inhibited by aspirin, causing the pain to be relieved)
Therapy = complete excision of nidus.
Osteoblastoma
This is a benign bone forming tumour.
Seen in younger age.
Most commonly seen in vertebral column
No sclerotic reaction
Pain is NOT relieved by aspirin
Therapy – curettage/resection.
Malignant tumours
Ostesarcoma
This is a malignant bone forming tumour.
Has bimodal age distribution.
Seen in young and elderly (i.e 2 peaks)
Effects the end of the bones. Most arising from the metaphysic. This is because it is the
most metabolically active part of the bone
Pathogenesis of osteosarcoma
Cabe sporadic or genetic (Rb, p16 and p3 have been implicated)
Secondary osteosarcoma can be associated with radiation and pagets disease
Clinical features of osteosarcoma
Tenderness and/or pain in affected region.
Fracture (since the bone is weakened – you can get a pathologic fracture)
Distant mets – commonest is lung.
Spread
Can spread within medullary cavity
Through the periosteum
Can spread across epiphyseal plate (into the joints)
Haematogenous.
Osteosarcoma
There are characteristic X-ray features in osteosarcoma.
Codmans triangle and sunray speculation.
Makes sense because this is a bone forming tumour – and thus the osteoid can be
deposited perpendicular to the bone (Hence called sunray speculation). You get the
codmans triangle due to lifting of the periosteum.
Treatment
Patients usually treated pre-operatively by chemotherapy and surgical resection.
Prognosis = poor – due to early metastasis (60% 5 year survival rate)
CARTILAGE PRODUCING TUMOURS
Osteochondroma
These are bony lesions with a cartilage cap.

Seen in young patients - <20 years.

Can be multiple (hereditary) or single (sporadic)
There are mushroom shaped bony projections from the lateral aspects of long
bones.
It may arise from the metaphysic.
Chondrosarcomas can occasionally arise in osteochondromas. The incidence
(En)chondroma
Any age, often affects the small bones of the hands and feet.
Tends to affect the small bones of the hands and feet.
Can be single or multiple sites.
Arise from the metaphysic
Sinle or multiple sites:
Associated with:
Oliers disease (usually one side of the body)
Mafucci syndrome (associated with haemangiomas of soft tissue)
There is also an increased risk of chondrosarcoma
There is a well circumscribed mature hyaline cartilage.
Chondroscarcoma

Affects older (>40)

This is a malignant tumour of cartilage
This is the second most common primary malignant tumour of bone (half after osteosarcoma)
Often associated with tiny calicifications
Can occur de novo or from a previous benign tumour
Axiel skeleton (bones of pelvis, shoulder, ribs and spine) are most common..
This is an aggressive tumour which can metastasize anywhere (lungs, kidney, liver and
brain are most common)
They are NOT sensitive to chemotherapy (only tx is resection). (Unlike osteosarcoma which
can be sensitive to chemotherapy)
Comparing osteosarcoma with chondrosarcoma:
Osteosarcoma = 10-25 years and elderly (Chondrosarcoma = >40)
Osteosarcoma = Affects long bones (chondrosarcoma = affects axial skeleton)
Osteosarcoma = Sensitive to chemotherapy (chondrosarcoma = NOT sensitive
to chemotherapy).
Giant cell tumours (osteoclastoma)

Occurs in adults (20-55).

Affects the epiphyseal ends (rather than metaphysic) of long bones.
There are stromal cells and multinucleated osteoclast like giant cells
It is a locally aggressive tumour (with high recurrence), may also metastasise. May also
cause haemorrhage which makes sense – since these are osteoclasts and are breaking down thte
bone.
(4% metastasise). (I.e this is a benign tumour but it may metastasise infrequently). Not easy to
know whether it will metastasise or not based on histological indicators.
Ewings sarcoma
These are neuroectodermal
Seen in children and young adults.
Site is medullary cavity (rather than metaphysic or epiphysis) in the diaphysis of long
bones, pelvis and ribs.
There is a translocation involving chromosome 11 and 22.
It is characterized by the proliferation of small blue cells (called this as there is very little
cytoplasm and large nuclei). Note these are known as small round cells of childhood, i.e this
is another neuroblastoma – e.g nephroblastoma, retinoblastoma, medulloblastoma
– all characterized by these small blue cells.)

Characteristic Xray is onion skinning.

It is highly aggressive and chemotherapy resistant.
With the advent of chemotherapy and surgery then survival has increased, but overall poor
prognosis.

Joints
Joints can be synovial or non synovial. They are a type of connective tissue.
Synovial - = movable joints e.g knee joints.
Non synovial joints – allow very limited movement but structural movement
(Cartilagenous – e.g intervertebral disks) and fibrous (e.g cranial sutures)
Structure of synovial joints

The articular surface is covered by haline cartilage – and the healing is poor.
The cartilage acts as a shock absorber between the bones
There are cells called chondrocytes which produce the matrix. They also produce enzymes
which degrade the matrix.
The matrix is made up of collagen type II (compare this to the collagen type one that is found in
bone matrix), proteoglycans and water.
The joint is surrounded by a capsule – which is rich in nerves (hence this is pain sensitive).
The synovial joints are supported by ligaments and bursa (which is a fibrous sac that acts as
a cushion to ease movement in areas that are subject to friction).
The whole synovial cavity there is a synovial membrane
The synovium lacks a basement membrane (therefore there is a quick exchange between
blood and synovium).
It contains 2 cell types. Type A synovial cells are macrophage-like and type B
synovial cells are fibroblast like (and produce protein)
The function of the synovial fluid is for lubrication and nourishment for the cartilage.
Synovial fluid
It is normally colourless and transparent
WBC = <200 and polymorphs make up less than 25%
Glucose = nearly equal to blood
Gram stain is negateive
ARTHRITIS
Osteoarthritis
Most common type of rheumatic disease.
It affects 80% of elderly.
It is a degenerative disease where there is progressive erosion of the articular
cartilage
It is NOT an inflammatory condition (hence some people prefer to use the term
osteoarthrosis – as osteoarthritis is a misnomer)
There is accompanied focally increased synthesis of cartilage matrix (however it is not
enough to keep pace with the continuing stress and eventually the articular cartilage
disappears)
Can be primary or secondary.
Primary osteoarthritis
It is idiopathic and affects the elderly.
Involves the weight bearing joints (e.g hips and knees). However it can also effect the
interphalangeal joints.
Some families have a mandalian pattern of inheritance of primary generalized
osteoarthritis – (this is a mutation in the gene for type 2 collagen – makes sense since type 2
collagen is the type that is involved in joints)
Note that main risk factors are obesity, increased stress to the joints and previous joint
injury (resulting in uneven application of stress to the articular cartilage).
Secondary osteoarthritis
Can develop at any age in a damaged joint e.g due to:
Trauma
RA
Gout
Tuberculosis
Acromegaly
Haemachromatosis
Deformity – e.g dislocation of the hip.
Note that exercise does not cause osteoarthritis (although are exceptions e.g certain sports – e.g
basketball and knees)
Pathogenesis
Aging and mechanical effects have a “wear and tear”
It is due to biomechanical stresses of weight bearing over time. Progressive erosion of
the cartilage with use.
Genetic factors
Osteoarthritis is characterized by changes in the composition and mechanical
properties of cartilage.
There is an increased water and decreased concentration of proteoglycans
Chondrocytes produce il-1, TNF-alpha and nitric oxide. These stimulate the production o
metalloproteinase which degrades the matrix. They also inhibit the production of type
II collagen and proteoglycan. This occurs with progressive age.
Morphology of osteoarthritis
There is destruction of the articular cartilage.
First step = chondromalacia (softening of the cartilage)
Second step = cartilage fibrillation (since the cartilage is soft, it starts to fragment). Note
that synovial fluid may enter the cracks and cause bits of cartilage to float around in the
synovial fluid – called loose bodies
(Note pic – left is picture of normal femoral head, while right shows cartilage fibrillation)

Eventually there is erosion.

As erosion continues, the subchondral bone is exposed and the constant brinding
against the opposite joint surface polishes the bone and makes it smooth and shiny
(hence known as ivory bone). This is called eburnation (also known as subchondral
sclerosis)

Cracks may also appear in the eburnated bone and synovial fluid can enter, which results
in the formation of subchondral bone cysts.
Osteophyte formation may also occur. This is outward growth of bone at the margins of
articular surfaces. This is formed by endochondral ossification (formation of new
bone from cartilage). (Also known as bone spurs – see why in picture) (remember these are
growths of bone, can be early sign of osteoarthrosis or of injury etc, I imagine they would be hard
nodules. They can cause pain and immobility, e.g hand…)

Sometimes the fragments can become detached which cause pain and recurrent locking
Also note that underuse (due to pain)of bone predisposes to osteoporosis.
Osteophytes
Herberdens nodes are osteophytes which produce a hard palpable enlargement at
the distal interphalangeal joints and often an early manifestation of osteoarthritis.
Bouchard nodes are similar but are on the proximal interphalangeal joints.

Secondary changes
You get thickening of the synovium with minimal inflammation
 Atrophy of the muscle (due to disuse)
Deformity of the joint (ostephyte formation – see above, or sublaxation).
Can also get osteoporosis.
Clinical features
May be asymptomatic
Can present with severe pain, morning stiffness or restricted movement
There may also be crepitous (cracking sound on movement of the joint)
There can also be compression of the nerve root by osteophytes
Deformity may result
Investigation
X-ray (characteristic features – e.g cysts)
Negative serology (i.e RA negative etc)
Synovial aspirate is clear and cell count is slightly raised or normal (makes sense,
since not an inflammatory condition)
New remedies for osteoarthritis
Glucosamine and chondrotin.
The mechanism of action is unknown.

RHEUMATOID ARTHRITIS
- This is an autoimmune disorder that affects many organs (joints, skin, heart, lungs, eyes, lymph
nodes and bone marrow)
- 3% women and 1% men
- Most cases arise in young or middle aged females
- Course is unpredictable (can be insidious or remittent)

Criteria for RA
Four or more of the following:
- Morning stiffness
- Arthritis of three or more joints
- Arthritis of the hands
- Symmetrical arthritis
- Rheumatoid nodule

Characteristic X-ray findings

Pathogenesis
It is due to an environmental agent that induces an autoimmune reaction in a genetically susceptible
individual

Agent
Most evidence points to EBV
This is because EBV as been detected in the synovium. Also the EBV and type II collagen
share similar epitopes.

Autoimmune reaction
There is a type 4 hypersensitivity reaction (CD4+ T helper cells are important). The
microbial agent induces the immune reaction in which the CD4+ helper cells produce
cytokines which destroy the joints. They also activate B cells.
Autoantibody production by B cells are important. The B cells produce antibodies
(autoantibodies against IgG – i.e RF)
Cytokines are produced (il-1 and TNF) which causes the injury.

Genetic susceptibility
It is associated with HLADR4.

Rheumatoid factor
Occurs in 80% of people with RA.
It is an Igm autoantibody (note it seems that RF refers to the autoantibody rather than the
complex) against another type of antibody. (FC portion of IgG)
The titre correlates with the severity of the disease.
Also RF can complex with IgG and the deposition can cause immune complex
deposition – e.g synovial fluid, kidney (causing glomerulonephritis) etc. They can cause
extra-articular manifestations.
However note that it is present in about 5% of normal elderly.
Pathology
If affects the synovium – especially of the small joints.
You get ulnar deviation of fingers, swan-neck deformity and boutonniere deformity
(see clin med lecture)
Can also get radial deviation of wrist.
It is symmetrical and polyarticular.

Secondary changes
Osteoporosis (due to not using the joints), osteoarthritis (due to damage of the articular
cartilage) and muscle wasting (due to disuse)

Pathological features
Synovial hyperplasia
Lymphocytes and plasma cells with lymphoid follicle formation and occasional
polymorphs in the synovium.
One histological feature that is seen is pannus formation (meaning cloth). This is an
inflammatory tissue which is made of granulation tissue and inflammatory cells. It
covers the synovium (like a cloth – hence the name)
Can get fixation of the joints (called fibrous ankylosis).
Extra articular manifestations
Can get rheumatoid lung – (pulmonary fibrosis and pulmonary nodules can occur)
Can cause uveitis and scleritis
Vasculitis – due to immune complex deposition
Amyloidosis – as with any chronic inflammatory condition, can occur. (A amyloid)
Subcutaneous nodules (can be seen in other organs though). Made up of degenerate
collagen with giant cells.
Lymphadenopathy
Can also get Sjogrens syndrome (xerostomia – dry mouth/eyes, and keratoconjunctivitis)
Feltys syndrome
This is where you have RA and splenomegaly.
You get severe leucopaenia and anaemia.
It occurs in severe longstanding RA.

Lab investigations
Can have normochromic normocytic anaemia (check – don’t know why)
Increased ESR (because it is a chronic inflammatory condition)
Other auto antibodies (e.g anti DNA antibodies etc)
Treatment
NSAIDS (since it is an inflammatory condition)
Steroids
Gold
Antimetabolites (azathioprine, methotrexate, cyclosporine)
Surgery (when there is subluxation of the cervical spine)
New drugs – e.g antibodies against TNF
Omega 3 (which blocks the production of leukotrienes )
JUVENILE RHEUMATOID ARTHRITIS
Also called Stills disease.
It affects under 16’s and peak is between 1-3 years
Females > males
It is a oligoarthritis (i.e single joint is usually affected – unlike the polyarthritis in regular RA)
Affects the large joints – especially the knees (unlike the small joints in RA)
Lymphadenopathy and splenomegaly
RF is usually negative but ANA is usually positive.
RHEUMATIC FEVER
Remember it is an acute or recurrent inflammatory disease which is usually secondary to
group A strep.
Joint disease – classically a migratory arthritis (Affects one joint, then moves to another etc)
Usually affects large joints (knees, elbows etc) and pain
There is usually no deformity
SLE
This is a systemic autoimmune disease
There is usually minimal joint deformity. It results in a non erosive synovitis
SERO-NEGATIVE SPONDYLOARTHRITIS
A group of diseases with negative RF
There is involvement of the sacroiliac joint and spine (sarcoilitis and spondylitis)
Usually affects patients with HLA-B27
Ankylosing spondylitis, reactive arthritis (such as reiters syndrome and
enteropathic arthritis) and psoriatc arthritis
Ankylosing spondylitis (bamboo spine)
This is a chronic inflammatory disorder of lumbar spinal and sacroiliac joints.
There is fixation and fibrosis of the spine – (which is why it is called bamboo spine)
Often affects young males.
Most have HLA B27.
They have autoantibodies directed at joint elements after infection.
Peripheral arthritis, uveitis, aortic incompetence and amyloidosis can occur.

Reiters disease/reactive arthritis

It is an autoimmune reaction following especially Chlamydia infection
Useful pneumonic = patient cant see, cant pee and cant bend the knee.
Can also be due to salmonella, shigella, yersinia and campylobacter
Defined by triad of arthritis (affecting knees, ankles and spine), urethritis or cervicitis and
conjunctivitis
Enteropathic arthritis
This occurs with chronic inflammatory bowel diseases (UC/Crohns) (remember the non
GI problems that these patients can get)
It can also occur following a bowel infection – e.g after salmonella, shigella, yersinia and
campylobacter
Psoriatic arthritis
Affects 5% of patients with psoriasis.
Arthritis which affects the distal interphalangeal joints, ankles, knees and spine
Again HLA-B27 is implicated
INFECTIVE ARTHRITIS
Haematogenous spread = most common
Spread from adjacent infective foci – (e.g osteomyelitis)
Direct inoculation – local trauma and insertion of surgical prosthesis
Suppurative arthritis
Staph aureus (most common in both young and old)
Haemophilus influenza = in young children
Gonoccocus (in healthy young sexually active individuals)
Strep, E.coli, pseudomonas and salmonella can all be causes as well.
Clinical features
Acutely painful
Sweollen joints
Fever
Decreased range of motion
Increased WCC
Joint aspiration
Not really recommended as you can spread the infection.
Yellow/green and purulent
WBC > 50,000
Polymorphs = >75% (makes sense – as mostly bacterial)
Gluocse < blood (makes sense – the bacteria are using up the glucose)
Gram stain + culture = often positive
TUBERCULOUS ARTHRITIS
Spread from adjacent tuberculous osteomyelitis or haematogenous spread
Spine = most commonly affected (Potts disease) followed by the hip.
It can cross cartilage barriers (unlike other bacterial infections)
There is a destructive arthritis and deformity
There is granulomatous inflammation
LYME DISEASE
Transmitted by tic. Borrelia brgdoferi = pathogen. It can also cause arthritis.
Remember skin manifestation – erythema migrans (seen at site of tic bite)
Second stage = CNS and heart involvement
Late stage = when you get destructive arthritis.
GOUT ARTHRITIS
(Note used to be called a disease of kings, because meat and wine cause it, which is more
expensive)
Males > females
Peak incidence = in 5th decades
¼ arfamilial
It is a disorder of purine metabolism which results in hyperucricaemia.
Serum urate level is above 7mg/dl
Hyperucricaemia can be primary or secondary
Primary
Can be due to undersecretion of uric acid (90%)
Overproduction of uric acid
Risk factors
Age (rare before 30)
Family history
Alcohol consumption
Obesity
Meat etc
Secondary gout
Secondary – affects 10% of cases.
Due to overproduction of uric acid usually associated with excessive breakdown of
nucleic acids (e.g due to leukaemia, multiple myeloma and massive cell lysis that
results from cytotoxic drug therapy).
Renal undersecrteion (e.g renal failure, diuretics (Both thiazide and loop. Remember
loop = hyperurcaemia, hypocalcaemia, hypokalaemia while thiazide = hypercalcaemia,
hypocalaemia and hyperuricaemia. Potassium appearing = hyperkalaemia)
Can also be due to an enzyme deficiency – (Hypoxanthine guanine phosphorybosyl
transferase (HGPRT) – this is important in uric acid metabolism.
Pathogenisis of gout
You have deposition of urate crystals on the surface of the articular cartilage
This results in interaction with leucocytes which result in degenerative changes.
Classical joint affected = big toe. (Metacarpophalangeal joint of big toe). ¾
affecrting the ig toe with first attack. (Note that apparently external joints are more readily affeceted
because these joints are more typically colder and therefore the uric acid is more readily able to
precipitate).
Sometimes there can be deposition of uric acid in tissue which results in tophus formation
(gouty tophi) – commonly in ear lobe. (Remember, differential is calcinosis and I imagine also
rheumatoid nodules?)
They occur in chronic hyperuricaemia and is due to the deoposition of uric acid in tissue.

