MRCP revision battle 38.1: Von Willebrands Disease

We're about to enter a 2 day fest of haematology.  Try to get through the dull battles of B and T cell disorders as the topics on the other side of them are slightly more stimulating.  Good luck!


MRCP revision battle 38.1: Von Willebrands Disease
MRCP revision battle 38.2: B cell disorders
MRCP revision battle 38.3: T cell disorders
MRCP revision battle 38.4: Combined B and T cell disorders
MRCP revision battle 38.5: Thrombotic thrombocytopenic purpura
MRCP revision battle 38.6: Microangiopathic haemolytic anaemia
MRCP revision battle 38.7: Sideroblastic anaemia




MRCP revision battle 38.1: Von Willebrands Disease


Von Willebrand's disease is the commonest inherited coagulopathy in the UK.


Von Willebrand's factor is a substance made in epithelial cells which:

• helps platelets bind to the exposed subendothelium
• helps platelets bind to each other
• binds to factor VIII,  helping prevent its destruction in the circulation

There are many types of Von Willebrand's disease.  The commonest 3 are:

• Type 1: decrease in Von Willebrand's factor 
• accounts for 80% of Von Willebrand Disease
• autosomal dominant
• Type 2: abnormal form of Von Willebrand's factor
• autosomal dominant
• Type 3: total lack of Von Willebrand's factor
• autosomal recessive

Symptoms/signs of Von Willebrand's disease include bruising, menorrhagia, epistaxis and increased bleeding after tooth extraction (a favourite in MRCP exams)


Diagnosis is by:

• low levels factor VIII
• low levels VWF antigen
• deficient ristocetin-induced platelet aggregation

Treatment is:

• DDVAP (=desmopressin) in mild disease
• factor VIII concentrate/cryoprecipitate in severe disease
• avoid NSAIDs.

Next up.... B cell disorders

MRCP revision battle 38.2: B cell disorders

B cells are lymphocytes involved in humoral immunity.  Their functions are:

• production of antibodies (=plasma B cells)
• memory of antigen (=memory cells, live for a long time and able to respond rapidly if body encounters same antigen again)
• antigen presenting cells

B cell disorders result in a failure of antibody synthesis, resulting in either hypogammaglobulinaemia or agammaglobulinaemia.  This causes recurrent infections with pyogenic bacteria and fungi.


Examples of B cell disorders include:


1. Common variable immunodeficiency

• commonest cause of hypogammaglobulinaemia
• not familial
• bone marrow shows a normal number of B cells but they fail to mature

2. IgA deficiency

• commonest isolated Ig in UK
• increased risk of giardiasis

3. Bruton's agammaglobulinaemia

• x-linked recessive
• no circulating B cells
• usually presents between 3 months and 2 yrs of age

Now on to the T cell disorders......

MRCP revision battle 38.3: T cell disorders

T cells are lymphocytes involved in cell-mediated immunity.  T cells mature in the thymus.

T cell disorders result in increased susceptibility to virus', mycobacteria and fungi.


Examples of T cell disorders include:




1. DiGeorge

• defect in development of thymus and 3rd/4th branchial arches
• mnemonic CATCH-22:
• cardiac abnormalities (tetralogy of fallot)
• abnormal faies
• thymic aplasmia --> lack of T cells
• cleft palate
• hypocalcaemia (due to absent parathyroids)
• 22 - recessive inheritance on chromosome 22

2. Nezelof syndrome

• absent thymus
• often some B cell involvement

3. Purine nucleoside phosphorylase deficiency

• prevents development of T cells

Onto the final battle of this dull triad - combined B and T cell disorders

MRCP revision battle 38.4: Combined B and T cell disorders

So having skated through B cell disorders and T cell disorders its on to combined disorders, the main 3 of which may be recalled as SCID WAS ATAXIC.


1. Severe Combined Immundeficiency

• autosomal recessive
• sometimes due to lack of adenosine deaminase

2. Wiskott-Aldrich Syndrome

• x-linked recessive
• characterised by recurrent infections, eczema and thrombocytopenia
• associated with an increased risk of maligancy

3. Ataxic telangiectasia

• autosomal recessive
• cerebellar ataxia and telangiectasia
• increased risk of malignancy
• low IgE and IgA

Lets now move back a bit more mainstream with thrombotic thrombocytopenic purpura...

MRCP revision battle 38.5: Thrombotic thrombocytopenic purpura

Thrombotic thrombocytopenic purpura is a condition in which large multimers of Von Willebrand's factor clump platelets together, activating the coagulation system, forming fibrin strands and causing microangiopathic haemolytic anaemia (MAHA).


The 5 key features are:

• Thrombocytopenia
• Fever
• Fluctating CNS signs (visual disturbance, fits, hemiparesis)
• MAHA
• Renal failure

Adult females are most commonly affected


The cause is often unknown.  Implicated factors include:

• drugs - clopidogrel, ciclosporin, COC
• pregnancy
• HIV
• SLE

 Treatment is:

• plasma exchange
• IV vincristine  (promotes premature release of platelets from marrow)
• steroids

Next up... more microangiopathic haemolytic anaemia...

MRCP revision battle 38.6: Microangiopathic haemolytic anaemia

Microangiopathic haemolytic anaemia (MAHA) is a nice condition to learn about as you can easily visualise it: it is mechanical disruption of red blood cells in the circulation, so in your mind's eye see the little RBC's being mangled by prosthetic heart valves or sliced by fibrin strands and then imagine them on the other side, reduced in number (anaemia), all with different amounts of haemoglobin in them after being sliced (polychromasia) and lots of partial fragments (schistocytes and helmet cells).


So to put that above paragraph into a nice list of haematological features of MAHA:

• anaemia
• polychromasia
• helmet cells
• schistocytes

Causes of MAHA include:

• DIC
• HUS
• TTP
• malignant hypertension
• severe pre-eclampsia
• prosthetic heart valves
• septocaemia

Now onwards to the last MRCP revision battle of the day, sideroblastic anaemia...

MRCP revision battle 38.7: Sideroblastic anaemia

Sideroblastic anaemia is a form of anaemia in which the body is not able to incorporate iron successfully in the haem molecule.


This results in:

• anaemia
• sideroblasts in bone marrow
• rarely haemosiderosis as the body keeps absorbing iron in its futile attempt to correct the anaemia (haemosiderosis may be revised in MRCP revision battle 28.1)

The image below from Wiki Commons shows ring sideroblasts:

Causes of sideroblastic anaemia include:

• congenital causes
• delta-aminolevulinate synthase deficiency
• x linked recessive, rare
• responds to pyridoxine
• acquired causes
• myelodysplasias
• alcohol
• lead
• chemotherapy
• anti-TB meds

Treatment is to treat the cause, supportive care and pyridoxine.

MRCP revision battle 37.1: TB

Today has a respiratory feel....


MRCP revision battle 37.1: TB
MRCP revision battle 37.2: DVT/PE in pregnancy
MRCP revision battle 37.3: Asthma
MRCP revision battle 37.4: Cor pulmonale
MRCP revision battle 37.5: alpha-1 antitrypsin deficiency
MRCP revision battle 37.6: Cystic fibrosis
MRCP revision battle 37.7: HPOA





MRCP revision battle 37.1: TB


TB is an infection caused by mycobacterium tuberculosis.  Primary infection is usually in the lungs (ghon focus, usually in the mid or lower zones).  Second favourite site for primary infection = GI, ileocaecal area.


Incidence =7000/yr in UK


Spread is by droplet infection. Household contacts have 1 in 4 chance of infection therefore contact tracing is very important and TB is a notifiable disease.


Primary TB is often symptomless. Although it may cause fever, sweats, anorexia, cough or erthyema nodosum.  If the immune system ‘wins’, the TB is walled off by calcification; however, the TB remains active in ~ 20% calcified areas and may be reactivated when immune system is weakened, eg steroids, diabetes, HIV.


Post-primary TB makes you ill – fever, malaise, weight loss, anorexia, tiredness, cough, haemoptysis, rarely night sweats.