Stages of gout
You have an acute inflammatory arthritis and asymptomatic periods in between the
attacks. Eventually it becomes a chronic inflammatory conditions
You have chronic deposition of urate in and around the joints (Known as tophi)
Complications of gout
Interstitial nephritis
Renal calculi (made of uric acid)
Renal failure
Diagnosis
Need to examine aspirated synovial fluid. It will show needle shaped crystals and
neutrophils.

Can do synovial biopsy.

Note that don’t put tissue in formalin container (as the crystals will dissolve in this, thus
have to put it in alcohol).
Treatment
Colchicine (remember, this is a drug that binds to tubulin and causes damage to mitotic cells.
Hence also used for cancer – and side effects = anaemia and neutropenia for this
reason, it is killing rapidly dividing cells. However, it also inhibits uric acid deposition and
for this reason it is used in gout). It is also an anti inflammatory effect – due to slowing down
the immune response – I imagine this is again due to the white cells are rapidly dividing)
Allopurinol (this inhibits uric acid synthesis) (It is a purine analogue that binds to the
enyme. It is not useful for acute gout but is more useful for chronic treatment = to lower
the uric acid levels in the plasma. It is commonly used in prophylaxis for patients who are receiving
chemotherapy. Makes sense, as the chemotherapy is likely to increase the uric acid levels).
PSEUDOGOUT
Also known as chondrocalcinosis
This is the deposition of calcium pyrophosphate on arcticular cartilage. (I.e different
crystal deposition)
Most commonly seen in over 50’s
Classification
They are classified into primary (idiopathic), hereditary and secondary (due to
hyperparathyroidism, hypothyroidism, haemochromatosis and DM)
Pathology
Asymptomatic until the crystals are shed into the joint space (spontaneous or due to
trauma)
Unlike the crystals in gout, the crystals here are rhomboid in shape.

Hypertrophic osteoarthropathy
This is new bone formation at the distal ends of the long bones, especially the
metacarpal and metatarsal bones.
It is a syndrome of painful, swollen joints, cubbing of the digits and the above. (I believe
it is clubbing with these other things associated)
Rarely it appears as an idiopathic disorder but the main significance is that there is usually
underlying disease – (usually bronchogenic carcinoma).

TUMOURS OF THE SOFT TISSUE

Extremely rare.
They are tumours of mesenchymal origin. (mesenchyme is the conncentive tissue of fetal and
developing organs which will develop into the stroma) and are classified based on their
histological differentiation.
They can be benign or malignant
Pathogenesis
Poorly understood but risk factors
Radiation, viruses (e.g kaposis sarcoma) and genetic syndromes (e.g li fraumeni)
Classification of soft tissue (benign and malignant)
Tuours of adipose tissue = lipoma and liposarcoma
Tumours of smooth uscle = leiomyoma and leiomyosarcoma
Tumours of skeletal muscle = rhabdomyoma and rhabdomyosarcoma
Fibrohistiocytic tumours = fibrous histiocytoma and malignant fibrous tumours
Vascular tumours = haemangioma and angiosarcoma
Peripheral nerve tumours = neurofibroma and malignant peripheral nerve
sheath tumours
Tumours of uncertain histiogenesis e.g synovial sarcoma (not does not originate from
synovium – uncertain origin)
More information about the soft tissue sarcomas
Note – this is not that important, main thing is to know the prognosis.
Malignant fibrous histiocytoma
This is the most common malignant soft tissue tumour of adults. Usually occurs in
deep soft tissues of an extremity. More common in adults over 50
Liposarcomas
Second most common.
Characterized by presence of lipoblasts
Rhabdomyosarcoma
Tumours with skeletal muscle differentiation
Most common sarcomas of childhood/young
Charactersed by rhabdomyoblasts
Synovial sarcoma
Typically affects young adults. Occur in proximity to joints but do not arise from the
synovium.
Pathogenesis of soft tissue sarcomas
Need to know this
Histologic type
Tumour grade: (as any type)
Degree of differentiation, cellularity, pleoorphism, number of mitoses, presence of
necrosis
Stage of tumour
Location (the more superficial have a better prognosis)
Dx
Histologic examination
Immunohistochemistry. Nearly all vimentin positive (remember from last year, vimentin
in all sarcomas)
Leiomyosarcoma (desmin and actin positive)
Rhabdomyosarcoma (myoglobin positive)
Molecular dx – some have specific genetic abnormality (e.g Ewings sarcoma –
t(11;22) and synovial sarcoma = t(X;18). I.e specific. There are others as well.
GISTS
Remember these originate from the interstitial cells of cajal.
Remember that most have mutations in c-kit (a protooncogene) and gleevec is a selective
c-kit receptor inhibitor.
Remember this is also used for CML (chronic myeloid leukaemia)

Skin diseases
There is a wide range of conditions – from inflammatory to neoplastic.
It is a common reason for consultation to GP’s
Skin neoplsms rarely poste threat to patients life. The exception is a melanoma.
Pigmented skin lesions are common but they are not necessarily melanoma (e.g some
squamous cell carcinoma can have melanocytes in it but it is not a melanoma). They may
sometimes be clinically distinguished, but it may be difficult.
Some benign lesions that form a tumour are not true lesions (e.g malformations,
harmatomas, infection (i.e warts) or cysts.
Structure of skin
The layers from superficial to deep@
Stratified squamous epithelium. This is specialized for keratin production and is
exposed to UV light. It also contains melanocytes and Langerhans cells (which are
specialized antigen presenting cells).
Dermis
Subcutaneous fat.

Stratified squamous epithelium

There is a layered, orderly maturation from the base to the surface.
There is a basal layer of small dark round cells.
The superficial layers flatten and acquire more abundant cytoplasm and produce
keratin
Dysplasia = showing disorderly maturation and abnormal cytological features.
UV light (especially UV-B) causes DNA damage.
Melanocytes
These are neural crest in origin. They migrate at 6 weeks in utero to the skin.
They produce melanin pigment and the melanin is transferred to adjacent squamous
cells.
The melanin protects the nucleus of squamous cells against UV damage to the DNA.
(Hence this is the reason why in human evolution those that lived closer to the equator/hot
countries developed darker skin (in order to protect themselves from skin cancer etc)
Dermis
This is a loose connective tissue which supports the epidermis. It contains:
Fibrous and adipose connective tissue, blood and lymphatic vessels, nerves,
smooth muscle (to control blood vessels, arrector pili – the smooth muscle that makes your hair
stand on end – etc). Additionally there are inflammatory cells (lymphocytes, macrophages,
mast cells etc)
Skin appendages (e.g sweat glands, sebaceous glands, arrector pili etc)
Can get tumours of any of these – they are generally benign. E.g can get haemangiomas,
lyomyomas, neurofibromas, scwannomas, dermatomycomas, skin appendage
tumours etc
Skin appendages
Pilo-sebaceous units e.g hair follicles and attached sebaceous glands. There are also
sweat glands
If the epidermis and superficial dermis is damaged/removed then the epidermis will
regenerate from surviving skin appendage epithelium (Hence you can do a split skin
graft and there can be regeneration. Additionally if you burn off the epidermis then it will
regenerate, while if you burn off deeper layers then there is no regeneration)
Skin tumours
These may be benign or malignant
May arise from epidermis (i.e squamous cell carcinoma), melanocytes (i.e malignant
melanoma), appendages or the dermis (from any of its constituent elements e.g
haemangioma, schwannoma etc)
The treatment of benign lesions is usually cosmetic (or to exclude malignancy).
Malignant tumours of the skin may be locally aggressive (i.e grow and destroy the area
they are in). However only very rarely will they have the potential to metastasise. The
exception to this, however is a melanoma.
Also note that malignant skin tumours are usually primary and you ill only develop secondaries
very late when there is a disseminated primary malignancy.
Primary skin malignancy
Squamous epithelium = much more common.
They are basal cell carcinoma or squamous cell carcinoma. Collectively they are known
as non-melanoma skin cancer.
Melanocytes = much less common origin for malignancy. However if it is not identified
early enough it poses significant risk for metastasis.
Also other types of primary skin malignancy (from dermal elements – e.g lymphoma,
appendages etc. These are rare though).
NMSC may be locally invasive however they rarely cause metastasis or death.
Melanoma however is more aggressive and the outcome depends on stage at dx.
Skin malignancy = related to UV-B light exposure:
Light skin, fair, red hair, pale eyes, tendency to freckling are prone to developing
freckling.
Outdoor work especially in areas in the equator
SCC is related to cumulative exposure (you usually also see some other UV related skin
damage)
Most melanoma however is NOT related to cumulative exposure but instead to intense,
intermittent exposures
BCC appears to be intermediate
UV-A is also important (which is used in sunbeds and to tx psoriasis patients).
Epidemiology of skin cancer
NMSK = commonest cancer but rarely causes death (I think). Melanoma on the other
hand (although is much rarer) causes far more deaths (than NMSC)
Epidemiology of NMSC
Incidence is strongle linked to age. (most occurring >65 years old)
Often multiple and usually in sun-exposed sites.
I.e face, legs, ears, nose, scalp (in bald men) etc
Small numbers will be on difficult areas to excise e.g eyelid,
BCC is exceptionally rare cause of metastasis.
SCC are uncommon cause of mets/death (however much more common than BCC).
Mainstay of treatment is local excision.
Basal cell carcinoma
It is derived from squamous epidermis

What characterizes it histologically are basal cells thataare palisading (i.e at the edge of the
groups of tumour cells, the cells and nucli are arranged in parallel)
Metastasis = incredibly rare
There can e local invasion with lisk of local destruction. (especially near the nose and eye –
termed a rodent ulcer)
Different histological types are less or more prone to recurrence – and this guides treatment)
Risk factors
UV light (UV-B), radiation, immune suppression.
Age and faire skin
Treatment
Surgical excision. Mohs micrographic surgery if high risk (this is where you take
slices (you remove as much as you can see, then you takiceand look at them under the microscope,
if you see tumour then you take another slice, wheras if you don’t then you stop).. Useful for tricky
arlocal destruction eas, or recurrent tumours etc.
Local destruction (cryotherapy, electrosurgery, radiotherapy etc)
Topical treatment – with 5-fluorouracil (an antimetabolite) or imiquimod. (This is an
immune modulating drug which is felt to help by altering immune targeting of the tumour)
High risk cases require specialist treatment (e.g if difficult to define, recurrent, post
radiation or large. As well as critical sites (mid face including eyes, nose etc)
Invasive squamous cell carcinoma

Derived from squamous epithelium of epidermis

Shows differentiation towards keratin production.
Metastasis can occur (but rare and late)
Overall good prognosis
If does metastasise then will go to regional lymph nodes.
Poorer prognosis – if lip, deep tumours and arising in non-sun damaged skin (e.g
genital area)
Also poorer if arising from chronic ulcers or skin disease
Tx = excision. (Tend not to do the cryotherapy, electrotherapy etc that you get with basal cell.
Probably because more risk of spread/invasion?)
Histological hallmark = keratinisation
Risk factors
By far, sun exposure = most important risk factor.
Historic (chimneysweapers being at risk for scrotal SCC – due to hydrocarbons)
Radiation treatment (over irradiated areas)
Edge of old scars, burns, sinuses, chronic ulcers etc (Makes sense – as rapid turnover etc
there)
Genetic – e.g xeroderma pigmentosum (being unable to repair UV induced DNA damage –
hence lots of skin cancer) and people with albianism (makes sense, as lack of protectivemelanin)
Immunosupression – post transplant, HIV – related to specific HPV types (not the
common HPV that causes warts (I imagine that this is because not immunosupressed individuals
will not get infected by these HPV virii)
Common HPV infection = NOT risk factor.
Dysplastic epidermal lesions

These show varying degrees of dyplasia but do not show invasion.

They can develop into invasive SCC (but unlikely and long time)
Tend to present as irregular crusted, keratotic lesions (or red patches)
Actinic (solar) keratosis
This is epithelium that shows dysplasia (ranging from mild to severe) but short of in situe
SCC.
Bowens disease
This is the term for in situ squamous cell carcinoma (i.e full thickness dysplasia/ keratosis)
This seems to be a rather flat lesion – which makes sense since it is a carcinoma in situ.

Pigmented skin lesions

Melanoma = typically pigmented.
However not all melanomas are pigmented and not all pigmented skin are
melanomas. (e.g BCC, keratosis etc). Vascular lesions are usually blue/red rather than
brown
Thus can be difficult to diagnose. Thus important to send all lumps and bumps to pathology.
Benign melanocytic lesions
Freckle - ephelisFreckle – ephelis
This is a localised area of increased melanin production. It is induced by the sun but
there are no increase in melanocytes
Benign lentigo
This is a flat lesion with increased numbers of melanocytes in the basal layer of the
epidermis.
They are fixed but may sometimes be promoted by long term sun exposure

Melanocytic naevus (pigmented mole). This is a clonal proliferation of melanocytes as

nests
Naevus
Naevus = benign proliferation of skin element (commonly refers to melanocytes – i.e
mole)
Implies a pigmented lesion which is present at birth
Commonest example is melanocytic naevus (which may be congenital or aquired).
Normally you stop producing naevi after 20 (if new naevi are formed after then you should
be converned)..
The lesions evolve with time – the location of the nests, amount of pigmentation and
degree of nodularity typically change with time.
They can be junctional (confined to basal layer), compound (basal layer and epidermis,. May
be slightly raised) or intradermal (they are only in the epidermis, usually form raised areas)
MALIGNANT MELANOMA
Can be aggressive and life threatening
Doesn’t cause high amount of deaths, but potentially easily recognised.
Also even though it is more common in elderly, it does not infrequently affect the young.
Usually associated with intense sun exposure not cumulative.
Can arise in sites outside the skin. E.g eye (most common malignant tumour affecting the eye),
meninges, mucosa etc.
Does NOT always produce pigment (i.e can be amelontic).
There has been a rise in incidence (with travel of fair skinned people to hot countries) as well as
increased detection.
It is an important dx (even if early – for insurance problems etc)
Development
Goes through stages.
Goes through in situ (confined to epidermis) – which is always cured. (i.e in these they grow
upwards into the epidermis)
Some of the in situ tumours will invade into the dermis (and then into the subcutaneous fat).
From there they can spread through the lymphatics to other sites (e.g skin, local lymph
nodes) and by blood stream to liver, brain etc.
Can also spread within skin and form satellite tumour nodules (which is why wide excision
of invasive melanoma is therefore performed)
Note that these tumours can be problematic, can be bizarre (e.g can excise melanoma, live 10 years
and then present with a met)

Prognostic factors
Stage
Most important
If there are mets (lymph nodes or distant). Distant mets = very bad prognosis, lymph
mets then poor prognosis
If the melanoma hasn’t metastasised then thickness
Breslow thickness
If no mets (i.e only primary lesion) then the thickness of invasion becomes important.
Best single thing for prognosis.
<0.75mm thick then nearly 100% survival
>2mm thick (about half way through the dermis) then drops to 50% 5 year survival.
Clarkes level of invasion
This was related to the level of invasion (was used, but in reality corresponds to thickness.
Other prognostic features
Ulceration = bad, mitosis.
Presence of tumour infiltrating lymphocytes then this is good.
Histological classification
Not that important because doesn’t have independent outcome in
Superficial spreading (where an in situ component can be identified), nodular (invasive at
the outset), acral (palms, soles and nails, rare but commonest form in black people – as they don’t
get them elsewhere (I imagine because these areas are relatively unprotected, with paler skin),
lentigo maligna melanoma (invasive melanoma developing in sun exposed skin on
background of lentigo maligna)
Also note lentigo maligna (hutchinson melanotic freckle) – this is a big flat pigmented
lesion (related to chronic sun exposed skin – especially in face of elderly). Evolves towards in situ
malignant melanoma (but low frequency will become this)

Treatment of melanoma
Primary excision of any suspicious lesion. (However don’t do incisional biopsies or
shave/hit etc it, as it can alter the morphology)
If it is melanoma then do re-excision to get clear margin. (As there is risk of satellites).
The margin of clearance relates to tumour invasion.
If more than 1mm in thickness then do sentinel lymph node biopsy (assessing for
subclinical lymph node metastasis).
Remember that purpose is to target the single lymph node that if one were to be involved you
can targe it, rather than take out all the nodes and get lymphoedema.) – you inject blue die and
radiolabel and see which nodes light up (nodes where tumour would have first spread – then
remove them and check for metastatic deposits. (If doesn’t have met then unlikely that other nodes
have met)
Note that not therapeutic (possibly marginal). Mainly done for prognosis
1/3 of melanomas arise from preexiting melanocytic naevi however most don’t.
Also note that any single naevi (even if they are strange, big etc) it is unlikely to become a
melanoma.
Also very rare families with high risk melanoma have unusual clinical features.
E.g atypical multiple moles and melanoma syndrome (have dysplastic naevi).
Risk factors: fair skin, tendancy to freckle and burn, blue eyes and red/blonde hair.
Congenital naevi: risk depends on size (only significant if very large)
Multiple dysplastic naevi (increased risk)
No excess risk in typical sporadic naevi or small congenital naevi.
Early detection
Clinical suspicion
A,B,C,D,E
A = asymmetry
B = border irregularity
C= colour variation
D = diameter >0.5cm
E = expanding
However most moles = harmless.
Sequential photography may help.
Other worrying singns = changing moles, new moles (beyond young adulthood), irregular
outline, bleeding, ulceration and development of satellite lesions.

Calcium metabolism
Normal calcium homeostasis
Remember that the bones that support us are not static. There is a constant turnover.
We absorb calcium from the diet, it is present in the ECF, soft tissue and bone etc. We are
constantly laying down calcium in the bone – as hydroxyapetite (as calcium phosphate)
and we are absorbing the calcium from bone

Also, it is removed by the kdieny.