 It can spread to:

• brain = meningeal TB
• spine = Potts fracture
• blood = miliary
• skin = lupus vulgaris

Diagnosis:
•    CXR
•    Sputum cultured/stained with Zielh-Nielsen – looking for acid-fast bacilli
•    Mantoux test of little help in the UK due to BCG

BCG = bacilli calmette-guerin – decreases risk of TB by 50%


Treatment: DOTS
•    2 months rifampicin, isoniazid, pyrazinamide and ethambutol (=RIPE)
•    then 4 months rifamicin and isoniazid
•    Pyridoxine throughout to protect against neuropathic effects of isoniazid



MRCP (and real life) side effects of TB meds to be aware of:

Rifampicin turns bodily excreations orange
Isoniazid and rifampicin cause cirrhosis – check LFTs
Pyrazinamide decreases urea excreation = risk of gout and CI in gout sufferers
Ethambutol can affect the optic nerve - check colour vision



On to DVT and PE in pregnancy...

MRCP revision battle 37.2: DVT/PE in pregnancy

It is one of those unfortunate situations: pregnancy makes DVT/PE more likely (increases risk around 6x), but the presence of a fetus also makes your preferred investigative tests more risky.


Risk is more increased if:

• >35 yrs
• higher parity
• raised BMI
• smoker
• sickle cell
• anaemic
• dehydration
• not blood group O

The consensus on management of ?PE in pregnancy seems to be:

• CXR in all cases
• compression doppler in all cases - if this shows DVT you can just treat without needing to investigate further

In terms of the next investigation if you clinically suspect PE but the doppler is normal there is a lack of consensus:

• CTPA delivers 10-30% less radiation to the fetus but
• V/Q scan causes less radiation to the maternal breast tissue

In general CTPA seems to 'win'



Note that d-dimer is usually 'normal' in the first trimester of pregnancy, rises in the second to third and then returns to baseline at 4-6 weeks post-partum.  However, it is generally not recommended as an investigation in pregnant women.



Treatment for DVT/PE in pregnancy is LMWH, continued for 6 months (with at least 6 weeks of anticoagulation post-partum)

For the really keen:

Patient plus article on DVT/PE in pregnancy

Next... MRCP revision battle 37.3...

MRCP revision battle 37.3: Asthma

Asthma is a condition characterised by periods of dyspnoea, cough and wheeze caused by reversible airways obstruction.


Asthma diagnosis

The table below (from the 2009 BTS/SIGN guidelines) lists the factors that increase or decrease the probability of the presentation being asthma:

If from history/examination you believe there is a:

• high probability the patient has asthma --> being a trial of treatment
• intermediate probability of asthma --> perform spirometry:
• FEV1/FVC <0.7 - trial asthma treatment
• FEV1/FVC >0.7 - refer to specialist

After a trial of treatment >400mls improvement in FEV1 or PEFR >15% is significant


In a peakflow diary, look for diurnal variation >25%


Treatment of asthma

Treatment of asthma follows a stepwise approach (BTS/SIGN guidelines):

1. Mild intermittent asthma
•  SABA (short-acting inhaled beta 2 agonist) PRN 
• salamol, salbutamol
2. Regular preventor therapy
• corticosteroid 200-800mcg per day
• beclometasone, fluticasone, budesonide
3. Initial add-on therapy
• LABA (long-acting inhaled beta 2 agonist (eg salmeterol))
• if this doesn't work, stop and trial an oral therapy such as leukotriene receptor antagonist or theophylline
4. Persistant poor control
• increase steroid inhaler up to 2000mcg per day
• add leukotriene receptor antagonist or theophylline
5. Continuous or frequent oral steroids

If stable for 3 months, consider stepping down a step.




Severity of asthma

In acute asthma attacks, severity may be graded as follows:

Severe:

• unable to complete sentences
• RR>25
• PEFR<50% predicted or best
• pulse >110

Life-threatening:

• silent chest
• PEFR <33% predicted or best
• bradycardia
• hypotension
• normal or raised CO2
• exhaustion

Management of acute severe asthma

Think 'O! sip Ma':

• high flow oxygen
• 5mg salbutamol neb
• 500mcg ipratropium neb
• 30mg prednisolone (or 100mg hydrocortisone IV)
• magnesium 1.2g and aminophylline if still not improving

And make sure ITU know if things aren't going well....


Now for a battle with cor pulmonale...

MRCP revision battle 37.4: Cor pulmonale

Cor pulmonale is right heart failure caused by chronic pulmonary hypertension

Normal pulmonary artery pressure = 15mmHg.

Pulmonary hypertension = pulmonary artery pressure >25mmHg at rest or >30mmHg on exercise

Causes of cor pulmonale include:

• lung disease - of which COPD is by far the commonest
• pulmonary vascular disease - PE
•  rib cage deformity

Presentation is:

• dyspnoea
• fatigue
• syncope

Signs:

• raised JVP, a and v waves
• RV heave
• loud P2
• pansystolic murmur - tricuspid regurgitation
• peripheral oedema
• hepatomegaly
• Graham Steell murmur = high-pitched early diastolic murmur, best heard 2nd left intercostal space with pt in full inspiration = pulmonary regurgitation

Investigations:

• CXR
• FBC - look for secondary polycythaemia
• ECG - R axis deviation, right ventricular hypertrophy

Management:

• treat cause
• treat symptoms
• ?heart-lung transplant

Next up: alpha-1 antitrypsin deficiency

MRCP revision battle 37.5: alpha-1 antitrypsin deficiency

alpha-1 antitrypsin is a serine protease inhibitor produced in the liver.


In the lung it prevents neutrophil elastase from breaking down the alveolar wall.
It is inactivated by cigarette smoke.


Genetic varients of alpha-1 antitrypsin exist and are labelled based on their electrophoresis mobility, with M (medium), S (slow) and Z (very slow).  MM is 'normal' while 'ZZ' has the worst prognosis with panlobular emphysema.


Patients with an alpha-1 antitrypsin defiency are likely to develop COPD early (even without smoking) and liver cirrhosis is common.



Now for a very straightforward battle - cystic fibrosis

MRCP revision battle 37.6: Cystic fibrosis

CF is an autosomal recessive genetic disorder which results in a mutation of CFTR, leading to Cl not leaving cells and so more Na and water entering, resulting in thick, sticky secreations.



The mutation is on chromosome 7.  70% are ΔF5O8


Incidence = 1/2000.  Carriers = 1/25


Presentation in neonates is failure to thrive, meconim ileus or rectal prolapse.
Later presentation tends to be recurrent respiratory infections, cough, wheeze, bronchiectasis.  85% have steatorrhoea.


Signs include:
-    cyanosis
-    clubbing
-    bilateral course crackles


Diagnosis is by pilocarpine sweat test.  Na/Cl>60mmol/l, usually Cl>Na.  CXR may show bronchietasis.  PCR can pick up 90% of mutations.  Faecal elastase is a good screening tool for exocrine pancreatic dysfunction.  Spirometry shows obstruction.


Treatment is MDT, physio, enzyme replacement, heart/lung transplant.


Complications include  

• diabetes (1/3) 
• gallstones
• cirrhosis
• OP
• male infertility (no vas deferens or epididimus)
• vasculitis
• nasal polyps (1/3) 
• HPOA (if you don't know what this is you will by the end of the next battle)
• infections
• s.aureus
• h.influenzae
• pseudomonas
• s.pneumoniae
• burkholderia cepacia (gram negative)
• aspergillos

It tends to be the upper lobes of the lungs that are damaged.




Mean age of death ~30.



So to the final battle of the day, HPOA...

MRCP revision battle 37.7: HPOA

HPOA = hypertrophic pulmonary osteoarthropathy is a paraneoplastic syndrome consisting of periostitis, arthritis and clubbing.



It is seen in around 50% of patients with mesothelioma.

Of the 'usual' lung cancers it is most commonly associated with adenocarcinomas and least commonly associated with small cell lung cancer.



Thats it for today

MRCP revision battle 36.1: Wilson's disease

Another set of battles written before commencing the joy of a 10 hour shift... and to think we all used to think revising for finals was hard!



MRCP revision battle 36.1: Wilson's disease
MRCP revision battle 36.2: Drugs causing impaired glucose tolerance
MRCP revision battle 36.3: Acromegaly
MRCP revision battle 36.4: Vitamin C
MRCP revision battle 36.5: Insulinoma
MRCP revision battle 36.6: Metabolic syndrome
MRCP revision battle 36.7: Phaeochromocytoma





MRCP revision battle 36.1: Wilson's disease


Wilson's disease is an autosomal recessive condition inherited on chromosome 13.
Approximately 1 in 400 people carry the gene, giving the disease an incidence of around 1 in 200 000


Wilson's disease is due to a mutation in the gene coding for a copper transporting ATPase, ATP7B.   This results in the failure of biliary copper excretion, causing raised urinary copper and raised tissue copper with accumulation of copper especially in the liver and basal ganglia.