Bone is the resevoir of calcium (hence the reason why when you have disorders of calcium
then it will affect bone).
Calcium is bound in plasma. Half is free (1.1mmol) – this is the biologically active form
About half is bound mostly to albumin (about 1 mmol). With total being about 2.4 (other bound
in other proteins as well as bicarbonate and phosphate). This is another resevoir of calcium.
Thus when albumin falls then the total calcium falls. (Most simple/cheap method of calcium
measurement measures the total calcium). (However point of care testing – e.g in ICU, the blood
gas analyser (in all the electrolytes – compared to lab result), then it measures free calcium –
which is about half the total calcium).
Note that no pathological conditions that give high albumin.
Note that there are various formulas that you can use to correct the ionised calcium for when
albumin falls.
Also note that free calcium can be displaced from albumin by hydrogen ions.
Thus in acidosis you will have higher calcium in the ionised fraction.
In renal disease you get total fall in calcium. This is due to a combination of lack of vit D
activation and phosphate increase (which causes fall in calcium)
However note that renal disease can also cause metabolic alkalosis (which causes an
increase in the proportion of free ionised calcium (I.e kind of like a correction, although
not really as it is a disease process). Thus if a patient with renal failure develops tetany,
confusion etc then don’t be immediately tempted to give calcium (as this may be due to the
uraemia rather than the calcium as the free calcium may not as low as you may think it is – if
patient wasn’t acidotic).
Factors affecting plasma calcium concentration
That is, the total concentration.
Plasma albumin concentration (see above
Dietry calcium intake/urinary loss
Hormones + vitamins
Parathyroid hormone
Vitamin D (active – dihydroxy vitamin D) – depends on dietary intake and intestinal
absorption
Calcitonin. (Doesn’t have a big role in physiological regulation, but can be used exogenously to
lower calcium)
End organ function – e.g celiac disease (causing impaired absorption), renal disease
(impair hydroxyilation of vit D), liver (the same, hydroxylation),parathyroid glands (e.g
adenoma etc)
Action of parathyroid hormone
It is a protein that stimulates osteoclasts in bone. This results in bone resorption
(which releases calcium AND phosphate from bone).
In kidney – it activates 1 alpha hydroxylase – which results in hydroxylation of 25
hydroxy vit D to 1,25 hydroxy vit D. (Note that 25 hydroxy vit D is a kind of “storage
form” of vitamin D – as there are much higher concentrations of it)
It also enhance the reabsorption of calcium from the renal tubules, but it also inhibits
phosphate reabsorption. This is significant because plasma calcium and phosphate
are at a concentration close to saturation point. (Thus if you alter the concentration of one then
it will precipitate – calcium and phosphate).
Thus if you increase calcium AND phosphate in plasma then you will get calcium
phosphate precipitation (especially in kidneys – resulting in nephrocalcinosis).
Thus by increasing calcium but decrease phosphate then this does not happen.
Thus overall effect is increase calcium conc and decrease in phosphate conc.
Vit D structure and synthesis
Remember you have vit D3 (generated through sunlight)
Vit D2 – This comes from ergosterol (a plant source)
(Vit D2 or D3 ) is then metabolized in the liver to 25-hydroxycholecalciferol (by 25-
hydroxylase)
In the kidney it is metabolized to 1,25 dihydroxycholecalciferol (1,25 hydroxy vitamin D) –
which is the active form.
The half life of the 25 hydroxy form = several weeks while the 1,25 dihydroxy is only a
few hours.
Note that have to have very extensive liver disease before you will have fall in 25 hydroxy
vit D. (Thus most patients with liver disease do not have fall in vit D).
Note that there are other forms of vit D that are not biologically active.
Note that anticonvulsants – e.g phenytoin will enhance the hydroxylation of 25
hydroxy vit D to number of non active forms. (Hence metabolic bone
disease/osteomalacia can result.
Control of calcium concentration
Parathyroid glands release parathyroid hormone in response to lowered calcium
level.
This acts on bone to increase bone resorption (increase in calcium in phosphate). Thus by
negative feedback it reduces parathyroid hormone level.
Also acts on kidneys to increase conc of 1,25 vit D, increased calcium in tubules.
The active Vit D will also increase calcium absorption.
Disorders of bone
Pyerparathyroidism
Primary, secondary or tertiary. This increases
Decreased bone mineralization
Osteomalacia (in adults) and rickets (in children)
E.g vit D deficiency and malabsorption.
This is associated with low plasma calcium levels.
Reduced bone matrix (type 1 collagen and proteoglycan remember)
Osteoporosis
Postmenopausal and senile osteoporosis. (also due to slight reduction in 1,25 vit D due to
reduction in renal function)
This does not cause a disturbance in plasma calcium levels.
Disordered bone mineralization
I.e Pagets disease of bone.
Disorder of osteoclast and osteoblast function (these 2 cell types no longer work in tandem,
hence disorgonisation of bone mineralization).
BIOCHEMICAL INVESTIGATIONS TO DX METABOLIC BONE DISORDERS
Plasma
Calcium – should be measured with albumin. (So can interpret total albumin/free albumin levels
etc.).
Note how sample taken is important. (Ideally should take off tourniquet for 20
seconds before taking the sample (so that you don’t concentrate the vascular
compartment – due to increased pressure causing movement of water out of vascular
compartment)
Phosphate (increases in patients with renal glomerular damage) – hence need to know
what renal function is (either creatinine or urea).
Alkaline phosphatase (bone isoenzmye) – marker of osteoblastic activity (remember
that this is also in the liver and other places)
PTH
25-OH vit D (don’t measure active vitamin D routinely due to the low levels of the active form,
so more expensive)
Urine
Calcium and phosphate
Pyridinoline and deoxypridinoline (markers of osteoclastic activity) – thus along with
alk phos can have knowledge of osteoblastic and osteoclastic activity.
How to investigate the disorders
If plasma calcium is high – then look at plasma phosphate. If have normal then would suspect
hyperthyroidism or hypervitaminosis (not sure why hyperthyroidism would cause this, but
TFT’s would naturally be used to dx hyperthyroidism)
If it was low then you would suspect hyperparathyroidism (makes sense – high calcium but
low phosphate – which is what parathyroid hormone does). You would do an X-ray to look for
cystic lesions (subperiosteal erosions in terminal phalynx – early sign, eventually can go on to
get osteitis fibrosa cystica). Also naturally do PTH hormones. Can also be malignancy
since some tumours can produce parathyroid like hormone. (Thus in this case the
parathyroid hormone will be undetectable)
If low calcium and low phosphate then differentials could be secondary
hyperparathyroidism due to vitamin D deficiency (i.e low calcium that is then causing too
much parathyroid hormone which decreases phosphate levels). Hence makes sense to measure the
vitamin D levels.
low calcium but normal/high phosphate suggests hypoparathyroidism (makes sense –
not enough calcium reabsorpion and too much phosphate reabsorption)
It can also due to renal failure (causing a secondary hyperparathyroidism) – in this case
the calcium would be down, however the phosphate would be up due to decreased
reabsorption.

Clinical presentations of hypercalcaemia

General
Non specific ill health (malaise, weakness, vomiting). Most patients picked up through routine
screening now.
Psychiatric disturbances (“groans”
Renal
Polyuria and thus polydypsia (along with hypokalaemia, as inhibit concentration mechanisms)
Renal stones and nephrocalcinosis (“stones”) – makes ses
Bones
Bone pain (“bones”)
Abdominal (“abdominal moans”)
Constipation (increases gastrin release)
Duodenal ulceration
Cardiac
Dysarrhythmias – (Prolongation of latent phase I think?)
Differential dx of hypercalcaemia
Hypercalcaemia associated with low plasma phosphate
Primary hyperparathyroidism (e.g adenoma), causing bone resorption and calcium goes up,
and phosphate goes down
Malignancy (ectopic hormone production – PTHrP)
Tertiary hyperparathyroidism (after treatment of secondary hyperparathyroidism – because
the hyperparathyroid glands have become autonomous – they may not be suppressed when the
calcium returns back to normal)
Normal plasma phosphate
Hypervitaminosis D and thiazide diuretics (makes sense, they cause calcium reabsorption)
Rarely – thyrotoxicosis, sarcoidosis, immobiliation with pagets disease of bone etc.
Sarcoidosis and other macrophage disfunction disease are associated with increased activated vit D
Primary hyperparathyroidism note
Note suppression of other hyperparathyroid glands due to the single adenoma.
 Note the symptoms and hypertension are due to the hyperparathyroidism.
Note that the calcium is not that high (because it isn’t in primary hyperparathyroidism – in
malignancy it is usually much higher).
Note that the albmin is a bit high (probably due to incorrect sampling technique) (and hence the
calcium is actually a little lower)
Note how the phosphate is at the lower end of the reference range (you would expect a
higher phosphate for that calcium, hence you can dx hyperparathyroidism based on these
results alone.)
Also the alk phos is high end of reference range (because early in the dx).
Note the parathyroid hormone is only slightly elevated. Note how even if PTH was e.g 10 and
calcium was high you would still dx hyperparathyroidism. (I.e need to compare the results
with each other)
Note that post op the patient became hypoparathyroid.
Note that the alk phos has probably rised because of immobilisation for a week.
The reason he got hypoparathyroidism is because the other 3 parathyroid glands remain
suppressed (after being suppressed by the adenoma). Thus need to maintain low normal
calcium levels in order to reactivate the parathyroid glands. I.e DON’T be tempted to give
calcium (unless very low)
So patient became hypoparathyroid but then was going back to normal.
 Note how levels of calcium is very high and even lower phosphate (than previous example).
Also note that when you get hypercalcaemia then you get polyuria and thus water
depletion. (Thus note how the sodium and urea are elevated in conc)
Also note that hypercalcaemia is frequently related to hypokalaemia (hence would think
about correcting the low potassium).
Also note the metabolic alkalosis (I believe this is secondary to the low potassium –
possibly due to potassium leaving cells and H+ entering?)
This is all due to ectopic hormone production (PTHrelated peptide) by breast
carcinoma recurrence.
Compare the 2 cases – note how in malignancy you get much higher calcium.
Clinical features of hypocalcaemia
Numbness and tingling of fingers and toes
Muscle cramps/spasms
Positive Trousseau’s sign (increase of 20 mm Hg over systolic pressure causing a claw like
appearance the hand) and Chvosteks sign (when tapping the facial nerve you get contractions in
the face)
Laryngeal spasm and stridor
Convulsions (mostly in newborn and infancy)
Proximal myopathy (causing waddling gait – especially in children)
Bone pain
Psychiatric disturbances
Cataracts
Differential dx of hypocalcaemia
Low plasma PTH concentration
Idiopathic and acquired hypoparathyroidism
High plasma PTH
Secondary hyPERparathyroidism
With low phosphate conc – due to Vit D deficiency (either nutritional, malabsorption – e.g
coeliacs and anticonvulsant therapy – due to conversion into inactive forms)
With high plasma phosphate – due to renal failure
Note that these secondary causes – when treated can result in tertiary
hyperparathyroidism (i.e going from low calcium to high calcium, but with the
parathyroid hormone not changing)
Pseudohypoparathyroidism – (see previous lecture)
Miscellaneous conditions
Renal tubular acidosis (not sure why)
Acute pancreatitis – (main reason is due to low albumin – also because of dystrophic
calcification?)
Note the high urea due to renal failure
Sodium – Would expect it to be low in person with renal failure (hence this is normal for
someone with renal failure)
Metabolic acidosis and hyperkalaemia (what you would expect)
Phosphate retention and calcium falls
The alk phos rises due to secondary hyperparathyroidism.
Classical findings in someone with renal disease.

Note low calcium and low phosphate. Urea is normal so not renal failure.
Since the phosphate is low rather than high (which is what you would expect with primary
hypoparathyroidism) this is a secondary hyperparathyroidism
Since it is not due to renal failure, most likely cause is due to vit D deficiency.
Additionally the raised alk phos gives a clue as to it being a hyperparathyroidism and that she
has metabolic bone disease and osteomalacia.
All this is worked out without having to measure the PTH and Vit D levels – which would take
much longer.
Note the high calcium and low phosphate is suggestive of a primary
hyperparathyroidism.
However the urine shows that the phosphate is low. Thus this is due to a phosphate
deficiency (which has caused the metabolic bone disease and increase in calciu,)
Summary of investigation of ostemalacia

Osteoporosis – classification
Primary
Type 1 = postmenopausal
Type 2 = senile
Also idiopathic (which occurs in under 50s)
Secondary
Endocrine e.g cushings, hyperthyroidism and hyperparathyroidism (I understand
cushings but not sure about the hyperthyroidism and especially the hyperparathyroidism, I would
think this would cause osteitis fibrosa cystica)
GI – malabsorption, liver disease (due to low calcium?)
Malignancy – multiple myeloma (possibly because it causes invasion of the bone marrow)
Drugs – steroids, anticonvulsants (again – due to vitamin D conversion to inactive forms)
Bone turnover markers
Note there are lots, but main ones for bone resorption are urine hydroxyproline and
pyridinole while for bone formation then alkaline phosphotase (especially skeletal
isoenzymes)
General considerations in using biochemical markers
Urinary markers are usually corrected for creatinine. Also need to be corrected by circardian
rhythm and are affected by age, oestrogen etc.
Summary of bone function level tests
Note how phosphate is increased in someone with primary/tertiary but is variable in
someone with secondary (as it is down in someone with renal failure, but decreased in someone
with rickets/osteomalacia)
Remember that in osteoporosis. (I believe that can be lower end calcium? But overall no
metabolic disturbance I think)
Pagets disease – you have normal but is very increased alk phos because of rapid
bone turnover. (If increases again then suggestive of a complication of pagets disease – namely
sarcoma)
Also note that immobilisation can be associated with hypercalcaemia.

Non-organ specific autoimmune disease

Revision of tolerance
Remember that tolerance = failure of immune system to respond to an antigen.
Remember that this is a leaky process and the failure in self tolerance results in
autoimmunity
Maintenance of tolerance
Central T cell tolerance (thymic education)
Peripheral T cell tolerance (active regulation and absence of secondary
signal/danger signal)
B cell tolerance
Thymus
Remember you have positive selection (T cells that can bind to own HLA type are
selected out – so you don’t waste time making T cells that cannot protect you from
infection).
Negative selection = where T cell receptors that bind strongly to the T cell receptor
undergo elimination by apoptosis.
Tolerance is a leaky process (thus everyone has some self reactive T cells). However
there are mechanisms in the periphery to switch off the autoreactive T cells.
Thus you need several signals (rather than just contact of the HLA molecule withn the peptide.
Thus you need costimulation (e.g CD40-CD40-L).
Also what is important is the danger signal (inflammation or infection – much easier to activate
the T cells) – note this is what adjuvants try to do in vaccines (to try and drive the immune
process)
Activation is manifest by proliferation and maturation.
However if they only get signal 1 they can either be anergic (“switched off” – but can be
reversed) or apoptosis. (remember “cure” for autoimmune disease would be to drive the cells
to apoptosis – but I believe all they can do so far is to push them to anergy, which doesn’t help).
B cell tolerance
They are kept under control mostly because T cell help is absent.
However ther are other mechanisms where B cells can be silenced (don’t think I need to know
much about this)
Remember the simple diagram below, Even if cytotoxic cells/B cells are activated but if Thelper
cells are not activated then there will be limited damage.
 Remember thate tolerance is leaky. Hence remember that there is a huge difference between
autoimmune reactivity and autoimmune disease. In autoimmune disease you have
tissue damage and organ dysfunction (while many people will have weakly active
autoimmune reactivity and be free from disease)
Mechanisms of autoimmunity
Often we don’t know why it occurs.
However some mechanisms we do understand.
Released of sequestered antigen
Antigens which the T cells are not used to seeing in the thymus are released (by other
disease) and hence they are not tolerised and will react
Important in eye and testis.
Intraoccular antigens are generally not expressed in the periphery (generally not a
problem because the cells don’t usually penetrate into the eye). However if you get penetrating
trauma to one eye then you can get release of the antigens and autoimmunity reaction
to both eyes.
(Previously, if had trauma to eye, then had to quickly remove it to prevent blindness in both
eyes. However now immunosupressants are used.)
Also occurs in testicular tortion (testicular antigens can activate the immune system and can
have both testis attacked, resulting in infertility)
Alteration of self
With infection or drug
Best example is drug induced lupus.
Some drugs e.g hydralazine (not a widely used drug for heart failure) can cause this.
It alters the DNA (by binding to it)
This can result in autoimmune reactivity
In most patients it is an autoimmune reaction to the hydrazalazine. (so when you remove the
drug, the drug induced lupus goes away)
However in some there is binding to the DNA itself. (so that when you remove the drug, the drug
induced lupus still remains)
Molecular mimicry
Some infectious agents are closely related to our antigens. (E.g strep A) hence cross
reaction with own tissues
Best example is rheumatic fever
Antibodies that are made in strep cross react with heart (resulting in pancarditis), brain
(chorea?) skin (subcutaneous nodules?) and joints
Superantigen stimulation
E.g Toxic shock syndrome – after this then it can overwhelm tolerance. Thus many
people that recover are left with autoimmune disease. (Makes sense, even though you have
recovery from the initial superactivation, you have so much disruption of the normal mechanisms of
self tolerance that you subsequently get autoimmunity)
Superantigens don’t have to be processed.
Thus activate huge numbers of T cells.
E.g TSS – (after staph, strep)
Another example is Kawasaki syndrome (which some people believe to be due to superantigen
activation). This tends to affect young children and effect the coronary artery which can cause
MI (obviously concerning in such a young child). Additionally it can cause scalded skin. Also
get generalised rash etc
Infection of antigen presenting cell
In the periphery the APC’s will usually be able to have signal 1 (self antigen + MHC
class I (because they have made it through the negative selection) but not signal 2 (the
costimulation – unless it is actually a true infectious process going on
However if the APC itselt is infected by a virus then it can cause the costimulation.
This is the mechanism that we believe type 1 DM occurs. (That there is a virus which infects
the APC and causes activation of autoimmunity causing destruction of the beta cells of
the Islet of Langarhans).
Mutations in genes controlling immune response
E.g ALPS (autoimmune lymphoproliferative syndrome)
This is due to mutations in the FAS/FAS ligand. This is a key pathway in switching off
the immune system.
This pathway induces apoptosis.
However if have mutation then once you switch on an immune response then you cant
switch it off. (Hence get lymphadenopathy, hepatomegaly etc).
Mechanisms of tissue injury
Type 1 = IgE influenced. Forms basis for most allergy. However no known
autoimmunity showing this mechanism yet.
Type 2 = humoural immunity
Type 3 = immune complexes
Type 4 = cellular immune response.
Also some that don’t fit neatly to this.
Autoantibodies
Remember presence doesn’t imply pathogenesis
However usually easier to measure than T cell reactions
E.g in hashimotos thyroiditis, the injury is actually T cell mediated, but the anti thyroid
antibody is used for Dx (as easier to measure)
Type II
This is antibody mediated cytotoxicity
Antibody binds, complement is activated and there is influx of inflammatory cells
which leads to tissue damage.
E.g anti GMB disease
Lab tests: look for the specific antibodies. (variable efficacy e.g GBM is 100% sensitive,
others less good).
Note that complement consumption is often masked (wont see change in complement
levels, because not that much is activated)
Gold standard = immunoglobulin deposition on biopsy.
Type III
Immune complex deposition.
Antibody binds to antigen (soluble or in tissue)
Complement is activated. If it is not cleared then it may get lodged in tissue.
E.g SLE and rheumatoid vasculitis
Remember that people have a way of removing antibody complexes.
This is by the complex binding to RBC’s which then go to the spleen. These are then stripped
off by macrophages.
Only when mechanism doesn’t work properly or it is overwhelmed, that you get
immune complex disease
When you get immune complexes in tissues then you get inflammatory cells that migrate
into the tissue, causing tissue damage.
Here you often find a fall in serum complex levels
C3 and C4 especially.
Also need to do CH100 to rule out complement deficiency
Also will do specific antibody tests e.g ANF/ANA (screening test, then go with
ENA) , RF (e.g rheumatoid arthritis), anti ds DNA (e.g lupus) and anti – ENA (I
believe this is a group of antibodies, e.g anti ds DNA)
Type IV
One of commonest mechanism
Delayed hypersensitivity.
Antigen is presented to T cells, the T cell is activated and secretes chemokines
Macrophages are activated by interferon and you get tissue injury
E.g RA and cellular rejection in grafts
Also what arises with granulomatous inflammation
ORGAN SPECIFIC VS NON ORGAN SPECIFIC
Organ specific e.g autoimmune thyroiditis, IDDM, pernicious anaemia,
autoimmune hepatitis etc.
Key is that the antigen that is targeted is specific to these organs.
In non organ specific then the antigen is expressed throughout the body (and thus any organ
can be effected)
Non organ specific
3 main categories are rheumatoid disease (key thing is that it is not just an arthritis – but
other effects)
Also connective tissue disease (e.g SLE, scleroderma, polymyocytis,
dermatomyositis, mixed connective tissue disease and Sjogrens syndrome)
And third main one is primary vasculitis
Also others e.g anti phospholipids syndrome
VASCULITIS SHOULD BE COVERED IN NEXT LECTURE, IF NOT THEN COME BACK TO
VASCULITIS, SIZES, GRANULOMA OR NO GRANULOMA
USE OF LAB TESTS
Remember they are useful to rule in, rule out or monitor disease activity.
Remember that false positives and false negative results are common.
Thus need to take history, have differential and have targeted tests.
Detection of autoantibodies
(skipped in lecture, probably not that important)
Agglutination assays
The antigen coated beads and serum
If there is no antibody then it remains in suspension
The antibody agglutinates to form a button (due to bridges that are formed between the
beads)
Simple and quick assay
Indirect immunofluorescence
Use slides with cultured cells.
Patient serum is added and incubated on the slides. If there is antibody then it will stick
to the nucleus of the cells. (I.e testing for ANF)
Then use fluorescent anti humoural antibody against the antibody (and see if there is
positive). Strong lighting in the nuclei is suggestive of lupus. (Need to do more specific tests to
refine the dx)