Features include:

• liver disease - hepatitis, cirrhosis
• CNS  signs - tremor, ataxia, dementia, emotional lability
• hypoparathyroidism
• haemolysis
• Kayser-Fleischer rings - copper deposits in descemet's membrane - pathognomonic
• blue nails
• hypermobile joints
• arthritis

Diagnosis:

• low serum caeruloplasmin
• raised urinary copper

Treatment: penicillamine - remember this can cause low platelets and white cells so patients should be warned to report bruising/fever/sore throat to their doctor.


Note that the liver aspects of Wilson's tend to be reversible while the neuro problems have limited reversibility on treating.



Now on for a short battle about drugs causing impaired insulin tolerance...

MRCP revision battle 36.2: Drugs causing impaired glucose tolerance

Drugs associated with impaired glucose tolerance include:

• thiazide diuretics
• furosemide
• steroids
• tacrolimus
• ciclosporin
• IFN alpha
• nicotinic acid

I'm afraid I can't think of any clever way to remember this list... if anyone can think of one please email me... marietreasure7 followed by at gmail .com.


Next up: acromegaly

MRCP revision battle 36.3: Acromegaly

Acromegaly is caused by excess growth hormone.  99% of cases are due to a pituitary tumour.  5% of cases are associated with MEN 1 (now might be a good time to re-revise battle 20.1 which covers MEN...)


For the purposes of revision I'll divide features into 'classical' and 'MRCP smaller print'


Classical features:

• soft tissue growth
• large tongue
• large hands
• big ears
• coarsening facial features
• widening of gaps between teeth
• impaired glucose tolerance (40%)/diabetes (20%)
• raised blood pressure
• horse voice

MRCP features:

• raised phosphate
• raised triglycerides
• pseudogout
• colonic polyps
• proximal muscle weakness
• arthralgia

Diagnosis:

• failure of GH to decrease (to a lab-specific level) after oral glucose tolerance test
• false positives to this test may occur in puberty, pregnancy, DM, renal/liver impairment
• serum IGF-1 is a screening test only

Treatment:

• transphenoidal surgery (40-70% cure)
• ocreotide = somatostatin analogue
• bromocriptine (<20% effective)
• pegvisomant = GH receptor antagonist, conclusive data on effectiveness still awaited

Now for a little vitamin C....

MRCP revision battle 36.4: Vitamin C

Vitamin C is an antioxidant.  It is found in many fruits, vegetables and in liver. 


A deficiency in vitamin C leads to scruvy:

• gingivitis
• loose teeth
• malaise
• poor wound healing
• bleeding

Causes of deficiency include poor diet and pregnancy.


Now for another short battle, insulinoma...

MRCP revision battle 36.5: Insulinoma

Insulinoma is the commonest pancreatic endocrine tumour.

10% are malignant, 10% are multiple.
If multiple, 50% are associated with MEN-1.


Presentation tends to be with the symptoms of hypoglycaemia (revise battle 29.1 if you need to be reminded of these)


Diagnosis is by supervised prolonged fasting.


Treatment is surgical excision.



Onwards for a quick tour of metabolic syndrome...

MRCP revision battle 36.6: Metabolic syndrome

Metabolic syndrome (AKA syndrome X) is a combination of disorders that increase a patient's risk of cardiovascular disease/diabetes.



It is defined as:

• central obesity (= waist >94cm in europeans) OR BMI >30 
• PLUS 2 of the following 4:
• triglycerides >1.7
• low HDL
• BP >130/85
• fasting glucose >5.6 or type 2 DM

Metabolic syndrome is associated with:

• raised uric acid levels
• non-alcoholic fatty liver
• PCOS

Now for the final battle of the day, phaeochromocytoma...

MRCP revision battle 36.7: Phaeochromocytoma

Phaeochromocytomas are rare, catecholamine (=adrenaline, noradrenaline, dopamine ) producing tumours.


Presentations are variable and can include:

• headaches
• visual disturbances
• chest tightness
• palpitations
• hypertension (70% persistent, 30% episodic)
• hypotension/postural hypotension is also possible
• faints
• abdominal pain

The triad of headache, sweating and palpitations is 90% predictive.



Lots of facts to remember about phaeochromocytomas follow the rule of 10%:
10% are familial (= MEN II, neurofibrosis, Von Hippel Lindau)
10% are bilateral, 10% are malignant and10% are extraadrenal


The commonest extraadrenal site is the organ of Zuckerkandl, which is adjacent to the bifurcation of the aorta.



Diagnosis is by VMA in urine and CT/MRI (show up bright white on T2 weighted MRI)



Treatment is surgery with pre-op alpha and beta blockade (alpha blocker of choice = phenoxybenzamine)



Recurrence is possible so these patients should be followed up lifelong.



Thats all for today, hopefully more tomorrow!

MRCP revision battle 35.1: Graves' disease

Today is going to be a bit of a thyroid binge with a little gap to end on...


MRCP revision battle 35.1: Graves' disease
MRCP revision battle 35.2: Subacute (de Quervain's) thyroiditis
MRCP revision battle 35.3: Hashimoto's thyroiditis
MRCP revision battle 35.4: Drugs causing hypothyoidism
MRCP revision battle 35.5: Thyroid storm
MRCP revision battle 35.6: Anion gap




MRCP revision battle 35.1: Graves' disease


Graves' disease is an autoimmune condition which causes hyperthyroidism.  Autoantibodies against the thyroid gland are present.  This may be antithyroid peroxidase antibodies or antithyroglobulin antibodies (neither are specific as they may also found in Hashimotos)  or TSH receptor antibody (specific)


Features of Graves' disease include:

• eye disease (see revision battle 29.2 to recap which features are Graves' disease specific)
• pretibial myxoedema - only found in Graves
• thyroid acropachy = clubbing, painful toe and finger swelling - also only in Graves
• diffuse thyroid enlargement

Associated with Graves' disease include:

• diabetes 
• vitiligo
• Addisons

Treatment options for Graves are:

1. titrate antithyroid drugs
• start at 40mg carbimazole
• continue for 12-18 months
• less side effects
2. block and replace
• start at 40mg carbimazole, levothyroxine once euthyroid
• treat for 6 to 9 months
• more side effects
3. radioiodine

on to battle 35.2...

MRCP revision battle 35.2: Subacute (de Quervain's) thyroiditis

Subacute (de Quervain's) thyroiditis is the label given to a viral infection which causes a painful goitre and potentially transient hyper or hypo thyroidism.


In addition to a painful goitre the patient may have a fever and dysphagia.


Classically it occurs following a upper respiratory tract infection but it may occur after any viral illness (mumps, adenovirus) and also post-partum.


Histology would show multi-nucleated giant cells.
Radioiodine uptake is typically less than 1% at 24 hrs.


Treatment is with NSAIDs.  It resolves spontaneously.


Onwards to Hashimotos...

MRCP revision battle 35.3: Hashimoto's thyroiditis

Hashimoto's thyroiditis is an autoimmune condition causing hypothyroidism.


It is associated with high titres of antithyroid peroxidase antibodies or antithyroglobulin antibodies (neither are specific as they may also found in Graves' disease)


Patients with Hashimotos have a goitre due to lymphocytic and plasma cell infiltration.  The gotire is firm and non-tender.


Clinically patients' with Hashimotos may be hypothyroid, euthyroid or occasionally initially even hyperthyroid!



So lets move away from this autoimmune cause of hypothyroidism to look at drugs causing hypothyroidism...

MRCP revision battle 35.4: Drugs causing hypothyoidism

Drugs which can cause hypothyroidism include:

• lithium
• interferon
• amiodarone
• phenytoin
• aspirin
• oestrogens
• furosemide

 On  to the final bit of thyroid for the day: thyroid storm

MRCP revision battle 35.5: Thyroid storm

Thyroid storms may be precipitated by:

• recent thyroid surgery
• radioiodine
• infection
• MI
• trauma

Iatrogenic thyroxine excess doesn't usually cause a storm.