ELISA
Antigen coated well, incubate patients serum, wash away excess
Then use enzymed linked antibodies (that are then washed away again).
The enzyme is used to catalyse a reaction with a colour change. (Thus the more antibody
that has linked, the more reaction occurs)
The intensity of the colour is suggestive of the level of antigen.
(come back if time)
RHEUMATOID ARTHRITIS
Arthritis = most common presentation.
However it can affect most tissues in the body
Also note that some extraarticular features may occur alone (atypical presentation)
Side note, very painful ulcers can occur due to vasculitis.
Note that the arthritis is mainly due to T cell mediated immunity while the vasculitis and
other extra articular is due to the immune complex deposition.
Epidemiologyu
Uncertain peak age
3:1 female male ratio
1% prevelance and 30/100,000 incidence (makes sense, much larger prevelance due to it
being a chronic condition)
There are genetic influences e.g HLA- DR4 (DR1 associated with Hispanic/jewish and asian
popns)
Presentations
Acute polyarthritis = common presentation
Will complain of inflammatory symptoms/signs. Mainly morning stiffness. (not really
fever, although may have some low grade). Key difference between mechanical
osteoarthrosis.
Minimum of 6 weeks to get dx.
Can be other presentations though.
E.g slow monoarthritis, acute monoarthritis, local and systemic extra-articular
disease
Patterns of progression
Most = polycyclic. (I.e relapsing remitting)
Some have monocyclc (more benign – i.e have few episodes)
Also progressive (where they have aggressive disease causing massive joint destruction)
Note currently no way of knowing who will progress in what way.
RA pathology
Have chronic widespread synovitis
Lymphocyte infiltration and hyperplastic synovium
Pannus formation at synovial interface which can eat in (causing marginal erosions).
This is an invasive type of altered connective tissue which eats its way into the the
cartilage (goes on to destroy the joint). This can cause collapse of the bone and cause an
irreversible deformity.
Nodules
Occur on the extensor surfaces in 20% of seropositive patients (I believe this is by
definition seropositive)
There is focal central fibrinoid necrosis. Thought to be due to a form of vasculitis
They are small HARD nodules. Commonly occur by the elbow
Rheumatoid vasculitis
Can be small vessel – i.e nailfold infarcts and spinter haemorrhages. (They don’t tend
to cause too many problems). (side note, remember that splinter haemorrhages can be cuased by
trauma but also vasculitis. This is why RA, SLE, scleroderma and other connective tissue
diseases can cause splinter haemorrhages. Also remember that infective endocarditis can cause
this, which makes sense since infective endocarditis is a cause of vasculitis.

Can also be medium vessel – i.e leg ulcers and neuropathy

The vasculitis is generally immune complex mediated. It may also be ANCA psotive
Rheumatoid factor
This is an antibody to the Fc portion of IgG and is present in about half of patients with RA.
However lots of weak positives (non specific) – e.g infection and especially older females
Strong positive however is highly suggestive of RA.
RA complications
Felty’s syndrome
Splenomegaly, RA and neutropenia
Amyloidosis
Remember, any chronic disease can cause amyloidosis
Vasculitis
(See above)
Pulmonary disease
Nodules, pleural effusion
Interstitial fibrosis
Obliterative bronchiolitis (small airways scar up and air cannot get in, most devastating)
(Note that may not notice getting restless on exertion due to lack of mobility due to the arthritis)
Occlar disease
Keratoconjunctivitis sicca (conjunctivitis and keratosis – inflammation of the cornea that is
associated with dry eyes/lack of tear production)

Episcleritis (inflammation of the episclera, the layer in between the conjunctiva and the sclera).

Scleritis (more severe, effecting the sclera, commonly in rheumatic conditions e.g RA, wegeners
granulomatosis etc)

Sleromalacia (Thinning of the sclera, exposing the choroids underneath, I believe this is the
wost) The eye can perforate from damage to the eye wall.
Making the diagnosis
To rule in
Clinical picture
Rheumatoid factor and anti-CCP antibodies
Xrays of hands and any affected joints.
This is because erosions on Xray (see below) help to make dx even in the event of seronegative
RA. Additionally it shows that the rheumatoid arthritis is an aggressive form.

Rule out alternative dx

ANF (to rule out the connective tissue diseases – e.g SLE, and follow up (i.e ENA I
believe)
ANCA to rule out vasculitis
Also need to think about the seronegative arthritis (with Hx and exam)
Also note that you can get transient arthritis in a viral arthritis (commonly following
rubella in adult). Dx by history and serology. (Need to think about this, especially if the first
line tests come up negative).
Monitoring disease activity
Clinical activity scores
CRP (best non specific – used to monitor inflammation)
ESR (but affected by lots of things, e.g NSAIDS, anaemia etc)
FBC – anaemia (normocytic normochromatic (anaemia of chronic disease – check why),
but may also see iron deficiency anaemia due to gastric irritation/bleeding from the
medications that these patients are on).
Monitor function of affected organs
Serial RF = little benefit

Immunology 2
CONNECTIVE TISSUE DISEASE
This is rheumatoid arthritis (says rheumatoid disease, but I assume she means this)
SLE
Polymyositis
Scleroderma and CREST
Mixed connective tissue disease
Sjogrens syndrome
(Vasculitidies).
Remember that there can be a lot of overlap between these diseases.
However many have well defined syndromes
Many respond to immunosupression. Notable exception is scleroderma.
SLE
Inflammatory multisystem disease
Unknown aetiology
Diverse clinical and lab abnormalities
Variable course and prognosis (can range from arthritis/skin rash to life threatening and
aggressive disease). (note about 5% of renal transplant lists are due to lupus)
Multiple autoantibodies.
Cytotoxic function (type 2 hypersensitivity to platelets, RBC’s etc)
Immune complex deposition (type 3 hypersensitivity)
I.e more than 1 mechanism of autoimmunity in this one disease.
Other lupus
This is classical lupus but there are others
Drug-induced lupus (e.g hydralazine which results in loss of tolerance due to altered
self – usually remit after removing the drug)
Neonatal lupus (antibodies (IgG – remember, IgM cant cross the placenta as it is too large)
from a mother with lupus may cross the placenta to induce lupus in the newborn.
Typically takes form of skin rash and congenital heart block. Note that especially the anti
Ro antibodies can bind to the conducting system (causing heart block and hearf
failure – thus needed to treat with pacing).
Latent lupus (those with serological evidence of lupus but don’t have symptoms –
however may go on to develop lupus themselves. Additionally can result in neonatal lupus
(if woman gets pregnant). However remember that vica versa (not all will get disease in those that
have antibodies)
Antiphospholipid syndrome (associated with thrombophilia, 30% of those with lupus have
this, although may get on its own)
End stage lupus (there is no more inflammation due to “burn out” of inflammation –
but can still have renal failure etc. Thus steroids/immunosupression is not necessary (as
no benefit, just giving toxicity)

Epidemiology
9:1 female to male
Peak age = 2nd – 3rd decade (young females = common)
Large geographical incidence (America more than Scandinavia for example)
Prevelance = about 50/100,000
Racial – black>white
Genetic: some genetic factors such as complement deficiencies and problems in the
mechanism for desposing immune complexes. (makes sense, if you don’t have a good
mechanism to dispose of complexes then you are more likely to get lupus)
Clinical features
Inflammation of any organ, predominantly:
Skin (classical rash = butterfly rash). (Remember it is one of the few rashes that goes up
above the nose – rather than just the cheeks). Generally is not itchy or sore. Also classically
photosensitive (so commonly after being in the sun it comes out)
Note that another rash that they can get is discoid lupus. (can be chronic, slightly raised. Skin
follicles plugged wth debris). Classically on biopsy then you can demonstrate immune
complex along the dermo-epidermal junction)
Also mouth ulcers etc

Joints (usually). (Skin and joint manifestation is generally

Kidneys (need potent immunosupression to prevent renal failure)
Brain (cerebral manifestation is one of the most severe
Serosal surfaces (can get pleural effusions and pericarditis)
Immune cytopenias and haemolytic anaemia is common. (Remember, anyone with
haemolytic anaemia should be tested for lupus)
Note that skin manifestations only = cutaneous lupus. However this may be part of
Renal pathology
Many different types you can get.
Focal segmental glomerulonephritis
Focal proliferative glomerulonephritis
Diffuse proliferative glomerulonephritis
Membranous glomerulonephritis (glomerulonephrosis)
Sclerosis.
Morbidity and mortality
Due to organ damage of disease itself
However also significant morbidity/mortality due to the effects of immunosuppressant
drugs.
E.g those with renal lesion treated with high dose steroids and cyclophosphamide
(alkylating agent that causes leucopenia and infertility)
Common autoantibodies
ANF = screening test.
If positive then go on to do other tests (anti dsDNA)
ENA (anti extractable nuclear antibodies) – especially Anti-Ro, Anti-La and Anti-Sm
Antibodies to RBC, WBC and platelets (especially if have neutropenias, anaemias etc)
Making the dx
Clinical hx and exam.
Uranalysis and urine microscopy (because patients may have silent renal failure)
ANF (if negative then unlikely dx of SLE)
If positive then go on to measure Anti-dsDNA
Also anti-ENA (note that anti-sm is an especially specific test – although only found in 30%
of those with lupus). Anti ro and anti la (found in other connective tissue disease, but support dx)
Also need to assess function of potentially involved organs.
Monitoring disease activity
Function of affected organs
FBC and ESR (remember that CRP = poor measure in SLE)
Complement levels (level of consumption – remember there is type 3 hypersensitivity and
thus could be lower levels of complement)
Anti-dsDNA levels reflects disease activity.
Examples
5 day old girl
Rash
Enlarged Liver & Spleen
Severe hepatitis
Normal heart rate
Mother had mild SLE diagnosed 1999
(intrauterine infections e.g rubella, herpes etc would be differential
The mild lupus is mother was key.
Intrauterine viral antibodies were negative
Infection screen negative
Anti-Ro positive
Anti-DNA negative
Rapidly worsening liver failure
Working diagnosis - Neonatal lupus
Note that IgG tests are used for this. Remember that in most neonatal diseases you are
looking for IgM (because IgG are mostly from the mother). However, since you are looking for a
disease that has been transferred from the mother to the child you are looking for IgG.
(mother)
Mother had been well during pregnancy
Never had systemic therapy for SLE
Generally unwell
Fatigue – anaemia (anaemia is common after pregnancy, but this was haemolytic anaemia, not
expected after pregnancy)
Joint pains
ANF >1/400 S&H
Anti-DNA 297iu/ml (Ref <50)
Anti-Ro Strong Positive (This is how it got into the child, remember anti ro is associated with
neonatal lupus)
Low complement (C3 & C4)
Advised re urgent rheumatological review
(Baby)
Transferred to Kings
Underwent Liver transplant
Explant - congenital haemachromatosis (rare, this is what caused the atypical presentation and
severity)
Excellent recovery
(Mum)
Became sicker in London
Advised to return home
Investigated locally in Donegal
Renal disease detected -referred to BH
10 weeks post delivery - Cr 222
Lymphopenia
Low platelets
Renal Biopsy - Diffuse proliferative GN
Treated with IV cyclophosphamide & steroids
Dialysis dependent within 2 weeks.
Skin rash & photosensitivity
Arthritis
Leucopenia & thrombocytopenia
Renal disease
Didn’t have:
Oral ulcers, cerebral disease, Serositis
Note 3 points. Without treatment then lupus can be very severe
Also lupus is responsive to hormonal levels (hence the pregnancy greatly exasserbated the
condition)
Also the transplacental passage of antibody which can occur in lupus.
SYSTEMIC VASCULITIS
Characteised by inflammation within the blood vessels. It disrupts the internal elastic
lamina.
It may involve one or many organs.
May involve vessels of one organ or many
Clinical features
Ischaemia to the tissues wich are supplied by the damaged vessel.
Features of widespread inflammation
Vessel rupture = extremely rare. (Contrary to what you might think, it is rare for vasculitis
to cause rupture).
Primary vs secondary vasculitis
Primary autoimmune disease of unknown aetiology
Secondary – vessel inflammation. Very important to find out if you have secondary. This is
because if they have an infection and you give immunosupression then you will kill the
patient. Need to treat by treating the infection (rather than immunosupression)
Can be secondary to infection (commonest is infective endocarditis (makes sense – you
have a chronic infection which gives off septic emboli and immune complexes. Hence things like
splinter haemorrhages etc) (Also others by direct infection e.g syphilitic aortitis and some fungal
infections)
Can also be secondary to malignancy, drugs and connective tissue disease.
Primary vasculitis classification
Lots of different classifications, not perfect but this is one of the best
Split on size of vessel and whether you see granulomata.

(Revision from last years lecture on vasculitis)

Vasculitis
= inflammation of vessel walls
Arteritis = inflammation in arterial walls
Cause = either direct infection, immunologic or unknown
Direct infection usually bacteria/fungi also rickettsial infection, RMSF (rocky
mountain spotted fever), syphilis etc, l
Immunologic = immune complex (major = SLE, Henoch-Schönlein purpura,
rheumatoid arthritis).
ANCA (Anti-neutrophil cytoplasmic antibodies - antibody circulating in the bloodstream,
different types - different conditions that antibodies produce is Wegener's granulomatosis,
microscopic polyangiitis and Churg-Strauss syndrome. (primary sclerosing
cholangitis????)
Direct antibody attack (Goodpastures/Kawasaki syndrome)
Cell mediated (in allograft organ rejection)
Inflammatory bowel disease and paraneoplastic effects
Unknown aetiology = giant cell, Takayasu and Polyarteritis nodosa
Non infectious vasculitis classification
Large, medium, small vessels
Immune complex vasculitis
Large vessel
Giant cell (temporal) arteritis - as tends to affect temporal arteries
Here it is a granulomatous arteritis. You get inflammation containing giant cells. Tends
to affect aorta/major branches. Tends to occur in people over 50 years old (very unusual
under this age). Associated with polymyalgia rheumatica - (pain in many muscles -
inflammatory condition of muscles). Severe complications may develop e.g
blindness/stroke.
Takayasu arteritis = similar look (granulomatous inflammation). However occurs in
under 50's. (rare). Note main difference is just the age. But only minor other differences.

Medium sized vessel vasculitis

Polyarteritis nodosa = you get a necrotising inflammation. It affects the renal and
systemic vessels but spares the pulmonary vessels. You get NO glomerulonephritis
(get involvement of vessels but not this - only affects medium sized vessels)
Kawasaki disease = disease of children. Often present with enlarged cervical lymph
nodes. (often get what is known as "scalded skin" - blisters, lose epidermis etc. Need to go to
intensive care. Often involves coronary arteries

Buergers disease = all you need to know is it occurs in smokers (if you have a case with
someone with vasculitis and they are a smoker it is likely to be this)
Small vessel vasculitis
Wegeners granulomatosis = (good exam question) - it is a necrotising vasculitis. It
involves granulomatous inflammation of respiratory tract and causes necrotising
glomerunephritis (something abnormal in kidneys, lungs and vasculitis = probably this). Note
can cause lesions on X-ray (suspicious carcinoma but biopsy proves negative)
Churg-Strauss syndrome - classily full of eosinophils. If the patient is an asthmatic the
diagnosis is likely to be this. Have a lot of eosinophils circulating in blood as well as being
deposited in tissues.
Microscopic polyangiitis = necrotising vasculitis - few or no immune deposits. Also have
necrotising glomerulonephritis. Different from polyarthritis nodosa (this affects the
glomerulus and affects pulmonary circulation)
Henoch-Schönlein purpura - tend to see in children - present with bruising on their
buttocks (see inflammation in small vessel walls. Affects the skin (bruising), but also
intestines and glomerulus. (also have joint pains). Often presents with parents thinking it is
meningitis (due to bruises)

Rarer things (just have heard of it)

Essential cryoglobulinaemic vasculitis (immune complexes in serum), affects skin and
glomeruli
Cutaneous lecocytoclastic angiitis (involves skin, blood vessels and involves leucocytes
Note all these conditions look the same down the microscope. Clues = history (e.g if
isolated in skin it may be CLA, if in smokers probably Buerger's etc
Temporal arteritis/polymyalgia rheumatica = pretty much only large arteritis in this part
of the world. Very sensitive to steroids
Churg strauss – asthma and vasculitis syndrome (marked eosinophilia)
Polyarteritis nodosa (first described vasculitis) – non granulomas. (This and churg strauss
are fairly unusual)
Wegeners granulomatosis = one of most common. Associated with granulomatous
inflammation.
Microscopic polyangiitis = small vessel form of polyarteritis nodosa.
Clinical features are highly variable even with each syndrome.
Mortality and mortality due to organ failure (especially renal, pulmonary and
neurological) as well as the effects of immunosupression
Dx of vasculitis
Only specific test we have for vasculitis is ANCA.
Useful for wegeners (C-anca) and some of the small vessel vasculitis but NOT that good
for most of the large and medium
Non specific: CRP/ESR
Biopsy = gold standard. Try to get the affected organ but occasionally blind.
Angiography – in large vessel disease (temporal artery I would imagine would be useful)
Wegeners granulomatosis
This is a multisystem disease of unknown aetiology
Clinical and pathological features are necessary for dx.
Most patients with active disease are ANCA positive.
Runs a relapsing, remitting course
Clinical features
Upper respiratory tract (e.g necrotic sinusitis, ulceration of nose, epistaxis, can
even have necrosis of nasal septum)
Lower respirotary tract – pulmonary haemorrhage (one of the lifethreatening
manifestations)
Glomerulonephritis (can be rapidly progressive leading to renal failure)
However ANY ORGAN can be effected. (I imagine these are just the most common)
2 cases.
15 yo male. Active sportsman, had bruise that wouldn’t go away (query vasculitis but also
haemophilia)
Became progressively more unwell (over 2 weeks) (Fevers etc), then started to cough up
blood.
Found to be in renal failure and pulmonary haemorrhage. (note that plasma exchange
= useful in this, to take off antibodies. Also received cyclophosphomide and steroids). Then
recovered but requires maintenance immunosupression.
18yo female had localised nasal disease. (not lifethreatening but nuicance. There is
constant crusting that needs to be frequently cleared)
Thus note the variatey of presentations.
Lab features
Granulomata
Vasculitis
Tissue necrosis (due to failure of blood supply)
Almost all are ANCA positive (C-ANCA)
ANCA in Dx of vasculitis
Less specific than hoped.
About 60% of ANCA positive subjects have vasculitis
False positives in infection, inflammatory diseases and other diseases – e.g
lymphoma.
ANCA disease monitoring
Important for monitoring disease
Increased ANCA = increased relapse rate
Successful tx = antibody tends to go down.
Suspected connective tissue disease or vasculitis workup/dx
Could this be CTD\vasculitis
What organs may be involved
Does it fit with a classical pattern
Could it be a secondary vasculitis (e.g infection)
Is serology helpful
What site is best for biopsy/angiogram.
Helpful dx tests
RF (looking for rheumatoid arthritis)
ANF (and if positive – anti-dsDNA and anti-ENA – looking for lupus and other connective
tissue diseases)
ANCA – and if positive anti PR3 (wegeners) and anti-MPO (other vasculitis) looking for
vaculitis
Complement (again SLE and other immune complex disorders I would imagine),
Anti-cardiolipin (antiphospholipid syndrome – see next lecture)
Cryoglobulins (cryoglobuminaemia I would imagine, see next lecture)
Biopsy (again vasculitis) and angiography (large arteritis such as temporal as well as medium
sized vasculitis I would imagine)
Assess disease extent
Clinical evaluation
FBC (assess severity of inflammation) and antibodies if cytopenias (in connective tissue
disease)
X-ray of joints (when joint involvement)
CXR, PFTs and/or high res CT (where pulmonary disease)
UandE, urinalysis, GFR and 24 hour protein (to assess renal disease)
CK (muscle enzyme, elevated if inflammation of muscles), EMG (electromyogram – helpful if
think you have inflammation in muscles – if positive you may want to do a muscle biopsy)
(for polymyositis etc I imagine)
Cardiac – ECG, ECHO, HOLTER, enzymes etc (as can affect this as well)
Neurological workup – imaging and neurophysiology (makes sense, as multisystem
disease)
Assessing disease activity
Inflammaion – ESR/CRP
Organ function (e.g PFT, renal function etc)
Immunology (specific for disease in question)
Summary
Presentation of CTD and vasculitis varies. Thus Dx varies on clinical awareness.
Lab tests = useful but not perfect
Innappropriate tests may be misleading.

Immunology 3
RHEUMATIC FEVER
This is an acute systemic inflammatory illness
It occurs 2-4 weeks after a group A beta haemolytic streptococcal pharyngitis (only
certain subtypes of group A strep)
Molecular mimicry – heart muscle, valves, articular structures and neurones may
all be involved.
Before penicillin this was very common but now has become much rarer.
Clinical features
Fever
Migrating arthritis (note that it doesn’t tend to destructive
Myocardium, endocardium and valvular destruction
Subcutaneous nodules
Chorea (10% of people get this)
Note that may get rash (tends to be very mild and comes and goes, generally seen more when
there is a fever)
Jones criteria
Need 2 major, 2 minor plus evidence of strep infection
Major
Carditis
Polyarthritis
Erythema marginatum

Subcutaneous nodules
Minor
Fever
Arthralgia
Hx of RF (as anyone that has had a bout of rheumatic fever is at increased risk of having
another bout – when get strep throat)
Longterm sequelae
Valvular heart disease
Increased risk of endocarditis
Chorea may be present.
Key points
Incidence is increasing (in areas of close proximity – there are bouts in
Tx is effective – prolonged courses of penicillin)
Prophylaxis is necessary against further streptococcal infection
SYSTEMIC VASCULITIS
Secondary vasculitis
Infection
E.g subacute bacterial endocarditis and cystic fibrosis.
Very important to rule this out, as if you treat with immunosupression then you can kill the
patient.
Note that subacute bacterial endocarditis is very different from the acute bacterial
endocarditis (with virulent organisms e.g IVDU – not associated with vasculitis due to not
enough time being available).
With subacute then can be a very innocuous. May have been unwell for weeks - months
weeks, fatigue, loss of appetite, spiking temperatures (as bits of bacteria embolise),
this can result in immune complex deposition.
On examination you look for murmers (typically new murmur)
Hence can get things like roth spots, splinter haemorrhages, janeway lesions
(remember, erythematous non tender nodes), oslers nodes (raised, tender nodules) are all due to
vasculitis associated with the immune complex deposition)
Also need to dipstick urine – looking for haematuria (patients can have glomerulonephritis)
Also systemic upset (low grade fever. Myalgia, fatigue. Weight loss – remember that
chronic inflammation burns calories)
Night sweats (again
Where this is a suspicion then you need to take multiple blood cultures before
Do echo (to look for valvular vegetations)
On blood tests you may see acute phase response (CRP, ESR etc)
May also have anaemia of chronic disease
Tx is with antibiotics (as you will treat the infection and hence remove the antigen). This
on its own will switch off the vasculitis
Note that very rarely you may need steroids to switch off the immune complex disease (if very
severe vasculitis associated with this)
Drugs
Neoplasia
Radiation
Cryoglobulinaemia
Connective tissue disease
CRYOGLOBULINAEMIA
These are abnormal immunoglobulins which precipitate out at the cold.
The clinical manifestations are due to Raynauds phenomenon and vasculitis.
(Because fingers and toes can be as low as 32 degrees, colder than core temperature, hence these
areas are more likely to be affected by cryoglobuminaemia)
typical rash – just like any vasculitis you have palpable purpura (raised rash – useful way to
check as a patient is to close your eyes and see if you can feel the rash)

Skin + Raynauds
Joint involvement
Renal
Neuropathy (due to vasculitis of vasa vasorum – blood supply to the nerves)
GI involvement
Can have vasculitis anywhere though
Meltzers triad
Purpura, arthralgia and weakness = KEY TRIAD. Suspect cryoglobulinaemia if you have
this.
Testing
Very important – otherwise you will get false negatives.
Serum is taken and kept at 37’C (special collection bottle and 37 degree water bottle)
Then take 1ml into 1ml syringe
Kept at 3 degrees and looked at 3 days and 7 days (i.e takes time to do the test)
If there is precipitate then you estimate the percentage.
Check that the cryoglublin goes back into solution when it is rewarmed to 37 degrees.
When positive then type and assess for the causes
False negatives
If the syringe is not warmed to 37
If the sample is not kept at 37 until clotting is completed
If the sample is centrifuged at temperatures below 37
If the sample is not stored at 4 degrees for 72 hours.
I.e have to be very careful about the way it is handled in order to get an accurate result.
Types of cryoglobulins
Type 1 = monoclonal cryoglobulin (associated with lymphoma or lymphoproliferative
disease) E.g B cell leukaemias/lymphomas, myeloma etc
Type 2 = mixed cryoglublin (monoclonal component and polyclonal Igs). Can be due to
infection (e.g hep C), connective tissue disease, B cell lymphoproliferative (i.e due
to the monoclonal aspect)
Type 3 = polyclonal cryoglobulin (due to immune complexes). Can be due to
connective tissue disease or chronic infection
Thus the monoclonal antibodies associated with lymphoproliferative process (hence 1
and 2) and the immune complex is associated with connective tissue disease (hence 2
and 3)
Therapy
Tx the underlying cause
Steroids +- immunosupression
Plasmapheresis if life or organ threatening.
ANTIPHOSPHOLIPID SYNDROME
This is an immune mediated ACQUIRED form of thrombophilia. These are conditions
that predispose you to clotting.
Compare with the genetic haemophilias
Due to antibodies against phospholipids
Clinical AND lab criteria must BOTH be filled to establish diagnosis (i.e lab results not
enough on its own)
May be primary or secondary (primary is not associated with another connective tissue disease
i.e occurs on its own)
Can be secondary (e.g lupus – about 30% will have antiphospholipid antibodies, but only 10% will
have actual disease from this)
Clinical features
Documented venous thrombobis
Documented arterial thrombosis
Pregnancy associated morbidity:
This is due to microthrombi in the placenta (hence can get placental failure, not enough
nourishments, hence growth retardation or failure of child to grow etc)
Mid or 3rd term pregnancy loss (1st term is commonto have miscarriage, however one in 3rd
term is more concerning)
Recurrent first trimester loss
Severe pre-eclampsia
Severe intrauterine growth retardation
Other features
NOT diagnostic but associated (as not specific enough)
Migrane, thrombocytopenia (drop in RBC’s)
Livedo reticularis (a type of rash)
Transverse myelitis (interference of blood supply to spinal cord)
Lab criteria
Lupus coagulant, OR
Anti-cardiolipin antibodies (most commonly detected) OR
Anti-beta 2 glycoprotein 1
These need to be positive on 2 occasions, 12 weeks apart (as lots of false positives, so
want to make sure)
Treatment
Varies with manifestation
Aspirin
However if more serious then lifelong anticoagulation (if significant thrombosis). May need
lifelong warfarin.

CLINICAL INVESTIGATIONS
Neurological investigations
Note that there are lots of different specialised tests. Don’t need to know all of them (e.g EEG used
for epilepsy, nerve conduction studies etc)
CSF – (need to know about this)
Why do a lumbar puncture
If you suspect a CNS infection (e.g headache, neck stiffness (known as emeningism) –
note can test for meningism (can get meningism with encephalitis, space occupying lesion
(large subarachno)id haemorrhage – moves down along meninges causing inflammation of
meninges) and most commonly meningitis)
Brudsinksi’s sign = If you flex neck (it will decrease meningeal space and thus irritate it) –
thus involuntary flex knee (to try and and increase the meningeal length again)
Kernigs sign (the opposite – when you flex the knee there will e involuntary neck extension
(trying to increase the meningeal length) and pain in the neck
Other signs of systemic feature (n+v, sweat, rigors, fever etc) + the CNS symptoms
Visual deficit (blurred vision/
Photophobia (person cannot tolerate being in a room with a light on) – causes pain (
Rash - (seen in N. meningitides) (don’t get rash in other causes of meningitis or encephalitis)
Thus if any of those you would suspect a CNS infection
Differentiation between meningitis and encephalitis
Encephalitis features:
(usually young person) with flu like illness for few days. Then have predominant
headache (over few days – rather than shorter period with bacterial meningitis – few hours)
Focal neurological signs = predominant features (defect where can identify specific
lesion associated) (don’t usually get this in meningitis). Commonest is 6th nerve palsy
(remember – long intracranial course – anything that causes raised ICP can compress the 6th nerve)
Confusion (some level of impaired consciousness is feature – while in meningitis usually
alert/orientated).
Meningitis features:
Meningism, photphobia, rash (if meningococcal) – symptoms occurring over few hours.
Continued
CSF inflammation – commonest being MS (likely to be female, under 50, more likely to be
Caucasian. Main/commonest presentation = visual (optic neuritis – painful loss of vision usually
unilateral), second commonest is gait ataxia, third commonest is abnormal
motor/sensory function in arm/leg (e.g parasthesia, weakness in arm/leg)
Vasculitis (commest cerebral vasculitis is lupus vasculitis) – can present with seizure,
stroke. (if get this in a young patient then can think of lupus vasculitis). Also history of fevers,
myalgia, arthalgia, photosensitive rash. (this would help differentiate it from MS)
Guillien Barre (autoimmune disease with infectious presipitent causing attacking of their nerve)
are other causes (post infectious/inflammatory ascending symmetrical motor/sensory
polyneuropathy). Most common infectious cause is campylobacter (but can be caused by any
RTI, GI infection etc). Classic features = patient feels weakness/parasthesia in their legs.
Starts in toes and works up. (Because ascending then hits diaphragm causes paralysis and
respiratory failure – key issue = peak expiratory flows hourly. If start to deteriorate
then incubate). IV immunoglobulin = tx. If doesn’t work then plasmapheresis
(removing antibodies from the plasma I believe)
Often have recent chest infection/diarrhoeal illness – then presented with weakness/numbness in
their legs, progressing upwards – eventually progressing to dyspnoea.
Remember can resolve spontaneously (but don’t wait and see due to respiratory failure
potential). Unpredictable how quickly they will resolve.
Note also poor prognostic factors are if it comes on quickly, if caused by campylobacter etc.
CNS infiltration (e.g tumour or sarcoidosis). (Classic history for tumour = older age, few
month history of headaches worse in morning – as due to raised ICP which would be highest in the
morning after night time with worse drainage, can also have N+V – due to increased ICP can
suddenly present with focal neurology – what it is depends on where the tumour is),
(Sarcoid history is likely to be female, under 50 – commonly black. Features = seizures, focal
neurology. Background of dyspnoea with dry cough, abnormal CXR and rash on shins – called
erythema nodosum – just like in IBD)
SAH (any age group – hx = acute onset headache (thunderclap) – usually occipital. Can lose
consciousness + features of raised ICP (N+V, hypertension, bradycardia, papilloedema etc)
TECHNIQUE FOR DOING LUMBAR PUNCTURE
Place patient in lateral recumbent position (usually lying, can also do while sitting upright)
Identify iliac crests (and join imaginary line between as guide to 4th lumbar space)
Insert needle anywhere from L3/L4 down (if any higher then can hit the spinal cord)
Patient asked to remain in foetal position (to increase intravertebral spaces)
Area is disinfected (using the wipes)
Local anaesthesia is given
Spinal needle inserted in space.
Advance very slowly (when think you have gone through subarachnoid space then you feel a loss
in tension) – you should pull it back slightly and see if some fluid comes out.
Then you remove style and collect fluid.
Then should attach manometer (to measure CSF pressure) – in meningitis, SAH and space
occupying lesion this is usually raised. (Remember it is contraindication to do LP because could be
cerebral oedema and so as you remove fluid then the cerebellar tonsils can herniated. If patient has
clinical features of ICP then should do brain scan (not sure if CT or MRI) first to check for
cerebral oedema (if none then can go ahead with LP).
Sometimes you are forced to do LP even in patient with cerebral oedema
Collect fluid in 3 tubes (in order of collection) – (as when you go in you may hit vein/artery so
fluid can be bloody – in traumatic tap then should be decrease in red cells)

CSF analysis
Normal CSF = colourless.
Bloody appearance = either traumatic tap or SAH. (Although traumatic tap usually wont
make it red, just pink).
Cloudy appearance = probably bacterial meningitis
Yellow appearance = also appearance
Doing LP immediately after SAH – (none of the blood would have entered yet), few hours
after = pink (as some of the blood entered and broken down), then yellow (because broken down
to bilirubin), then red (due to frank blood being present)
Ideal time to do a lumbar puncture = 12 hours after onset of symptoms.
Complication of LP
Big life threatening one = herniation
Can haemorrhage (if you hit an artery/vein) – that is treated by going back into the space and
insert a sclerosing agent or lignocaine to cause constriction.
Infection (if you don’t have an aseptic technique) – commensals from the skin can be pushed into
the subarachnoid space, and you can cause meningitis (if patient gets feverish after LP then
suspect meningitis – commense them on IV cephalosporins)
Most common complication = headache (can be avoided by prehydrating patient –
IV fluid few hours before the LP).
CSF analysis
Cells
Normally CSF = acellular. Up to 5 RBC/WHCs are considered normal when sampled by LP
Lymphocytes = usually indicate viral infection. Can also mean Tb meningitis.
Neutrophils = usually indicate bacterial infection.
In early hours of viral meningitis then neutrophils = predominant.
Protein
Most protein = excluded by CSF by BBB. Normal CSF rotein conc ranges from 15-45mg/dL.
Elevations in CSF protein conc occurs in both infectious and noninfectious
conditions (including those associated with CSF flow obstruction)
High protein causes (in order of importance)= Guillian Barre, Tb meningitis, lymphomal
meningitis. Less commonly found in bacterial and viral.
Note that peole think that this is due to immunoglobulins and other proteins synthesized in response
to inflammation.
Glucose
CSF to serum glucose ration = about 0.6 in normal individuals. Thus need to take blood
samle at the same time.
Low glucose can occur in bacterial meningitis and mycobacterial and fungal CNS
infections, herpes simplex encephalitis and occasionally in SAH.
Glucose is normal in most viral meningitis (this all makes sense, viruses are not going to be
using up the glucose, while bacteria are)
Immunoglobulins
Also need to do serum protein
Almost totally excluded from CSF in normal individuals.
Elevations can occur in any disorder that disrupts the BBB
Oligoclonal bands (on electropheresis – proteins that recipitate on electropheresis on CSF but
none in the serum) that represent IgG are found in most people with MS (it is suppoirtive
rather than diagnostic feature of MS (remember dx is based on clinical and MRI radiological
features – classically periventricular plaques are found)
In MS the immunoglobulins are synthesized in the CSF so they will be found in the CSF but not in
the systemic circulation (hence when you do electropheresis there will be a band which is present in
the CSF but not in the serum)
Cytology
Cytology = occasionally useful for dx of malignancy involving the CNS.
Remember for any dx of cancer, need to get cells – either histology or cytology
Gram stain + culture
Findings in each of the following
Bacterial meningitis
Macroscopic appearance: cloudy
Opening pressure: high
Cells: usually neutrophils
Cytology: negative (only in cancer remember)
Protein: high
Glucose: <60% serum
Immunoglobulins: (none – unless very chronic – I think)
Viral meningitis
Macroscopic appearance: clear
Opening pressure: usually normal
Cells: usually lymphocytes (can be neutrophils if very early)
Cytology: negative (only in cancer remember)
Protein: usually normal (I think)
Glucose: usually normal (>60% of serum)
Immunoglobulins: (none – unless very chronic – I think)
Tuberculous meningitis
Macroscopic appearance: turbid (not sure what turbid means)
Opening pressure: high
Cells: lymphocytes
Cytology: negative (only in cancer remember)
Protein: very high
Glucose: <60% serum, often is very low (prognostic indicator – lower it is the more severe
the infection)
Immunoglobulins: (none – unless very chronic – I think)
SAH
Macroscopic appearance: clear (if early), bloody (if late) or xanthachromia (if in
between – I believe xanthachronmia refers to the pink/yellow appearance that it can take)
Opening pressure: high
Cells: no white cells but usually red cells (can have a few white cells – due to inflammatory
response)
Cytology: negative (only in cancer remember)
Protein: normal (but can be high – due to inflammation I believe)
Glucose: normal (>60% serum)
Immunoglobulins: (none – unless very chronic – I think)
Comparison with abscess/encephalitis
I believe that LP for encephalitis would be normal (not entirely sure though)
Note that abscess would be present likely in an immunocompromised indivual. The
symptoms would be going on for months and you dx by CT (ring enhancing lesion) and blood
cultures.