Features of a thyroid storm include:

• fever >38.5C
• tachycardia
• confusion
• nausea and vomiting
• hypertension
• heart failure

Treatment:

• treat precipitating event
• propranolol
• antithyroid drugs eg propylthiouracil or carbimazole
• dexamethasone/hydrocortisone - blocks T4 to T3 
• Lugol's solution
• ?digoxin to slow heart.

Thats the end of the thyroid binge - now to 'mind the gap..'

MRCP revision battle 35.6: Anion gap

If you have a patient with metabolic acidosis you need to calculate their anion gap.  This is very simple to do, so long as you can remember the following formula (which unfortunately I never can):

Anion gap = (Na + K) - (Cl + HCO3)

A 'normal' anion gap is 10 to 18mmol/l (which can be recalled as roughly the ages you attend secondary school for)


Causes of a raised anion gap may be recalled as LUKES:

• lactic acid (shock, infection, hypoxia)
• urate (renal failure)
• ketones (diabetes, alcohol)
• ethylene glycol/methanol
• salicylate

A more comprehensive list can be recalled by 'cute dimples' = cyanide, urate, toulene, ethylene glycol, diabetic ketoacidosis, isoniazid, methanol, propylene glycol, lactic acid, salicylates




Causes of a metabolic acidosis with a normal anion gap can be recalled as FUSEDCARS:

• fistula (pancreatic)
• uretogastric conduits
• saline administration
• endocrine (hyperparathyroidism)
• diarrhoea
• carbonic anhydrase inhibitors (acetazolamide)
• ammonium chloride
• renal tubular acidosis
• spironolactone

Hopefully thats demystified the anion gap for you.

MRCP revision battle 34.1: The first heart sound

I've just had a whole week off revising.  Very bad from a passing MRCP point of view.  Very good from a remaining sane, keeping friends and staying up-to-date with all the other bits of paper medicine in the UK requires.  Since the exam is now under a month away however I'd better buckle down to it...


MRCP revision battle 34.1: The first heart sound
MRCP revision battle 34.2: The second heart sound
MRCP revision battle 34.3: The third and fourth heart sounds
MRCP revision battle 34.4: Sodium Valproate
MRCP revision battle 34.5: Salicylate overdose
MRCP revision battle 34.6: Haemodialysis in overdose
MRCP revision battle 34.7: Cyanide poisoning
MRCP revision battle 34.8: Phentolamine





MRCP revision battle 34.1: The first heart sound



The first heart sound is made by the closure of the mitral and tricuspid valves.



A loud S1 may be due to:

• mitral stenosis
• hyperdynamic states
• short PR

A soft S1 may be due to:

• long PR
• mitral regurgitation

A    s p l i t  S1 is caused by:

• RBBB
• LBBB
• VT 
• inspiration
• Ebsteins abnormality

A variable S1 is caused by:

• complete heart block
• AF

On to the second heart sound....

MRCP revision battle 34.2: The second heart sound

The second heart sound comprises of the closure of the aortic and pulmonary valves.They usually close <0.05secs apart and in alphabetical order, with the aortic valve closing first.



A loud S2 may be due to:

• systemic hypertension (=loud A2)
• pulmonary hypertension (=loud P2)
• tachycardia

A soft S2 may be due to aortic stenosis.



A  w i d e l y   s p l i t  second heart sound occurs in:

• RBBB
• deep inspiration
• mitral regurgitation
• pulmonary stenosis

A reverse split (=paradoxical split) second heart sound occurs in:

• LBBB
• severe aortic stenosis
• right ventricular pacing
• WPW type 2
• patent ductus arteriosus

Onwards for the third and fourth heart sounds...

MRCP revision battle 34.3: The third and fourth heart sounds

Third heart sound

Third heart sound, AKA gallop rhythm, can be perfectly normal in children and young adults.

It is due to passive filling of the ventricles when the atrioventricular valves open.


In the over 40s it is pathological and may indicate:

• mitral regurgitation
• VSD
• CCF
• constrictive pericarditis

S1          S2  S3

The sound of the 3rd heart sound may be remembered as 'Kentucky' or 'SLOSH-ing in'




Fourth heart sound

A 4th heart sound is caused by atrial contraction against stiff ventricles.

It occurs in:

• aortic stenosis
• HOCM
• hypertension

S4  S1     S2

It can be remembered as 'Tennessee' or  'a STIFF wall'




I thoroughly recommend this website to listen to them http://www.wilkes.med.ucla.edu/Rubintro.htm



Now away from cardiology and to a bit of pharmacology - sodium valproate....

MRCP revision battle 34.4: Sodium valproate

Sodium valproate is a drug used in epilepsy.


It is a P450 inhibitor.


It has the highest risk of birth defects of any of the anti-epileptic drugs.


Sodium valproate also has an impressive plethora of unfortunate side effects which often appear in MRCP questions:

• alopecia
• nausea
• gynaecomastia
• weight gain
• tremor
• hepatitis
• pancreatitis
• tetratrogenic
• ataxia
• thrombocytopenia

As always with long lists of side effects its probable best to try and imprint on your mind a cartoon image of an unfortunate patient who is suffering from all of these side effects.   Personally I have a bald man who has big breasts and a fat, pregnant stomach, who is walking along in an ataxic way, covered in bruises (from his thrombocytopenia and crashing into things with his ataxic gait) while also vomiting and pointing with his trembling fingers to his liver and pancreas.



On that pretty image, lets move on to battle 33.5...

MRCP revision battle 34.5: Salicylate overdose

Patients who have taken a salicylate overdose are potentially more interesting than those who have taken a paracetamol overdose as salicylate poisoning actually has early clinical features you can look out for,  such as:

• sweating
• tinnitus
• dizziness
• pyrexia
• hyperventilation

A blood gas should show a mixed respiratory alkalosis and metabolic acidosis, and potentially a low potassium.


The sweating and pyrexia are due to uncoupling of oxidative phosphorylation.




The effects of salicylate are dose related:

• 150mg/kg: mild
• 250mg/kg: moderate
• >500mg/kg: severe

Later features of salicylate poisoning include:

• renal failure
• hypo or hyperglycaemia
• seizures
• acidosis

Treatment:

• activated charcoal if within 1 hr
• correct acidosis with 1.26% sodium bicarb
• haemodialysis if:
• conc >700mg/l
• metabolic acidosis resistant to treatment
• acute renal failure
• pulmonary oedema
• seizures
• urinary alkalinization is rarely used and is contra-indicated in cerebral or pulmonary oedema

Lets move on to consider use of haemodialysis in overdoses in general...

MRCP revision battle 34.6: Haemodialysis in overdose

Haemodialysis is not helpful in removing a drug if:

• the drug has a large volume of distribution (eg amiodarone, paraquat)
• the drug is highly protein-bound (digoxin, phenytoin)

The drugs that are appropriate for haemodialysis can be remembered as BLAST:

• Barbituates
• Lithium
• Alcohol (methanol/ethanol)
• Salicylate
• Theophylline

Charcoal haemoperfusion may be considered for:

• paracetamol
• theophylline

Now for a touch of cyanide poisoning....

MRCP revision battle 34.7: Cyanide poisoning

Cyanide is used in insecticides, photography and found in some metals.


It's toxicity comes from inhibition of oxidising enzymes, which happily is reversible.


The classical features of cyanide poisoning are:

• brick red skin
• smell of bitter almonds

Acute signs of cyanide poisoning include:

• hypotension
• hypoxia
• headache
• confusion

Chronic signs of cyanide poisoning include:

• ataxia
• peripheral neuropathy
• dermatitis

Treatment is with 100% oxygen and IV dicolbalt edetate



Onwards for a very brief final battle of the day: phentolamine

MRCP revision battle 34.8: Phentolamine

Phentolamine is a non-selective alpha-antagonist.

Its main action is vasodilation due to alpha-1 blockade.



In the context of MRCP the most important snippet to remember is that phentolamine is used to treat adrenaline-induced ischaemia (eg idiot houseofficer uses lidocaine with adrenaline in ring block, what ya gonna do? or clumsy dentist stabs little finger with his anaesthetic needle and its going blue, how will you treat it?)


In a broader context it can also be helpful in hypertension due to phaeochromocytoma or cocaine.



Thats all for today, more tomorrow!