DEXA scans
Osteoporosis = disease characterized by low bone mass and microarchitectural
deterioration of bone tissue (thus increase in bone fragility and susceptibility to fractures.)
Dx = with dual energy X-ray absoptiometry (DEXA) of the spine, hip and forearm.
Also monitoring of changes in bone mass density over time.
Dexa instrument
X-ray tube generates photon beams of 2 different energy levels (hence the name dual energy).
Differences in attenuation of the beams as they pass through the body tissue allows
quantification of BMN
T score
This is used for the Diagnosis of osteoporosis. It is characterized by substracting the
mean BMD of a young adult reference population from the patients BMD and
dividing by standard deviation of young adult popn
This makes sense, useless to use Z score – see below – to dx osteoporosis as
e.g all 90 year old women would be expected to be osteoporotic
Z score
Same but using comparing BMD with age, sex, ethnicicty etc matched peers. (not really
sure what the point of this would be)
Indications of DEXA scans
Women >65 and men >70
Postmenopausal woman <65 with risk factors
Adults with fragility fracture or condition associated with loss of bone mass.
Risk factors
Female, Caucasian, hx of maternal hip fracture.
Age: (critical – BMD decreases after mid 30’s)
Sex hormone deficiency
Low body mass, lifelong low calcium intake
Sedentary lifestyle, excessive alcohol/cigarettes.
Endocrine disorders (especially Cushings but also pituitary and parathyroid disease)
Vit D deficiency (or lack of sun)
Genetic disorders (e.g osteogenesis imperfecta)
Malignancies (e.g MM)
RA, IBD etc
WHO CRITERIA FOR DX OF OSTEOPOROSIS (women >65 and men >70)
Note since they are negative numbers I don’t know whether more than means lower negative
number or higher negative number, if you see what I mean
Normal = T score ≤ 1.0SD
Osteopaenia = -1.0 – 2.5SD
Osteoporosis = ≥-2.5 SD
Severe osteoporosis = ≤ -2.5SD WITH fragility fractures
Men 50-65
T score >2.5 + risks or family history
Men <50
Uze Z SCORE ONLY (and risks/family history)
Pre-menopausal women
Use Z SCORE and only dx if clinical suspicion (fractures or multiple risks)
SERIAL TESTING
Serial BMD testing = recommended for patients being treated for osteoporosis (with goal of
stabilising or increasing BMD
Consider repeat BMD testing 1 or 2 years after starting pharmacological therapy and as
soon as 6 months after starting glucocorticoids.
The site for serial BMD monitoring is usually the lumbar spine
BONE TURNOVER MARKERS
May provide information about expected rates of bone loss and fracture risk that cannot be
obtained from measurements of BMD
Elevated bone turnover makrers are associated with increased risk of vertebral an
non vertebral fractures (idependantly of BMD) (not sure exactly what they are)
RISK FOR FRACTURE
Can do this with the FRAX tool (fracture risk assessment tool). Estimates the 10 year
probability of hip fracture. Using risk factors, T score and simple clinical findings)
WHEN TO START TX
Postmenopausal women with T scores (greater than or less than, not sure) -2 or -1.5 (if
risk factors present)

Examples

Case 1:
A 28-year old man is playing in a rural pub as a drummer with his part-time band. During the gig he
experiences a sudden severe occipital headache and falls to the ground with a 20 second loss of
consciousness. An ambulance is called and on his way to hospital he vomits twice. The hospital has
no CT scanner and as the patient is stable, transfer to a tertiary centre is deferred until the morning.
Note vomiting – so sign of raised ICP, should be scanned before LP done

The morning after admission a lumbar puncture is performed which reveals the
following:

Bottle 1 2 3
RCC (per CMM) 21,800 22,500 20,900 (consistently high, and very
high so unlikely to be traumatic tap)
WCC (per CMM) 18 19 17 (slighly elevated due to
inflammation of the meninges)

CSF protein (mg/dL) 72 (15 - 45) (slightly due to inflammation)

CSF glucose (mmol/L) 3.5
Serum glucose (mmol/L) 5.1

Gram Stain - Organisms not seen

Red cell count is high and remains high in all 3 samples.

DX = SAH (note subdural haematoma would not cause blood in the CSF space
and hx would be different – would be older person who had a fall, then few
weeks later develop headaches and visual problems – dx made on CT)

Diagnosis ?
Case 2:
A 22-year old engineering student misses her Monday morning lectures because she has been at
home all weekend trying “to shake off a cold”. Her symptoms are a worsening headache, dislike for
light [photophobia] and general malaise. She has vomited twice. By Tuesday morning, her headache
is quite severe and she feels bad enough to present herself to the Emergency Department.
(most likely meningitis, photophobia and no focal neurological signs)

Her lumbar puncture shows:

Bottle 1 2 3
RCC (per CMM) <1 <1 <1
WCC (per CMM) 75 70 72 (all lymphocytes)

CSF protein (mg/dL) 55 (15 - 45)

CSF glucose (mmol/L) 3.9
Serum glucose (mmol/L) 5.8

Gram Stain - Organisms not seen

DX = viral meningitis

Diagnosis ?
Case 3:
An 82-year old pensioner with type 2 diabetes is found by a neighbour, collapsed on her living
room floor. An ambulance is called. On arrival in the Emergency Department she is obtunded
(unrousable), cold and clammy and mumbles incomprehensible sounds. Her temperature is 39.1°C
and heart rate is 96 and regular. BP is 106/66 (means patient is septic – high temp, high HR and low
BP). She will not allow the A&E registrar to perform fundoscopy (would probably find
papilloedema) or much of the examination but he thinks her neck is stiff. After a normal CT, a
lumbar puncture is performed which shows :
(more likely to be meningitis rather than encephalitis. First – DM so more likely predisposed to
bacterial infection. Also with encephalitis is unlikely to get this sick this quickly – usually occurs
over few days. Also high temp is indicative of bacterial infection (whereas viral infection
would be slightly elevated temperature)
Note that the impaired consciousness is more because she is in septic shock (rather than due to
the CNS infection)
Remember that elderly people are likely to impair consciousness much more than young people in
response to sepsis.
Also no focal neurology here.
Bottle 1 2 3
RCC (per CMM) 326 112 38 (traumatic tap)
WCC (per CMM) 228 225 230 [predominantly
neutrophils]

CSF protein (mg/dL) 96 (15 - 45)

CSF glucose (mmol/L) 5.2
Serum glucose (mmol/L) 12.0
Serum leucocyte count (/L) 17 x 109 (93% neutrophils)

CSF microscopy:
 Diagnosis ?

Case 4:
A 32-year old bank teller leaves work early because of gradual onset of painful blurring affecting
vision in her right eye since earlier that morning. Six months ago she had an episode of numbness
over the lateral aspect of her left leg which resolved. That evening she attends A&E. While awaiting
an MRI of her brain, the medical team decides to perform a lumbar puncture:

Bottle 1 2 3
RCC (per CMM) 23 8 3
WCC (per CMM) 7 8 6

CSF protein (mg/dL) 43 [15 – 45]

CSF glucose (mmol/L) 2.4
CSF IgG index elevated
CSF IgG pattern oligoclonal
Serum glucose (mmol/L) 4.1

Diagnosis
MS

Inflammatory markers
Note C-anca would be good for renopulmonary syndrome.
ESR and CRP
These are the most common inflammatory markers which are used. They are part of the
acuse phase proteins which accompany both acute and chronic inflammatory states.
They are used diagnostically in that they suggestive to the diagnosis. However they are
NEVER SPECIFIC for any diagnosis. (Always add them in later as an answer for diagnosis –
since they would only be suggestive if other things were also raised).
Also used for monitoring response to therapy.
They can also help in differentiating between an infection and active connective tissue
disease.
CRP
This is produced in the liver
(some do mg/L, others mg/dL – Beaumont does mg/L). Normal = 0-4mg/L
If higher than 100 then vast majority = bacterial infection.
4-100 = usually caused by inflammation or non bacterial infection.
If patient is septic but patient is less than 100 then sepsis is usually due to non bacterial
infection (e.g viral/fungus). (side note – remember the different parts of septic syndrome –
temperature >38.5 or <36, hypotension, high or very low white cells, tachycardia)
ESR
This is a measure of how rapidly RBC’s form sediment when a column of blood is kept
upright for 1 hour. (i.e in inflammation the RBC clump together and thus sink faster)
Normally the CRP and ESR rise together.
CRP increases and decreases faster than ESR.
High ESR but normal CRP
Main one = SLE (remember that main features would be fever, photosensitive rash and
fatigue – while in RA it would be mostly arthralgia (where RA would be also in younger
population, mainly women, but mostly symmetrical polyarthalgia with sparing of the dips
(distal interphalyngeal joints) and always have lasted a minimum of 6 weeks (so meets criteria)
and stiffness.
Thus CRP = not useful for monitoring of lupus.
Another important one is when ESR = falsely positive (this happens frequently because the
way you measure ESR is by sedimentation rate – the more active cytokines there are, the more
viscous the blood becomes and the quicker it descends)
However other things can cause this (e.g polycythaemia)
Thus ESR is only reliable if patient has normal haemoglobin (as well as other factors).
ESR continued
Counts as millimitres in first hour. Very easy/quick to do (can do in AandE)
It is slow to rise in disease states (days) and slow to decrease after resolution (days to
weeks)
Normal = age + 10/2. (Females tend to have slightly higher than males) (not sure why, you
would think that with the lower haemoglobin they would sink slower
ESR above 35mm/h should raise suspicion of a disease process in any age group.
Causes of raised ESR
Many – (I believe the ones mentioned here are the more chronic infections/inflammation that result
in a persistently elevated ESR)
Same/similar as the causes of PUO (fever persistently for greater than 2 weeks for where all routine
tests have failed to elicit a cause)
Inflammatory processes – most commonly UC and Crohns, (MI, pleural effusion)
Malignancies – especially haematological (especially multiple myeloma – remember
commonly over 50, fatigue and bony pain, bloods shows pancytopenia (abnormal plasma cells –
infiltrate rest of bone marrow and take place of other blood precursors), hypercalcaemia, very raised
ESR – lytic lesions on bone scan) and lymphoma (usually younger person and have isolated
lump often in neck, more male, fever anorexia, weight loss and night sweats – low haemoglobin and
lymphocytosis), and renal cell carcinoma.
Lots of the connective tissue diseases (e.g arthritidies, vasculitidies etc) present with non
specific symptoms e.g fever, arthralgia, myalgia, weight loss, fatigue. Would also
get raised ESR in this
Infectious disease (Tb and infective endocarditis = most important. – but also any
other chronic infectious process, osteomyelitis (insidious onset, pain, fever, leukocytosis,
ESR but routine tests fail to show abnormalities), pneumonia, abscesses etc. (Not septic, not
always feverish but quite unwell – losing weight, anaemic without acute septic syndrome – these
patients would get very high ESR
Vasculitidies – classically SLE and temporal arteritis (V important) – (remember
symptoms of frontal headache, jaw claudication (when eating then get angina of temporal artery
– thus pain in jaw and head when eating – almost pathognomonic) an tenderness over the area of
temporal artery. Then there can be visual loss (medical emergency as can cause
blindness). (Need to give very high dose corticosteroids first and then order ESR as it is an
emergency). Disease of elderly
Polymyalgia rheumatica (disease of elderly, more common in women). Main feature =
weakness of shoulder girdle and stiffness of shoulder girdle but don’t have feature of
arthralgia (as it is a tendonitis). (over half develop temporal arteritis) (e.g typical scenario
would be chronic weakness of shoulder, then suddenly presents with headache – i.e pmr and then
temporal arteritis)
ANCA associated vasculitidies
Pulmonary renal syndrome
Specific applications
RA – the ESR and CRP are used to help with dx and for assessment of disease activity
Polymyalgia rheumatica and giant cell arteritis – (associated with high ESR – higher than
100) and the ESR is used to help with dx and monitor therapy
SLE – ESR (makes sense as CRP normal)used for marker of disease activity and predictor of
organ damage
AUTOANTIBODIES
Remember you are looking at titres (i.e how dilute the sample has to be before you detect it.
I.e lower fraction = more autoantibody (e.g 1 in 200,000 = way more antibody than 1 in
200)
Remember that they can be found in healthy people (but in low concentrations(
Vica versa (if has clinical features of autoimmune disease and test is negative then doesn’t mean
that they don’t have disease – may be producing other antibodies that we don’t routinely test for)
Also a lot of overlap with different disease states.
Note that most of the antibodies we test for are IgG
Rheumatoid arthritis
Rheumatoid factor
SLE, sicca, dermatomyocitis etc as well as RA.
Normal = <20.
Negative = RA is less likely
If someone has rheumatoid nodules then they will always be RA positive.
Serial monitoring = NOT useful (i.e does not decrease in response to therapy). What is
useful is knowing concentration at initial dx (as if high then will have worse prognosis)
I.e RA = useful for dx and prognosis only.
ESR + CRP + clinical features = good for monitoring therapy.
Anti-CCP
Anti cyclic citrillanted peptides.
It is more specific and sensitive for RA.
No relation between this and RF (can be one or other or both or neither etc)
Should check for both RF and anti-CCP.
Other findings in RA – Xrayu
PECS
Periarticular porosis, erosions, chondocalcinosis, soft tissue swelling (also
narrowing of joint space)
Autoantibody screen
Some may be ANA positive (atypical serology – may have this rather than RF/anti-CCP)
Other tests done for RA
FBC (look for anaemia), ESR/CRP (monitor response to therapy)
Could also do complement levels (normal in RA but decreased in SLE – linked to SLE disease
activity – useful for differentiating) (makes sense – lots of antibody complexes are produced and so
you get lowering of the overall antibody levels)
Autoantibodies in mixed connective tissue disease
Remember that there is an overlap between connective tissue disease and vasculitidies
(spectrum of illnesses).
Remember SLE, systemic sclerosis, CREST syndrome, large, medium and small
vessel vascultis have very similar and overlapping symptoms/signs.
Connective tissue disease – commonly fever, myalgia, arthralgia and then depending
on what systems are involved you get
Vasculitis – can also present with fever, fatigue but mostly rashes and haematuria and
serositis etc
ANA
Cornerstone of dx for vasculitis/connective tissue disase
They promote phagocytosis of the nuclei of the disrupted cells.
Many of them (each targeted at different part of the nucleus) (some associated with
different illnesses)
They are used to establish dx in patient with symptoms suggestive of
autoimmune/connective tissue disorder
Then use it to sublassify which condition it is.
Also used to monitor disease activity.
Thus first test is just ANA. They will come back as either negative, weakly positive or
strongly positive. If they have no symptoms and it comes back negative/weakly
positive then don’t need to do anything else.
However if symptoms and comes back weakly/strongly positive then you order an ENA
(extractable nuclear antibodies).
Note that you also want to know what the staining pattern on immunofluorescence.
Different staining patterns associated with different connective tissue diseases
Anti ENA antibodies
This is looking for the specific nuclear antigens. You look for specific target antigens
(which help narrow down the diagnosis)
Anti ds DNA – associated with SLE (can also be found in autoimmune hepatitis). Useful for
monitoring disease activity in SLE
Anti SM (also associated with SLE – and more specific)
Anti Ro and anti La (SLE or Sjorgrens syndrome).
Anti RNP (associated with mixed connective tissue disease)
Anti-Jo-1 (polymyositis)
Anti-SCL-70 (scleroderma)
ANCA ASSOCIATED ANTIBODIES
This is against neutorphil cytoplasm.
(Previously could only tell if positive or negative, now we can say the subtype as well)
(learn this – but don’t need to understand this for now)
Anti MPO is associated with p-ANCA
Anti PR3 associated with c-ANCA
C-ANCA = means wegeners granulocytosis (remember affects central structures –
nose, respiratory tract, sometimes GI tract and renal tract (causes necrotizing vasculitis)
– men slightly more than women, young (30-40), sinusitis, epistaxis, haemoptysis,
fibrosis and renal vasculitis (i.e haematuria/proteinuria)
P-ANCA = means any other vasculitis (commonst = microscopic polyangiitis)
Note microscopic polyangiitis = another cause of renopulmonary syndrome (usually
starts with renal and then develops pulmonary). Wont have sinusitis/epistaxis. (just have
haemoptysis, haematuria and fibrosis – dyspnoea/dry cough).
So you order a C-ANCA and if positive you check for anti PR3 (if positive then highly
suggestive of wegeners), also do P-ANCA (if positive then do anti MPO) – (if both positive tells
you a vasculitis is occurring but doesn’t tell you which one)
Vasculitis
= inflammation of vessel walls
Arteritis = inflammation in arterial walls
Cause = either direct infection, immunologic or unknown
Direct infection usually bacteria/fungi also rickettsial infection, RMSF (rocky
mountain spotted fever), syphilis etc, l
Immunologic = immune complex (major = SLE, Henoch-Schönlein purpura,
rheumatoid arthritis).
ANCA (Anti-neutrophil cytoplasmic antibodies - antibody circulating in the bloodstream,
different types - different conditions that antibodies produce is Wegener's granulomatosis,
microscopic polyangiitis and Churg-Strauss syndrome. (primary sclerosing
cholangitis????)
Direct antibody attack (Goodpastures/Kawasaki syndrome)
Cell mediated (in allograft organ rejection)
Inflammatory bowel disease and paraneoplastic effects
Unknown aetiology = giant cell, Takayasu and Polyarteritis nodosa
Non infectious vasculitis classification
Large, medium, small vessels
Immune complex vasculitis
Large vessel
Giant cell (temporal) arteritis - as tends to affect temporal arteries
Here it is a granulomatous arteritis. You get inflammation containing giant cells. Tends
to affect aorta/major branches. Tends to occur in people over 50 years old (very unusual
under this age). Associated with polymyalgia rheumatica - (pain in many muscles -
inflammatory condition of muscles). Severe complications may develop e.g
blindness/stroke.
Takayasu arteritis = similar look (granulomatous inflammation). However occurs in
under 50's. (rare). Note main difference is just the age. But only minor other differences.

Medium sized vessel vasculitis

Polyarteritis nodosa = you get a necrotising inflammation. It affects the renal and
systemic vessels but spares the pulmonary vessels. You get NO glomerulonephritis
(get involvement of vessels but not this - only affects medium sized vessels)
Kawasaki disease = disease of children. Often present with enlarged cervical lymph
nodes. (often get what is known as "scalded skin" - blisters, lose epidermis etc. Need to go to
intensive care. Often involves coronary arteries

Buergers disease = all you need to know is it occurs in smokers (if you have a case with
someone with vasculitis and they are a smoker it is likely to be this)
Small vessel vasculitis
Wegeners granulomatosis = (good exam question) - it is a necrotising vasculitis. It
involves granulomatous inflammation of respiratory tract and causes necrotising
glomerunephritis (something abnormal in kidneys, lungs and vasculitis = probably this). Note
can cause lesions on X-ray (suspicious carcinoma but biopsy proves negative)
Churg-Strauss syndrome - classily full of eosinophils. If the patient is an asthmatic the
diagnosis is likely to be this. Have a lot of eosinophils circulating in blood as well as being
deposited in tissues.
Microscopic polyangiitis = necrotising vasculitis - few or no immune deposits. Also have
necrotising glomerulonephritis. Different from polyarthritis nodosa (this affects the
glomerulus and affects pulmonary circulation)
Henoch-Schönlein purpura - tend to see in children - present with bruising on their
buttocks (see inflammation in small vessel walls. Affects the skin (bruising), but also
intestines and glomerulus. (also have joint pains). Often presents with parents thinking it is
meningitis (due to bruises)

Rarer things (just have heard of it)

Essential cryoglobulinaemic vasculitis (immune complexes in serum), affects skin and
glomeruli
Cutaneous lecocytoclastic angiitis (involves skin, blood vessels and involves leucocytes
Note all these conditions look the same down the microscope. Clues = history (e.g if
isolated in skin it may be CLA, if in smokers probably Buerger's etc
Anti GMB
Another renopulmonary syndrome (Goodpasteur syndrome). Different antibodies
involved (anti GMB rather than ANCA)
Anti-Cardiolipin antibodies
Associated with antiphospholipid syndrome (can occur on its own or with SLE).
Causes recurrent arterial and venous thrombosis. (Tx on lifelong warfarin)
Anti liver kidney microsomal (LKM) antibodies
Type 2 autoimune hepatitis
AMA (antimicrobial antibody)
Found in primary biliary cirrhosis
Anti – gastric parietal antibodies
Found in most people with atrophic gastritis/pernicious anaemia (B12 should also be
checked)
Anti intrinsic factor antibodies
Found in most patients with pernicious anaemia as well (again, B12 should be checked)
Anti thyroid antibodies
Anti thyroid microsomal antibodies = almost always found
Anti thyroglobulin antibodies (1%) (note I am not sure about these 2- doesn’t say much
here). Don’t think it is as important
Anti-endomysial antibodies
Positive test suggests celiac disease
Complement – C3 and C4
When both reduced then associated with consumption of classical pathway – and hence
usually associated with active lupus.

Diabetic history
Note that best place to inject is where there is the most. This is usually the abdomen or legs.
Note you need to vary place where you inject (because it is not absorbed properly. Additionally,
this means that if you increase the dosage and then suddenly inject into another place you can get a
hypo)
Note that expensive drugs but covered by government.
Note you do not have to clean before you inject
However you have to clean hands before taking blood sugar (because sugar on your hands
after food can interfere with the results)
Blood sugar checking – do on side of finger. Note only a point of doing it after 2 hours
(right after meal there is no point at all)
Note have to dispose of needles in special box that you get in the
Note 7% is ok for type 2. However 4-6.5 in type 1 is better.
Note CSII (continuous subcutaneous insulin) – need to know what you are doing to do it.
Note inhaled insulin isn’t very useful because only 10% entales
Note 4.4-6.6 =
Remember – hypoglycaemia – intense feeling of hunger, anxiety, palpitations. Carry
After hypo- drink lucozade. Then relax. Then 15 mins recheck. If still low then do more etc
etc. About half a cup of fruit drink, half cup of lucozade.
Remember that after a while you can get hypo unawareness – don’t know about. IF they are in
diabetic clinic – need to check if they are hypo aware. Remember that people on beta
blockers will not be as aware.
Remember need to tell who they live with that if severe hypo – give glucagons. This is given
intramuscularly.
Remember – severe hypo = need someone else to help you. (Either because confused,
unconscious etc)
KNIVES – complications – kidneys, nervfes, infection, vascular, eyes, skin.
BP – 125/80 you want even lower BP than in general population.

Remember that if you are doing a neurological exam of the upper limb, the first thing that you want
to do is ask to hold arms up and ask to close their eyes, check for evidence of drifting
You would also like to check for winging of the scapula.
When checking tone – (make sure your checking 2 joints at the same time and at least in 2 different
lains. To be slick get the patient to relax
Look up difference between spasticity and rigidity.
Don’t present as you go along (try to make a decision before you do so)
When testing power, try and test like with like (test your muscle group against theirs – don’t have to
but at final med level it is better,
Remember know how to grade power.
Note that if patient has impaired power you cant check coordination (don’t know if ataxic or know.
For reflexes, make sure you put them in the correct position
Remember that te patient needs to be completely flaccid/limp. Can put a pillow under to relax their
arm.
Remember to expose the patient so you have sleeves up to shoulder, so that you can see the biceps
muscle.
Make sure that when you present, don’t move your hands about.
When testing for cerebellar disease and asking patient to stand up, make sure that you stand beside
to make sure the patient doesn’t fall over. Make sure that they have their walking stick readt etc.
Note that the ataxia that they have depends on where the lesion is (if right sided lesion, then move
to the right etc)
Cerebellar ataxia = instantly ataxic
If
Ask the patient to turj around really quickly when they are walking (thus parkinsons
Remember that rombers sign = not a sign of cerebellar disease (this is a sign of sensory
ataxia – if they had motor ataxia they would already have ataxia. If it is sensory then they have
compensation via the eyes etc.)
For coordination – make sure for you are on the same level. You also want to make sure that their
full span is tested (length of arm span).
Past pointing is called dysmetria.
Remember to test for nystagmus vertically as well as horizontally.
Note pendular movement (best demonstrated in the knees)

Work up of someone with emipuresis, etc or assessing clinical stroke.

Remember to do the most important first (Dx the patient)
So for a stroke, most important is non contsast CT brain. Can note down any features that
could be there. E.g evidence of haemorrhage, evidence of ischaemia, cerebral oedema, blood in the
ventricles. Sometimes for posterior you may need an MRI. In north America they may do MRA as
well.
Then after identifying problem, add the tests to diagnose aetiology
Do ECG to check for afib, however would want a holter to check if they have paroxysms of afib.
Do echo to check for mural thrombus. (echo for MI would be for dyskinesia, echo for heart failure
would be to look for lowered ejection fraction etc).
Aortic stenosis
Septic emboli from IE can cause it as well. (if young then would want to do blood culture, echo –
looking for vegetation on the valve and ecg – bundle branch block, heart block etc can result from
IE. to check for it.)
Note dyspraxia = not able to do learned functions (parietal lobe damage).
Know anterior and posterior circulation – inside out. Anterior circulation
Patent foramen ovale = common, ¼.
Screen for high BP, DM, high cholesterol (fasting cholesterol testing)
In younger patients – can do vasulitic studies.
Note MI as well (if can lead to arrhythmias that can lead to
Then do investigations to determine severity.. In stroke – clinical exam = main way of
assessing severity. Then checking if they are in inspiratory compromise – as aspiration is a common
complication of stroke. Want to do CXR to check for consolidation. Do ABG looking for
hypoxia/respiratory failure/acidosis etc.
Check for hyperglycaemia – as poor prognostic indicator.
Could do septic screen to check for other infections (check for UTI etc, due to the stroke). CXR,
blood cultures, urine cultures, stool culture. If wounds then swab them as well.
Tests that help influence management. Want to do coagulation screen before
thrombolysing etc. Want to do FBC to check haemoglobin isn’t too low.
ALWAYS IN THIS ORDER! Dx,
Try and divide this into this

assess aetiology, assess severity, tests to

influence management
Midline cerebellar lesion = wide based git
Right sided cerebellar lesion = le
Difference between someone with cerebellar lesion is whether they have their eyes open or closed,
they will be ataxic.
If you ask them to close their eyes, it makes no
Dorsal column problem – proprioception difficulty – can have balance
Remember that with a right cerebral hemispheric stroke there is overactivity of the flexor muscle.
Asking to test on their toes – they cant in an S1 lesion (
L4 lesion – foot drop.
Posterior circular
Infective – a midline abscess can cause cerebellar problems.
Pattern to weakness. Get spastic paraparesis. (spasticity and weakness). If have high tone in legs
then havse scissoring gait.
Proximal myopathy – cant get up with their arms folded. Get waddling gait. (trying to compensate
with weakness
Dermatomyocitis,
Duchennes and any other muscular dystrophy can cause it
Steroids can also give proximal myopathy.
Note that bring their elbow right up when testing coordination. Be very clear
Note that can also ask patient to touch index finger with their thumb. This tests for coordination but
also you are testing for parkinsons. This is because you get smaller and smaller as they do it (same
as writing which is
Remember that if you have weakness then you will not be able to accurately assess coordination.
Tapping foot on the ground – is another one of checking amplitude and rate (check for parkinsons
again, will get smaller and smaller)
Nystagmus – it is named for the fast component.
(Cerebellar lesions will be ipsilateral to the fast component.)
PNEARDS= pneumonic for cerebellar exam. Past pointing (should not overstretch) , nystagmus,
ataxia, dysdiadochokinesis, Scanning speech (ask them to read short paragraph. Describe
something e.g what did you have. The talking comes out in bursts. Dysarthia = global cerebellar
problem – i.e just like someone who has had too much to drink.
Note that anything that can cause encephalitis can cause asterixis (
Note types of tremors
Note rebound tremor – cannot stop, arms keep moving.
Note neglect syndrome – can ask to draw a clock (they will not
Ask them to make the time – (point the hands to a certain time)
Note specific phrases for testing cerebellar speech problems – “ ritish constitution”– british
constitution

Module case – differential dx of RA

Septic arthritisi – infection in joint, patient will be acutely unwell
Osteoarthritis – differential between RA and OA by morning stiffness
SLE – uusually female aged 20-40s. Usually presents with extra articular manifestations. Butterfly
rash etc
Gout – tohpi – excruciating, severe pain, usually affects the big toe. Joint aspiration helps you to
differentiate between gout and pseudogout
Psoriatic arthritis – 5 patterns. 1 is a rheumatoid pattern
Reactive arthritis – systemic reactive arthritis in response to infection. Reiters syndrome
Enteropathic arthritis – wont be small joints and symmetrical
Ankylosing spondylitis – AAAA – anterior uveitis, aortic regurgitation, Achilles tendoinitis an
apical fibrosis. Bamboo spine – sacroiliatis (this could be due to ankylosing spondylitis or IBD)

Investigations
Blood tests, radiological investigations
Blood tests
ESR, CRP, RF, anti CCP, ANA, FBC (normochromic normocytic anaemia, haemolytic
anaemia – due to feltys syndrome, methotrextate – a folate deficiency megaloblastic anaemia, or
NSAIDS resulting in a microcytic iron deficiency anaemia)
U+E – (drugs such as methotrexate can cause renal impairment)
LFT’s (drugs such as methotrexate can cause liver failure)
APP (more commonly done than CRP)(such as albumin)
If acute presentation then blood culture and joint aspirate.

Radiological investiagations
X-ray of hands – joint space narrowing, bone erosions, osteopaenia around joints or joint
deformity

– joint space narrowing, bone erosions, osteopaenia around joints or joint deformity

Management
Acute exasserbation
NSAIDS#
Steroids (if big joint such as knee – intraarticular steroids with leukopein. We don’t usually use it
for acute presentation but for long persistent inflamed joint because could lead to infection)
Oral steroids (prednsolone)
Iv steroids (methylprednisolone)
Paracetamol
Opiods

C/I of NSAIDS
You can – previous peptic ulcer
Also give PPI to protect the stomach (due to bleeding problems)

A flare of RA sually may last weeks

Chronic administration:
DMARDS – biological or non biological
Biological – TNF inhibits, e.g infliximab. Il-1 receptor antagonists, il-6 receptor (e.g entercept etc)

Non biological – methotrexate, sulfasalazine, hydrochloroquine or fluoroqine)

Administer biologic if do not respond to non biologic.

Non pharmacologic
Physiotherapist – exercises to keep as much function of the joint.

Social worker
OT – occupational therapist. What aids and adaptions patient may need e.g at home –
rails,wheelchair etc

Surgery – joint replacement most commonly knee replacement – carpal tunnel syndrome tx too.