MRCP revision battle 33.1: Myeloma

So today is going to be a galavant through the world of paraproteinaemias, taking in 4 of the top 6 causes (myeloma, Waldenstrom's, MGUS and amyloid; lymphoma/leukaemia related are not discussed, nor is heavy chain disease)

While on the topic of paraproteinaemia is seems appropriate to cover hyperviscosity syndrome, which lends itself to a quick forray into polycythaemia and then on to two completely random topics to round off the day.

Enjoy!


MRCP revision battle 33.1: Myeloma
MRCP revision battle 33.2: Hyperviscosity syndrome

MRCP revision battle 33.3: Waldenstrom's macroglobulinaemia
MRCP revision battle 33.4: MGUS
MRCP revision battle 33.5: Amyloidosis
MRCP revision battle 33.6: Polycythaemia
MRCP revision battle 33.7: Levels of evidence
MRCP revision battle 33.8: Holmes Adie pupil



MRCP revision battle 33.1: Myeloma


Myeloma is a malignant monoclonal proliferation of plasma cells.
The commonest subclass is IgG (IgG>IgA>IgM)



Symptoms:

• osteolytic bone lesions --> backache/pathological fractures
• symptoms of hypercalcaemia
• bacterial infections due to immunoparesis
• renal impairment due to light chains

Investigations:

• Bloods:
• normocytic normochromic anaemia
• rouleaux on blood film
• raised calcium (40%)
• raised urea and creatinine
• raised ESR
• Urine
• Bence Jones proteins (=free serum light chains) in urine (66%)
• XR
• ?pepper pot skull, vertebral collapse

The diagnostic criteria for myeloma is:

1. monoclonal protein band in serum or urine electrophoresis
2. increased plasma cells on BM biopsy
3. evidence of end organ damage from myeloma

Treatment:

• supportive
• chemo
• younger patients: aggressive (VAD - vincristine, adriamycin, dexamethasone)
• older patients: less aggressive (CDT - cyclophosphamide, dexamethasone, thalidomide)

Complications of myeloma include:

• Hyperviscosity syndrome
• Hyperviscosity syndrome occurs most commonly in IgM myeloma (IgM>IgA>IgG)
• Transfusions should be avoided in hyperviscosity syndrome.
• hypercalcaemia
• spinal cord compression
• acute renal failure
• AL amyloidosis (15%)

Survival with myeloma tends to be 3-4 yrs. 
Higher beta 2 microglobulin implies a worse prognosis.



Onwards for a bit more about hyperviscosity syndrome....

MRCP revision battle 33.2: Hyperviscosity syndrome

Hyperviscosity syndrome is a condition in which the viscosity (='stickiness') of the blood has increased to a degree which prevents easy flow through the microcirculation.



This causes symptoms such as:

• lethargy
• confusion
• headache
• visual disturbances
• spontaneous bleeding

The visual disturbance is described as 'looking through a watery car windscreen'
The optic disc may occur blurred.



Normal plasma viscosity is 1.4-1.8.  Hyperviscosity syndrome develops above around 4.



Causes of hyperviscosity syndrome include:

• myeloma
• Waldenstroms macroglobulinaemia
• leukaemias
• polycythaemia

Treatment depends on the cause; in myeloma/waldenstroms the patient needs plasmaphersis whereas in polycythaemia the treatment is venesection.



So now seems a good time to battle Waldenstrom's macroglobulinaemia...

MRCP revision battle 33.3: Waldenstrom's macroglobulinaemia

Waldenstrom's macroglobulinaemia, AKA lymphoplasmacytoid lymphoma, is a condition in which monoclonal proliferation of terminally differentiated lymphocytes results in a monoclonal IgM paraprotein.

The significance of this is that IgM carries a high risk of hyperviscosity syndrome.



Treatment for Waldenstom's:

• none if asymptomatic
• plasmapheresis if hyperviscosity
• ? chemo

On to another paraproteinaemia, MGUS...

MRCP revision battle 33.4: MGUS

MGUS stands for monoclonal gammopathy of undetermined significance.
As the name suggests, it is a low-level paraproteinaemia of unknown relevance.

It is common, affecting around 3% of those over 70 yrs of age.


For MGUS to be diagnosed the following diagnostic criteria must be met:

1. low level paraprotein (<30g/l)
2. less than 10% plasma cells on BM
3. no clinical evidence of myeloma.

Around 10% have myeloma at 5yrs so management tends to be yearly observation.


On to amyloidosis...

MRCP revision battle 33.5: Amyloidosis

coming soon....


for now skip on to polycythaemia..

MRCP revision battle 33.6: Polycythaemia

Polycythaemia is a raised red cell count and haemocrit, defined as >0.52 in males or >0.48 in females.


The first thing to establish is if the polycythaemis is 'true/absolute' or 'relative/pseudo'.



Relative/pseudo polycythaemia occurs due to decreased plasma volume.  This may occur due to dehydration (eg vomiting, diarrhoea, diuretics)

A special form of relative polycythaemia is Gaisbocks.  This tends to affect middle-aged men and is attributed to stress (hypertension, smoking, mild obesity) causing a chronically reduced plasma volume.




True/absolute polycythaemis is due to raised red cell mass.
It can be further divided into primary true polycythaemia and secondary true polycythaemia.





Primary true polycythaemia = polycythaemia rubra vera


Polycythaemia rubra vera is associated with JAK2 mutation in 95% of cases.

It peaks in the 6th decade.


Features include:

• hyperviscosity-syndrome symptoms
• pruritis, especially after a hot bath
• splenomegaly
• plethoric features
• hypertension in 1/3
• haemorrhage secondary to abnormal platelets
• DVTs/arterial thrombosis
• peptic ulceration
• gout

WCC/platelets/neutrophil alkaline phosphatase are raised; this helps distinguish primary from secondary polycythaemia.




Secondary polycythaemia 


Secondary polycythaemia is due to raised erythropoietin.

Causes:

• physiological - neonates, high altitude
• congenital cyanotic heart disease
• smoking/COPD
• HbM
• renal cysts
• post renal transplant
• fibroids
• hepatoma

Management of true polycthaemia is:

• venesection
• hydroxyurea to supress erythropoesis
• aspirin

Now for something completely different - levels of evidence...

MRCP revision battle 33.7: Levels of evidence

In this age of evidence-based medicine there is a scale to judge how "good" the evidence is:






Ia: metaanalysis of RCT
Ib: RCT


IIa: controlled trial
IIb: experimental trial


III: case series, case-control studies


IV: 'expert' opinions



Remember these because the odd MRCP question asks you what level of evidence a particular study is providing.


To the final MRCP revision battle of the day...

MRCP revision battle 33.8: Holmes Adie pupil

Holmes-Adie pupil is a dilated (myotonic) pupil.


It is a benign condition.

Females (70%) > males (20%)
Unilateral in 80% of cases


A Holmes-Adie pupil is sluggish to accomodate and reacts poorly, if at all, to light.



If a Holmes-Adie pupil is associated with absent leg reflexes it is known as Holmes-Adie Syndrome.





Since that was such a short battle lets just throw in a quick recap of the diferentials for a dilated pupil:

• third nerve palsy
• drugs
• antidepressants
• amphetamines
• atropine
• tropicamide
• Holmes-Adie
• trauma - sphincter pupillae rupture

MRCP revision battle 32.1: Deafness: Rinnes and Webers

Final day in the hat trick of eyes and neurology battles...


MRCP revision battle 32.1: Deafness: Rinnes and Webers
MRCP revision battle 32.2: Tinnitus
MRCP revision battle 32.3: TIA
MRCP revision battle 32.4: Epilepsy
MRCP revision battle 32.5: Macular degeneration
MRCP revision battle 32.6: Glaucoma
MRCP revision battle 32.7: Autonomic neuropathy



MRCP revision battle 32.1: Deafness: Rinnes and Webers

Hearing loss and Rinne and Weber's tests are MRCP favourites.


Remember there are 2 types of deafness:

• conductive deafness
• ear wax
• otosclerosis
• otitis media
• glue ear
• sensorineural deafness
• acoustic neuroma
• Pagets
• MS
• CVA
• Menieres
• head trauma
• noise exposure
• drugs
• aminoglycosides (gentamycin)
• furosemide
• lead

Tests are done with a 256- 512 Hz tuning fork





Rinne's test:

• hold vibrating tuning fork next to ear meatus, then place on mastoid
• ask which is louder
• air conduction (AC) > bone conduction (BC) = normal, or, if hearing is decreased, suggests sensorineural loss
• BC>AC = conductive deafness = Rinne negative
• Remember as: ALS (like the course) - air loudest: sensorineural.  