HLMT AND TROPICAL MEDICINE|

PATHOLOGY
Benign lymphoid reactions
Lymphoid tissue
This can be divided into primary and secondary lymphoid tissue.
Primary (central) lymphoid tissues are the bone marrow and thymus
Bone marrow = source of stem cells (eryrhroid, myeloid and lymphoid cells). It is also the
site of differentiation of lymphoid cells into B lymphocytes
Thymus = site of differentiation of T cells
Secondary lymphoid tissues = lymph nodes, spleen, tonsils, adenoids and Peyer
patches
Remember that the lymphoid cells circulate in the peripheral blood and migrate to the
secondary organs
Lymph node
You have a capsule,
Cortex (with follicules and parafollicular cortex)
Medullary cords
Sinuses
Afferent and efferent lymphatics and high endothelial venules
B cell rich areas = primary follicules (have mature resting B lymphocytes which are not
stimulated by antigens)
Secondary follicules = develop after antigen challenge. The follicular dendritic
cells present antigens to the T cells. These stimulate B cells to proliferate and produce
antibodies
The parafollicular cortex lies in between each follicle and has T cell rich regions
The medullary cords contain scattered lymphocytes, macrophages, dendritic cells and plasma cells
Lymphadenopathy
Can be localised or generalised.
Dx requires tissue sample (either by FNA or biopsy)
Can be reactive (either acute – seen in area of or chronic) or neoplastic.
Biopsy is better for dx (as see architecture around the cells)
Acute lymphadenopathy/lymphadenitis (not that important, everyone has had this)
Usually secondary to bacterial or viral infection in the area drained by the lymph node
(e.g cervical nodes in strep throat)
They are enlarged and tender
Histological features = follicular hyperplasia but preservation of architecture
Chronic reactive lymphadenitis
A response to chronic antigen stimulation. Depending on the stimulus then different regions
of the lymph node may become enlarged.
E.g can get follicular hyperplasia, para-follicular hyperplasia, necrotising
lymphadenitis or granulomatous reaction
Follicular hyperplasia
Can be due to syphilis, toxoplasmosis, RA, SLE and early HIV infection
(other things and types mentioned in lecture but don’t think it is important)
Side note: Toxoplasmosis.
It is caused by toxoplasma gondii (a protozoan). Usually sub-clinical but may present with
mild painless lymphadenopathy (especially in posterior triangle of neck)
It is however a serious condition in fetus (in pregnant woman) and HIV. You see follicular
hyperplasia, clusters of epitheloid cells (mini granulomas). (Can dx based on the histology of
the lymph node or serology)
Syphilis – can occur due to primary and secondary syphilis (skipped but similar features on
histology – follicular hyperplasia, mini granulomas etc)
Lymphadenopathy in HIV
There may be transient lymphadenopathy at the time of seroconversion (i.e early in the
infection)
There may also be persistent generalised lymphadenopathy – (in the early stages –
follicular hyperplasia and then follicular involusion)
Bacillary angiomtosis – bartonella henselae (transmitted by cat scratches, fleas etc)
Can also be due to opportunistic infections (i.e due to the immunodeficiency)
Can be due to neoplasia (e.g Kaposi’s sarcoma – an AIDS defining illness due to human
herpes virus 8 coinfection)
Non hodgkins lymphoma (e.g burkitts I would imagine due to EB virus costimulation would
be common)
Metastatic carcinoma
Paracortical lymphoid hyperplasia
Can be due to drugs (e.g phenytoin)
Can be due to viral infections – especially infectious mononucleosis
There is expansion of the T-cell region. (makes sense, the cortical regions congtain B cells and
the paracortical regions T cells. Hence when there is a viral infection it makes sense that the T cell
areas proliferate)
Infectious mononucleosis
Transmitted by kissing frequently. Infects adolescents and young adults. It is usually self-
limiting
Clincally manifests as fever, malaise, pharyngitis, cervical lymphadenopathy and
splenomegaly
Dx (there is para-cortical hyperplasia, reactive atypical lymphocytosis, reed-
sternberg like (makes sense, since EB virus is thought to be implicated in hodgkins lymphoma
as well) cells and monospot test is positive
Sinus histiocytosis (not important)
Can be associated with chronic inflammation, lymph nodes draining cancer etc
Granulomatous lymphadenitis
Can be due to infection or foreign body
Bacteria = Tb, cat scratch disease. Can be fungi, parasites (e.g toxoplasmosis) and
spirochetes (syphilis)
Can be due to foreign body and unknown aetiology (sarcoidosis and Crohns) (Can also
be due to neoplasm)
Tb
Remember that hilar and mediastinal lymphadenitis occurs in primary Tb
(ingested mycobacteria can also cause cervical lymph node enlargement)
Sarcoid
Remember granulomatous condition of unknown aetiology – may affect any tissue and is
commoner in black people. There can be interstitial lung disease, lymphadenopathy,
arthropathy, CNS involvement and others.
Histological features = non caseating granuloma (schaumann bodies, asteroid bodies and
negative Zn stain)
It is a dx of exclusion
Crohns disease
The lymph nodes that drain the bowel are affected
Necrotising lymphadenitis
You see necrosis within the node.
Cat scratch disease
Can be due to cat scratch disease. This is a self limiting lymphadenitis. Commonly
axillary lymphadenopathy caused by bartonella henselae. It is usually secondary to a
feline scratch. There is a granuloma with necrotizing lymphadenitis and the bacteria
are visualized with a silver stain
Lymphogranuloma venereum
STI caused by Chlamydia. Limited to tropics. Caused by a type of Chlamydia and there are
genital skin lesions and inguinal lymphadenopathy
Kikuchis disease
Common in asia (painless lymphadenopathy + fever. Young females, unknown aetiology)
Yersinia enterocolica
There is mesenteric lymphadenitis which resemble acute appendicitis (there is
necrotizing granulomatous inflammation)
Also mucosal ulceration and mesenteric node hyperplasia
POST TRANPLANT LYMPHOPROLIFERATIVE DISORDERS
May occur after solid organ or bone marrow transplantation
Most associated with EBV.
Often occurs in extra nodal sites (CNS/small bowel etc) and may progress to lymphoma
NEOPLASTIC LYMPHADENOPATHY
Metastatic tumour – carcinoma, melanoma, germ cell tumour (very rarely sarcoma,
remember sarcoma mainly spreads haematogenously) or lymphoma
CLINICALLY DIFFERENTIATING REACTIVE and MALIGNANT LYMPHADENOPATHY
Malignant = tend to stick together, non tender (as develop over long period), hard, tend
to grow slowly.
Non malignant = tender (as develop quickly and stretch the capsule), less firm, tend to
grow quickly
Plasma cell dyscrasia
Come back to this lecture as there was a bit from another lecture.
Dyscrasia = abnormal material in the blood
Thus these ar disorders of the plasma cells. The commonest is multiple myeloma
Thus there is a problem with either the plasma cells or the B cells.
It is characterised by immunoglobulin production.
Classification
Multiple myeloma
Solitary plasmacytoma
Waldenstroms macroglobuminaemia
Heavy chain disease
Primary amyloidosis of AL type
Monoclonal gammopathy of undetermined significance
Multiple myeloma
Myo means bone marrow and oma meaning tumour
Epidemiology
Multiple refers to the fact that it is a multiple bone marrow disease
(accounts for 15% of haematological malignancies and 1% of all cancer deaths – i.e relatively
common)
Affects adults – (usually > 50) (i.e this is a disease of the elderly)
M and Black = more affected than F and white.
Pathogenesis
Very complicated and many interconnected pathologies
Previous exposure to irradiation
Exposure to asbestos, petroleum products, rubber or plastic products
HH8 (not sure why, I know that this causes kaposis sarcoma, as far as multiple myeloma is
concerned I am not too sure)
Cytogenetics (e.g deletion of 13q or translocation of 4;14)
Myeloma cells produce Il-6. This is important because it induces myeloma cell growth
and induces osteoclast activation.
Hence you get breakdown of the bone. (This makes sense, this is the reason why even if there is
no direct infiltration of the myeloma cells, there is osteoclast activity and hence lytic lesions. E.g
in the skull it is called a pepperpot skull
The plasma cells secrete a MONOCLONAL Ig.
Usually they are IgG or IgA (the other types are uncommon)
In 2/3 of patients they have Bence Jones proteins. These are light chains of
immunoglobulins that are found in the urine. They are able to be found in the urine because
they are light chains (hence they can be filtered in the glomerulus) (possibly the reason why only
2/3 of patients have this is because the other 1/3 produce heavy chains?)
Dx of MM
Radiology
You may see specific punched out lytic lesions (makes sense, since these would be due to the
osteoclast activation) E.g
(e.g note below the multiple lytic lesions in the metaphysic and diaphysis of the humerus and in the
ribs. There is also a small fracture in the proximal metaphysic)
Also note the pepper pot skull on the right

You can see multifocal destructive lesions (

Bone marrow sampling (a bone marrow aspirate or biopsy)
Serum and urine electrophoresis and immunoglobulin levels (You would have a
monoclonal spike, urine electrophoresis would be the Bence Jones criteria I would imagine).
Could also see multifocal destructive lesions (multiple punched out lytic lesions)
They can soap bubble appearance
Can also have pathologic fractures (makes sense, they have bony infiltration and lytic lesions)
Note that you mal also get a diffuse osteoporosis (because of Il-6 secretion which results in
infiltration of the bone even if there is no infiltration of the bone)
Bone marrow sampling
Can do a bone marrow aspirate or a bone marrow biopsy
Normally plasma cells form about 10-20% of the bone marrow. (I think lecturer is saying that
normally 10-30% but when there is multiple myeloma there is a greater percentage. Not sure.
Remember the normal morphology of plasma cells. You have a nucleus which is pushed to one
side and perinuclear clearing (because of golgi bodies - to make the immunoglobulins I
believe)
However, in multiple myeloma you can have abnormal cells e.g bi-nucleated, tri-
nucleated or multi-nucleated forms.

Can have immature blasts

Intracytoplasmic inclusions (Russle bodies large eosinophilic cells)
Immunohistochemistry (will see a single type of Ig – monoclonal remember). They can be
either kappa or lambda (never both, usually kappa). Remember that they are the type of light
chains?)
Serum and urine analysis
Monoclonal globulin spike on serum electrophoresis (note that small percentage, 1%
secrete neither Bence Jones proteins or monoclonal spike)
The absence of Ig or its components from blood or urine does NOT exclude myeloma
(because of the 1% of the non secretors I would imagine)

Clinical features of multiple myeloma

CRAB (hypercalcaemia, renal failure, anemia and bone lesions)
Infiltration of bones (hence bone lytic lesions) (the hypercalcaemia would cause
hyperparathyroidism too I would imagine? Additionaly there would be il-6 secretion and therefore
resulting in osteoclasts being activated also causing lytic lesions?) (Remember that a patient with
back pain especially if it is unremitting even in the night then suspect MM. Additionally another
feature that maybe present is tender ribcage)
Hence get bone pain and pathologic fractures
Hypercalcaemia – (due to resorption of bone I would imagine, Not all patients get this I believe
it is 10%)
Infiltration of bone marrow (hence the anaemia)
Renal insufficiency (just due to amyloid or due to infiltration as well?)
Infiltration of other organs is rare.
Amyloidosis – AL chain.
Recurrent infections
This is the most common cause for death (renal failure being the second most common)
This is due to a combination of decreased production of normal immunoglobulins (and
hence there is particular risk from encapsulated organisms) (antibody mediated immunity)
Additionally infiltration of the bone marrow causes leucopenia (and hence cell mediated
immunity is also reduced)
Hypercalcaemia
Additional symptoms due to this (Bones, stones, groans and psychiatric moans remember)
Lethargy, nausea, vomiting, abdominal pain (due to ulcers or pancreatitis I believe)
Renal stones
Depression (psychiatric moans)
Bone lesions
Amyloidosis
Remember that you can get a AL type of a amyloidosis (it is the most common type of systemic
amyloidosis I believe)
It is a systemic amyloidosis with deposits in many places
Remember from BED. It occurs with about 10% of MM patients and when you have this then
generally very poor prognosis.
Note however that most people with Al amyloid do not have MM (but probably some
lymphproliferative disorder. Not known if they will eventually develop myeloma because the
amyloid will usually kill the patient first.
Dx = kidney (more invasive) or rectal biopsy (remember, rectal is often used I believe in
systemic amyloidosis, possibly because it is a good and minimally invasive procedure)
Then stained with congo red stain
Complications associated with amyloid deposition
Restrictive cardiomyopathy
Enlargement of the tongue

Athropathy (basically the same as arthritis)

Tendency for prolonged bleeding (due to binding of clotting factor X by the amyloid fibril)
Skin changes

Renal failure
This is the second most common cause of death
The renal failure is multifactorial
Obviously if the patient has amyloidosis then amyloid deposits can cause
However myeloma kidney (myeloma cast nephropathy due to deposition of cast within the
tubules) (just a feature that suggests myeloma I would imagine – I think just meaning direct
invasion of the myeloma cells?)
Light chain nephropathy (this is due to deposition of light chain in the glomeruli)
Hypercalcaemia (causing renal calcinosis?) and hyperuricaemia
Pyelonephritis (not sure the mechanism)
Prognosis of multiple myeloma
Very poor
6-12 months if untreated
Median survival = 3 years if treated
Causes of death = infection and renal failure.
Treatment of multiple myeoma
Currently it is not curable
However, chemotherapy, steroids, and radiation may help
Bisphosphonates are also used (I imagine as symptomatic therapy in order to prevent fractures
and build up bone bulk)
Thalidomide = tx for multiple myeloma (remember, it caused birt defects in women before, but
now used again as a tx for this condition).
Thalidomide used in combination with dexamethasone
Bone marrow transplant (either autologous or allogenic can also be used)
SOLITARY PLASTMACYTOMA
This is like a multiple myeloma but it is a solitary tumor which is growing within the soft tissue
or skeleton
The serum immunoglobulin concentrations are within normal limits
The patients are younger than patients with multiple myeloma
It involves the spine, pelvis and femur
Can present with a single symptomatic area of bone destruction.
Plasma cells account for more than 15% in the bone marrow
It may however progress to multiple myeoma (10-20 years later)
Extra medullary plasmocytoma = often involved in the lung, oronosopharynx and
nasal sinuses
Extra-osseus lesions can be cured by local resection or chemotherapy. Progression
to multiple myeloma is rare. (I believe the skeletal forms are worse because you are far more
likely to progress to multiple myeloma)
WALDENSTROMS MACROGLOBUMINAEMIA
(apparently not that important) Just know a bit about it
Occurs in the elderly and more in females
The neoplastic cells this time produce IgM (whereas multiple myeloma usually produces IgG, but
can produce others) and this is the reason why it is called macroglobuminaemia (as the
immunoglobulins are large)
Weakness and weight loss
Lymphadenopathy, hepatosplenomegaly, autoimmune haemolysis and
hyperviscosity syndrome
Hyperviscosity syndrome = visual impairment due to distention of the retinal
blood vessels. There can also be neurological symptoms, bleeding (due to
macroglobulins binding to clotting factors and interfering with platelet function),
cryoglobuminaemia and Raynauds phenomenon
HEAVY CHAIN DISEAES
These are monoclonal proliferations of B cells with increased production of heavy
chains
(kind of like amyloidosis in a way. Light chain production forms AL amyloidosis, while this is
heavy chain disease)
Note that this, amyloidosis and waldenstroms macroglobuminaemias are all types of
paraproteinemias (which indicate an underlying immunoproliferative disorder). That is, excessive
amounts of single monoclonal gammaglobulins. (Light chains – amyloidosis, heavy chains – heavy
chain disease or full polymers – waldenstroms macroglobuminaemia)
There can be production of alpha heavy chain disease, gamma heavy chain disease
or mu heavy chain disease
(more information about this in the lecture, come back to this in the very unlikely situation of
having excess time)
MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE
This is the most common cause of monoclonal gammopathy
3% of adults >70 will have this.
This is a monoclonal immunoglobulin spike in the serum or urine without evidence of
MM or other disease
It is asymptomatic and usually picked up incidentally
The plasma cells form <5-10% of nucleated cells in the bone marrow.
There are no bence jones proteins, no bone lesions and dx requires exclusion of
other causes of monoclonal gammopathy
It is generally a benign clinical course
However 20% will develop MM over 5-10 years (so should be followed up even though most will
not develop myeloma)

Blood transfusion
When you take the sample from the donor it is then spun out to get the variout components.
Can get cellular components (red cells and platelets)
Can get plasma (Due to variant CJD risk then plasma thrown out in this country, plasma comes
from USA that is well screened). This is the fluid part of blood.
This can be separated further into:
Cryoprecipitate (high in factor VIII and fibrinogen – used to use this for haemophiliacs, but
now recombinant – so no HIV/hep C risk)
Cryosupernatant (albumin and immunoglobulins)
Indications
Whole blood: Large acute blood loss (need to give fresh blood full of platelets and
coagulation factors)
Packed red cells (leukodepleted): This is the mainstay for anaemia tx. Usually for Hb
<8h/l. This is stored in SAG-M (saline, adenine, glucose, manitol – to keep it fresh)
Platelet concentration: Given to patients with low platelets. Normal = 150 (X10^9).
Thus when <10 (X10^9). May also give for <50 for surgical procedures and if dropping
quickly or a little higher but actively bleeding
Fresh frozen plasma (from USA – also processed to reduce risk of viral contamination). Given
to replace coagulation factors (if bleeding or surgery with bad coagulopathy)
Also used for liver disease, after a massive transfusion of packed cells (as this would
have diluted the clotting factors). Other uses are DIC and TTP (thrombotic thrombocytopenic
purpura). Here then you take off plasma and you replace with this.
Prothrombin complex = contains factors II, VII, IX and X (i.e all the factors that warfarin
blocks. Remember same name as prothrombin time which is used for warfarin monitoring) for
emergency reversal of warfarin (only temporary – while giving vitamin K). Better than
plasma as you don’t fluid overload. Thus don’t use FFP (even though some people do it, but it is
incorrect)
Cryoprecipitate (rich in I and VIII) – used to be used for factor VIII haemophilia (before
recombinant therapy used) and in DIC for when fibrinogen is low (however now it has been
replaced by fibrinogen concentrate)
Albumin – as replacement fluid in plasmapheresis (which is done in guillian Barre,
Goodpasteurs etc (except TTP – as here the problem is with the plasma components) (remove
the antibodies from the plasma)). Also used as plasma volume expander in
hypoalbuminaemia states (e.g burns liver failure, nephritic syndrome etc)
IV immunoglobulins – e.g in hypogammaglobulinaemia (remember a type of humoural
deficiency) (Note transient causes include multiple myeloma and chronic lymphocytic
lymphoma/leukaemia (makes sense – B cells) (as reduction in normal immunoglobulins)
Thrombocytopenic purpura (gets the platelet count up – no idea why) For anti D
immunoglobulin (remember fetus +ve, mother –ve. Mother develops IgG antibodies against Rh.
Thus subsequent pregnancy – if Rh +ve then will cause destruction of blood in the fetus. Hence
give this to tx.)
Transfusion of RBC
400 RBC antigens. However ABO and rhesus = major clinical significance.
Naturally occurring antibodies: E.g Group O individual having anti A, B. You do not have
to be exposed.
These react primarily at 4 degrees an IgM
Immune antibodies = occur in response to introduction of antigens. (E.g rhesus disease).
Usually IgG and react optimally at 37. Only IgG antibodies can cross the placenta.
ABO system
Group O = anti A and B
Group A = Anti B
Group B = anti A
AB = no naturally occurring antibodies
Rh system
15% = rh –ve
Blood group and antibody screen
Blood group for ABO and RH D
Then you do an indirect coombs test for an antibody screen. You take the patients serum
and you combine it with screening red cells (NOT the donor blood) This blood has known
antigens (different antigens to the ABO). Then you add antihuman globulin (to see if there is
aggregation). If positive then can combine with other known antigens on RBC’s and by
repeating the test you can work out what the antigens are.
Cross match with patients serum against donor cells (using indirect coombs test) (Often
not done if the antibody screen is negative)
Complications of blood transfusion
Early complications
Haemolytic reactions (antibodies attack the red cells and the red cells are destroyed by IgM
(remember these are the natural antibodies) causing major anaphylaxis (this would occur if you
give someone the wrong blood group). Have intravascular haemolysis, anaphylaxis,
renal failure etc
Infection (e.g virus) (More likely in platelet transfusion as stored -at higher temperature)
Allergic reactions to other parts of blood (e.g platelets, proteins (now less common due to
leukodepletion of the blood. Originally done to reduce transmission of variant CJD which was
concentrated in white cells)
Fevers (due to action on plasma protein or HLA antibodies)
Circulatory overload (especially in elderly)
Thrombophlebitis (at the area you are giving it)
Citrate toxicity (citrate is in it to stop it anticoagulating). Hence if give lot of blood then can get
citrate toxicity
Hyperkalaemia (if lots of red cells die off then can release
Note that lots of these (e.g citrate toxicity, circulatory overload etc) are more common in children
(as less volume)
Clotting abnormalities (after very large transfusions – due to diluting clotting factors)
Delayed
This is much more common then the acute complication. This is due to antibodies against one of
the other antigens on the red cells. The antibodies coat the red cells, not destroyed in
circulation, but in reticuloendothelial system broken down.
May only happen over few days. Become a bit jaundiced, expected rise in haemoglobin doesn’t
happen.
Transmission of disease (esp hepatitis, CMV (common virus that many of us) have – important
in transplant patients as high risk of getting severe CMV
Hence give CMV products to CMV negative transplant patients
Immunosensitise (e.g give Rh+ve blood to Rh-ve mother)
For chronic blood transfusion:
E.g thalassaemias, myelodysplastic syndrome etc.
At risk of iron overload (makes sense, cant get rid of it)
Haemovigilance
Reduce the risks of transfusion
Only transfuse when necessary
Traceability (every blood product must be fully traceable to donor – so can trace back to what
went wrong)
Make sure that clerical error never occurs (as ABO mismatch can kill the patient). Thus strict
labelling.
Any serious blood transfusion effect has to be reported.
Emergency issue of pretransfusion testing blood (for emergencies – when patients
exhanguinating)
Group O Rh –ve
Management of severe transfusion reaction (If mild – e.g fever, rash) then can slow transfusion
down
If more severe then have to stop blood flow (could be anything e.g contamination with
bacteria, red cell reaction etc). Return to blood lab and take patients blood. See what the reaction is.