Weber's test:

• hold vibrating tuning fork on forehead
• ask which side it is heard loudest in
• in sensorineural loss it laterals to the unaffected side
• in conductive loss it laterals to the affected side
• midline if normal, or bilateral sensorineural loss
• Remember as: SUCA - sensorineural unaffected, conductive affected.

Next up - a spot of tinnitus...

MRCP revision battle 32.2: Tinnitus

Tinnitus is ringing/buzzing in ears.


Causes include:

• eax
• viral infections
• presbyacusis
• head injury
• Menieres
• drugs
• aspirin
• furosemide
• gentamycin

Pulsatile tinnitus may indicate carotid artery stenosis or dissection



Now on to the meatier topic of TIAs...

MRCP revision battle 32.4: Epilepsy

Epilepsy is defined as a recurrent tendency to spontaneous, intermittent, abnormal electrical activity in part of the brain, manifest as seizures (OHCM definition)



Epileptic seizures are subdivided into:

• partial seizures = features come from one part of the brain
• simple partial = consciousness not impaired
• complex partial = consciousness impaired - usually temporal lobe, aura may preceed and automatisms may feature
• generalised seizures = features not localisable to one part of the brain
• absence = petit mal = brief <10 second pauses - 3Hz spikes
• atonic = becomes flaccid
• tonic-clonic - classic stiffening and jerking
• myoclonic

Treatment is usually started after the second seizure.   It would be started after the first if any of the following conditions apply:

• neurological deficit
• structural abnormality
• EEG unequivocal
• pt/family/carers keen for treatment

First line treatment depends on the seizure type:

• generalised
• 1st line: sodium valproate
• 2nd line: lamotrigine
• partial
• 1st line: carbamezepine
• 2nd line: sodium valproate
• absence
• sodium valproate or ethosuximide
• note that carbamazepine may worsen absence seizures

Remember that both sodium valproate and lamotrigine are associated with Steven Johnson syndrome.




Cannot drive until seizure-free for 1 yr, or 3 yrs of night time only seizures.
HGV drivers need to be off meds and seizure-free for 10 yrs.



If a pt has no seizures for 2 yrs, you may consider stopping meds over 2-3 months.


On to battle 32.5...

MRCP revision battle 32.3: TIA

TIA (=transient ischaemic attack) = sudden onset of focal CNS phenomena which last <24 hours.  Caused by temporary occlusion of part of the cerebral circulation.



Causes of TIAs:

• thromboembolism
• chiefly from carotids
• may be from heart - AF, mural thrombus etc)
• hyperviscosity
• myeloma
• polycythaemia
• sickle cells
• very high white cells

Management depends on the ABCD2 score, which is calculated as shown below:

• age >60 : 1 point
• BP greater or equal to 140/90 : 1 point
• clinically:
• unilateral weakness : 2 points
• speech disturbance without weakness : 1 point
• duration
• >60 mins : 2 points
• 10 - 59 mins : 1 point
• diabetes : 1 point

ABCD2 score of 4 or more, or crescendo TIAs (=2 or more in one week):

• specialist review within 24 hrs
• start 300mg aspirin OD

ABCD2 score of 3 or below, or symptoms >1 week ago:

• specialist review within a week
• start 300mg aspirin od

After specialist review, usually 75mg aspirin OD and dipyridamol OD for 2 yrs.
If pt is aspirin intolerant, prescribe monotherapy of clopidogrel.




If assessed to be a candidate for carotid endarterectomy, imaging should be performed within 1 week of symptom onset and if carotid stenosis of:

• 50–99% according to NASCET criteria, or 
• 70–99% according to ECST criteria 

carotid endarterectomy should be performed within 2 weeks of symptom onset.



Remember pt must inform DVLA and no driving for 1 month (car) or 1 yr (lorry).  This increases to 3 months for car if multiple TIAs.



Of course other risk factors (hypertension, alcohol, smoking, etc etc etc) should also be addressed.




Differentials for TIA may include:

• migraine
• epilepsy
• hypoglycaemia
• malignant hypertension 
• MS

Lets move on to tackle epilepsy...

MRCP revision battle 32.5: Macular degeneration

Macular degeneration is the commonest cause of blindness in the UK.


There are 2 types:

• dry 
• drusen - yellow spots in Bruchs membrane
• wet
• choroidal neovascularisation
• worse prognosis

Below is an image of dry macular degeneration showing drusen.  To link to an image of wet macular degeneration click here

Risk factors for macular degeneration are:

• age >60
• female
• smoking
• caucasian
• family history

Treatment - there is no cure:

• high dose beta caratene - but may increase risk of lung cancer in smokers
• vitamin C and E - but vit E may increase risk of heart failure
• zinc
• for wet:
• photocoagulation
• anti VEGF
• Ranibizumab
• photodynamic therapy

Keeping on eyes, next up is glaucoma...

MRCP revision battle 32.6: Glaucoma

Glaucoma is damage to the optic nerve, generally due to increase in intra-ocular pressure.


There are 2 types of glaucoma:

1. acute = closed angle glaucoma
2. chronic = open angle glaucoma

Acute closed angle glaucoma

Acute closed angle glaucoma presents as:

• pain
• decreased visual acuity
• worsening of pain with mydriasis
• hard, red eye
• halos around lights
• semi-dilated, non-reactive pupil
• pt systemically unwell

Risk factors for closed angle glaucoma include hypermetropia and pupillary dilation.


Management is:

• urgent opthalmic review
• IV acetazolamide (a carbonic anhydrase inhibitor; decreases aqueous secretions)
• topical pilocarpine (constricts pupil)

Open angle glaucoma


This affects 2% of over 40s.


Risk factors include:

• family history
• black
• myopia
• hypertension
• diabetes

Features include:

• peripheral field loss
• decreased visual acuity
• optic disc cupping

Treatments include:

• eye drops (beta blockers or prostaglandins)
• possibly surgery.

Now to our final battle of the day, autonomic neuropathy

MRCP revision battle 32.7: Autonomic neuropathy

Autonomic neuropathy is characterised by:

• postural hypotension
• erectile dysfunction
• constipation or diarrhoea
• urinary retention
• inability to sweat
• loss of decreased heart rate on deep breathing
• Horners
• Holmes-Adie pupil

Causes:

• endocrine
• diabetes
• infective
• HIV
• syphilis
• leprosy
• autoimmune
• SLE
• other
• GBS
• MSA
• parkinson's disease
• liver/renal failure.

Treatment is symptomatic; remember fludrocortisone as an option for severe postural hypotension.


On that list-intensive battle lets retire for the day.

MRCP revision battle 31.1: Wernicke's Encephalopathy

Day 2 of 3 for lots of neuro...


MRCP revision battle 31.1: Wernicke's Encephalopathy
MRCP revision battle 31.2: Korsakoff's Syndrome
MRCP revision battle 31.3: Multiple Sclerosis
MRCP revision battle 31.4: Menieres Disease
MRCP revision battle 31.5: CJD
MRCP revision battle 31.6: Herpes Zoster Opthalmicus
MRCP revision battle 31.7: Ramsey Hunt Syndrome




MRCP revision battle 31.1: Wernicke's Encephalopathy


Wernicke's encephalopathy is caused by thiamine (=vitamin B1) deficiency.


The classic triad associated with Wernicke's encephalopathy is:

• opthalmoplegia
• ataxia
• confusion

There may also be hypothermia and hypotension.


Thiamine deficiency may result from:

• alcoholism
• carcinoma of stomach
• anorexia
• vomiting

CT brain may show petichial haemorrhages and a low red cell transketolase blood test could prove thiamine deficiency (rarely performed)


Treatment is parenteral thiamine (pabrinex)

If untreated, 20% of patients will die and 85% will develop Korsakoffs.


Which leads us nicely into revision battle 31.2: Korsakoffs syndrome....

MRCP revision battle 31.2: Korsakoff's Syndrome

Korsakoff's Syndrome is a condition in which there is an inability to build new memories but preservation of other cognitive functions.


It is a chronic disorder, usually following Wernicke's encephalopathy.


The patient has an inability to consolidate new info, retrograde amnesia, patchy preservation of long term memory, a lack of insight and confabulates (=fabricates information to make up for memory loss)


Treatment is with thiamine but under 20% of patients respond.


On to 31.3... MS...

MRCP revision battle 31.3: Multiple Sclerosis

Multiple sclerosis is a cell-mediated autoimmune disorder characterised by plaques of demyelination at sites throughout the CNS but not in the peripheral nerves.


4 main types:

1. relapsing-remitting
• accounts for 80% of cases
2. secondary progressive
• up to 50% of relapsing-remitting patients eventually develop this
3. primary progressive
• 10-15% of cases
• older age of onset
4. progressive-relapsing

Initial presentation tends to be a single symptom, such as:

• optic neuritis 
• pain on eye movement and rapid deterioration in central vision, loss of colour vision
• treatment is methylpred
• single episode gives 40-60% chance of subsquent MS
• numbness or tingling in limbs
• leg weakness
• ataxia

Diagnosis is by (NB none is specific):

• lesions disseminated in time and location
• T2 weighted MRI showing demyelinating plaques
• delayed visual evoked response potentials
• oligoclonal bands in CSF but not serum

Good prognostic factors are:

• relapsing-remitting course
• female
• young onset
• sensory symptoms

Risk of MS is increased 20-40% in siblings and there is 25% concordance in monozygotic twins.



Treatment is:

• IV methylprednisolone
• shortens relapses
• no effect on incidence of attacks
• beta interferon
• decreases relapses by 30%
• given if
• relapsing-remitting course and 2 relapses in 2 yrs and can walk 100m unaided
• secondary progressive and 2 relapses in 2 yrs and 100m aided
• side effect: flu-like
• baclofen
• decreases spascity

Now for the less heavy-going Menieres disease...

MRCP revision battle 31.4: Meniere's Disease

Meniere's Disease is a disorder of the inner ear causing vertigo and hearing loss.


Features include:

• vertigo
• tinnitus
• sesorineural hearing loss
• aural fullness

There may be nystagmus and a positive romberg's test


It is usually unilateral and is believed to be associated with endolymphatic hydrops (=increased fluid in ear)


Rarely it may be associated with drop attacks - no LOC or vertigo, but suddenly falling to one side.


Management:

• prochlorperazine
• inform DVLA and stop driving until controlled.

 Next up: that formally very topical topic CJD...

MRCP revision battle 31.5: CJD

Creutzfeldt-Jakob Disease (=CJD) is a prion disease which causes a rapidly progressive dementia with myoclonus.



The majority of cases are sporadic.  There is also an inherited form and an acquired form (=varient CJD, from meat infected with BSE)


CSF examination is usually normal but EEG shows characteristic biphasic high-amplitude sharp waves.


Death is usually within 6 months.


On a lighter note lets look at herpes zoster opthalmicus...

MRCP revision battle 31.6: Herpes Zoster Opthalmicus

Herpes zoster opthalmicus is the reactivation of varicella zoster in the area supplied by the opthalmic division of the trigeminal nerve.


It occurs in roughly 10% of cases of shingles.


There may be Hutchinson's sign = rash on the tip of nose, which indicates nasocillary involvement and is a strong risk factor for ocular involvement.


Treatment is oral antivirals for 7 to 10 days and urgent opthalmic review if there is ocular involvement.



On to the final revision battle of the day...

MRCP revision battle 31.7: Ramsey Hunt Syndrome

Ramsey Hunt Syndrome is the reactivation of varicella zoster in the geniculate ganglion of the facial nerve.  


It is characterised by:

• herpes zoster oticus (=herpetic eruption in external auditory meatus)
• facial nerve palsy
• +/- deafness, tinnitus and vertigo

Treatment is with oral antivirals

MRCP revision battle 30.1: Retinitis Pigmentosa

Today is the start of a 3 day neuro/opthalmology blitz, so hold on to your hats....


MRCP revision battle 30.1: Retinitis Pigmentosa
MRCP revision battle 30.2: Oculogyric Crisis
MRCP revision battle 30.3: Myotonic Dystrophy
MRCP revision battle 30.4: Trinucleotide repeat disorders
MRCP revision battle 30.5: Huntington's Chorea
MRCP revision battle 30.6: Friedreich's ataxia
MRCP revision battle 30.7: Alzheimer's Disease




MRCP revision battle 30.1: Retinitis Pigmentosa

Retinitis pigmentosa is a type of progressive retinal dystrophy which eventually leads to blindness.

It has a very characteristic fundoscopic appearence with black mottling of the retina and a pale optic disc, as illustrated below in an image by Christian Hammel (from wiki commons):

It can be inherited in an autosomal dominant, autosomal recessive or X linked recessive fashion.



Night blindness is often the first sign.
Later comes funnel/tunnel vision.


It is associated with many conditions, including:

• Kearns Sayre (remember battle 15.1?)
• Ushers syndrome = retinitis pigmentosa with sensorineural deafness
• congenital toxoplasmosis

There is no cure for retinitis pigmentosa but progression of the disease can be slowed by vitamin A.



On to the second battle of the day...

MRCP revision battle 30.2: Oculogyric Crisis

The key features of an oculogyric crisis are restlessness and upward deviation of the eyes (although this only occurs in severe cases).


Oculogyric crises may be precipitated by a range of drugs including:

• neuroleptics
• metoclopramide/domperidone
• nifedipine
• TCA
• carbamazepine

Several clinical conditions can also cause oculogyric crises, for example:

• parkinsons disease
• post encephalitis
• bilateral thalmic infarction
• MS

Treatment is with procyclidine, an anticholinergic.


On to the next battle...

MRCP revision battle 30.3: Myotonic Dystrophy

Myotonic dystrophy is an autosomal dominant condition in which there is muscle weakness and myotonia.  It is a trinucleotide repeat disorder.

Onset tends to be in the 30s.


There are 2 types:


Dystrophia myotonica (=DM) 1

• 98% of cases
• more severe
• distal muscle weakness
• chromosome 19

Dystrophia myotonica 2:

• 2% of cases
• less severe
• proximal muscle weakness
• chromosome 3

Features associated with myotonic dystrophy include:

• long faces
• frontal baldness
• myotonia and weakness
• testicular/ovarian atrophy
• bilateral ptosis
• cateract
• cardiomyopathy
• diabetes
• miotic pupils 
• mildly decreased IQ

It is incurable but phenytoin can improve the myotonia.


Lets move on to consider an overview of trinucleotide repeat disorders

MRCP revision battle 30.4: Trinucleotide repeat disorders

Trinucleotide repeat disorders are conditions in which 3 nucleotides in the DNA are expanded.

The most 'famous' are:

• Huntingtons chorea (CAG) - covered in next battle
• Fragile X (CGG)
• Myotonic dystrophy (CTG) - covered in previous battle
• Friedreichs ataxia (GAA) - covered in battle 30.6

Two concepts to be born in mind for trinucleotide repeat disorders are:

Anticipation = the disease presents earlier and is worse in successive generations

Somatic instability = expansion increases as patient gets older


So lets briefly cover the most famous, Huntingtons...

MRCP revision battle 30.5: Huntington's Chorea

Huntington's chorea is an autosomal dominant condition due to CAG repeats.

It is carried on chromosome 4.


Symptoms tend to start in the 40s with a progression from chorea to irritability to dementia and death.


There is no cure.  The chorea may be treated with a dopamine antagonist such as tetrabenazine.



Note that Hunington's has complete penetrance so a child of a sufferer has a 50% chance of being affected.  Due to anticipation if they are affected they are also likely to develop symptoms earlier.



Next up: Friedreich's ataxia...

MRCP revision battle 30.6: Friedreich's ataxia

Friedreichs ataxia is an autosomal recessive trinucleotide repeat disorder (GAA)


It causes degeneration of nerve tracts resulting in cerebellar ataxia, dysarthria, nystagmus and dysdiadocholokinesis.


Muscles are weak, reflexes are depressed but plantars are upgoing.


There is often scoliosis and high arches of the feet.

Cardiomyopathy is another complication.


There is no cure.


Lets now try and forget all these incurable diseases with a touch of Alzheimer's...

MRCP revision battle 30.7: Alzheimer's Disease

Alzheimer's disease is the leading cause of dementia.  This battle aims to pick out a few juicy facts for MRCP; http://alzheimers.org.uk/ can provide more in-depth information if you are interested.


The earliest symptom of AD is typically forgetfulness.



5% of cases are autosomal dominant, with chromosomes 1, 14, 19 and 21 implimented.

After age, apoE4 (chromosome 19) is the most significant risk factor for AD.


Beta amyloid plaques and hyperphosphorylated tau protein tangles are found within neurones post-mortem.
The density of the tangles can correlate with the severity of the dementia.




Hippocampal atrophy is prominant.





Cholinesterase inhibitors such as donepezil, rivastigmine and galantamine are licensed for patients with a MMSE of between 10 and 20.

Memantine (an antiglutamatergic) may be useful in severe AD.



As Bugs Bunny would say, thhhhatttttts alll folllkkkksss.... until tomorrow!

MRCP revision battle 29.1: Hypoglycaemia

After nearly a week away I'm back with a bumper set of battles, the first of which is hypoglycaemia, which has been a recurring theme in both my patients and myself this week!  Enjoy!


MRCP revision battle 29.1: Hypoglycaemia
MRCP revision battle 29.2: Thyroid eye disease
MRCP revision battle 29.3: Hyperlipidaemia
MRCP revision battle 29.4: Lipid-lowering treatment
MRCP revision battle 29.5: Restless legs syndrome
MRCP revision battle 29.6: Histocytosis X
MRCP revision battle 29.7: Bartter's Syndrome
MRCP revision battle 29.8: Gitelman Syndrome
MRCP revision battle 29.9: Liddle's Syndrome




MRCP revision battle 29.1: Hypoglycaemia


Hypoglycaemia is defined as plasma glucose <3mmol/l.


In general in diabetics autonomic symptoms of hypoglycaemia (sweating, anxiety, tremor, palpitations) occur below 3.5mmol and neurological symptoms (confusion, drowsiness, seizures, coma) occur below 2.5mmol.

If a diabetic has frequent hypos they may become 'insensitive' and no longer experience symptoms before becoming unresponsive.  Symptoms may be 'restored' by carefully avoiding hypos for 3 months.


Causes of hypoglycaemia are easy to remember as it "IS PLAIN" to see...

• Insulin
• Sulphonyureas/other drugs
• Pituitary insufficiency
• Liver failure
• Addisons disease or alcohol
• Insulinoma
• Neoplasms eg retroperitoneal fibrosarcomas than secrete IGF

Take bloods for glucose, insulin, c-peptide and plasma ketones.
Normal/high insulin, no ketones: insulinoma, drugs
Insulin low, no ketones: non-pancreatic neoplasm
Insulin low, ketones high: alcohol, addissons, pituitary insufficiency.





Post-pradial hypoglycaemia can occur post-gastrectomy





Whipples Triad is a set of criteria which if fulfilled suggest a patient's symptoms are due to hypoglycaemia:

• symptoms suggestive of hypoglycaemia
• BM < or equal to 2.5
• symptoms relieved by food.

Treatment

I'm sure this is all old-hat to you all... get the pt to eat if they can, 1mg IM glucagon if they can't and no IV access (remember glucagon effects only last for 20 mins and may not work at all in alcoholics) and if IV is an option the 50mls of 50% glucose or the more modern 200mls of 10% (less abrasive to the veins)


Now for some TED time...

MRCP revision battle 29.2: Thyroid eye disease

Thyroid eye disease, referred to by its friends as 'TED', can occur in people who are hyperthyroid, hypothyroid or euthyroid.


Thyrotoxicosis from any cause can cause lid lag and lid retraction.


However, only Graves disease causes:

• periorbital oedema
• conjunctivial injection
• proptosis/exophthalmos
• opthalmoplegia/diplopia
• papilloedema

(as an aside, I've always been mystified by the difference between proptosis and exophthalmos.  Unfortunately it appears I'm not the only one as some sources suggest the difference is related to the degree of protrusion whilst others say exophthalmos is used if the aetiology is endocrine and proptosis is used if the aetiology is not endocrine...)



25-50% of patients with Grave's disease have TED.


Risk of TED is increased in smokers.


The danger of TED is optic nerve compression.  Symptoms/signs of optic nerve compression include:

• blurred vision/decrease VA
• decreased colour vision
• a relative afferent papillary defect

Treatment for TED is topical lubricants, steroids if severe and possibly even surgery.



Now for a horrid battle with hyperlipidaemia...

MRCP revision battle 29.3: Hyperlipidaemia

This battle is quickly going to get complex and aims only to be an MRCP-focused overview rather than a comprehensive discussion.  It is divided into 5 stages:

1. The basics
2. Hypercholesterolaemia
3. HDL - the good cholesterol
4. Hypertriglyceridaemia
5. Mixed

1. The Basics

Hyperlipidaemia = raised lipids.  Lipids come in 4 main 'flavours':

1. chylomicrons = carry triglyceride
2. LDL = mainly cholesterol (50%, 10% TG) = the 'bad' flavour
3. HDL = mainly phospholipid = the 'good' flavour, carry cholesterol back to the liver
4. VLDL = mainly triglyceride (60%, 20% cholesterol)

Signs:

• corneal arcus = grey-white ring around cornea
• xanthelasma = yellow collection of cholesterol under skin
• xanthomata = 'lumps' of cholesterol
• eruptive xanthomata = small yellow-orange papules that appear all over body
• lipaemia retinalis = 'creamy' appearence of blood vessels on fundoscopy

So lets look first at cholesterol and hypercholesterolaemia.




2. Hypercholesterolamia

a. Familial

• LDL receptor dysfunction
• cholesterol 7.5-16
• raised LDL
• tendon xanthomata, corneal arcus and xanthelasma
• heterozygous prevalance 1/500 --> MI in 40s
• homozygous --> MI in 20s
• Polygenic hypercholesterolaemia
• cholesterol 6.5-9
• raised LDL
• xanthelasma and corneal arcus

 b. Acquired

• nephrotic syndrome
• renal transplant
• cholestasis
• hypothyroidism

3.  HDL

HDL is 'good' cholesterol

It is higher in:

• thin people
• exercise
• oestrogens
• alcohol
• low triglycerides

It is lower in:

• obesity
• sedentary states
• post-puberty males
• smoking

4. Hypertriglyceridaemia

a. Familial

• failure to metabolise chylomicrcons
• features include:
• eruptive xanthomata
• lipaemia retinalis
• retinal vein thrombosis
• pancreatitis
• hepatosplenomegaly

b. Secondary

• diabetes
• obestiy
• alcohol
• chronic renal failure
• liver disease
• drugs such as thiazides, beta blockers or oestrogens

5. Mixed hyperlipidaemia

• Look for palar xanthomas and tuberous xanthomas

After that wordy and depressing battle, lets move on to treatment of hyperlipidaemia...

MRCP revision battle 29.4: Lipid-lowering treatment

NICE recommends that all those with a 10 yr cardiovascular risk of >20% should be offered lipid-lowering therapy.

1st line: 40mg simvastatin
Measure LFTs when starting, at 3 months and at 12 months.


In primary prevention there is no 'target' cholesterol
In secondary prevention the target is less than 4mmol/l cholesterol and less than 2mmol/l LDL



If statins are not tolerated consider:

• fibrates
• ezetimibe
• nicotinic acid

Mechanisms of action


Statins are HMG CoA reductase inhibitors.  They therefore work by decreasing the production of cholesterol in the liver.  The decreased production of cholesterol in the liver also results in the liver absorbing and processing more LDL, hence further reducing cholesterol.


Grapefruit juice decreases the metabolism of statins.  Patients on statins are therefore advised to avoid grapefruit juice as it would increase the risk of the rare side effect of rhabdomyolysis



Ezetimibe works by preventing intestinal absorption of cholesterol.



Fibrates are PPAR alpha receptor agonists.  They therefore increase clearance of VLDL and remnant particles and decrease TG secreation.

Fibrates and statins tend not to be used together due to increased risk of rhabdomyolysis.



Nicotinic acid (=vitamin B3) blocks breakdown of fats in adipose tissue. 
It can cause facial flushing.

For the really keen:

NICE lipid modification guide

After those heavy-going battles lets tackle something light - restless legs syndrome...