Medicine 2 Flashcards
Thrombophilia
= inherited / acquired coagulopathy predisposing to thrombosis (usually venous).
Causes of Inherited vs Acquired thrombophilia
INHERITED
- APC resistance / Factor V Leiden mutation
- Antithrombin III deficiency
- Prothrombin gene mutation
ACQUIRED:
APL syndrome
Indications for screening a patient for thrombophilia
- Arterial thrombosis <50
- Venous thrombosis <40 with no RFs
- Familial VTE
- Recurrent unexplained VTE
- Unusual site of thrombosis (e.g. mesenteric or portal vein thrombosis)
- Recurrent miscarriage (>3)
Thrombophilia- Ix
- FBC
- Clotting
- Fibrinogen concentration +/- APC resistance test
- Lupus anticoagulant / anti cardio-lipin antibodies
- Anti-thrombin and Protein C/S assays for deficiency
- Factor V Leiden mutation PCR (if APC resistance test positive)
- PCR for prothrombin gene mutation
Definition of anaemia
What can cause it ?
= decreased haemoglobin in the blood, such that there is inadequate oxygen delivery to tissues.
=> Hb <135 g/L in men; Hb <115 g/L in women.
Patients become anaemia when they are:
1. Not making enough RBCs
=> Reduced erythropoiesis (or haematopoiesis)
- Losing or breaking down RBCs too quickly.
=> Bleeding
=> Haemolysis
Anaemia - symptoms
Often asymptomatic => a slowly falling Hb allows for haemodynamic compensation.
Non-specific = Fatigue, weakness, headaches
CV = dyspnoea, intermittent claudication, palpitations
Anaemia - signs
GENERAL:
Pallor
Tachycardia
Systolic flow murmur
Cardiac Failure
SPECIFIC:
Koilonychia – IDA
Jaundice – haemolytic anaemia
Leg ulcers – often seen in sickle cell disease
Bone marrow expansion, leading to abnormal facial structure or pathological #s in thalassaemia
Transfusions in anaemia
Transfusion is generally not indicated if there is no acute bleed, and the patient is not symptomatic.
If the anaemia is severe and requires transfusion, beware of associated heart failure:
=> Transfusion should be given very slowly, alongside furosemide.
RBC Lifecycle
Erythropoiesis occurs in the bone marrow.
=> Stimulated by erythropoietin (EPO) produced by the kidneys.
Average RBC lifespan is 120 days.
The ageing RBC are removed from the circulation.
This process normally occurs at the same rate of production by erythropoiesis, balancing the total circulating red blood cell count hence patients have a stable Hb.
Microcytic anaemia - causes
Low Hb, Low MCV
Iron deficiency anaemia (IDA)
Thalassaemia
Lead poisoning
Sideroblastic anaemia (rare)
Normocytic anaemia - causes
Low Hb, normal MCV
Acute blood loss
Anaemia of chronic disease
Renal anaemia
Haemolytic anaemias (or macrocytic)
Marrow failure
Pregnancy
CTDs
Macrocytic anaemia - causes
Low Hb, High MCV
B12 deficiency
Folate deficiency
Alcohol Excess (or severe liver disease)
Myelodysplastic Syndromes
Severe hypothyroidism
Iron deficiency anaemia - causes
BLOOD LOSS UNTIL PROVEN OTHERWISE
Hookworm
Heavy menstruation
GI bleeds
DECREASED ABSORPTION
Coeliac disease
Patients on antacids (less ferric to ferrous iron conversion)
Post-gastrectomy
INCREASED DEMAND
Growth
Pregnancy
INADEQUATE INTAKE
Iron Deficiency Anaemia - Ix
- Clinical examination for signs of iron deficiency
- Koilonychia
- Angular stomatitis
- Brittle nails/hair - Blood Tests:
- Iron studies
- Blood film:
=> Microcytic anaemia is generally also hypochromic (pale on the blood film, representing MCH)
=> Film may show signs of sideroblasts/signs of thalassaemia
- Further tests:
=> If there is a good history of menorrhagia, start oral iron and only further Ix is coeliac serology.
=> In all other patients, without an obvious cause of bleeding:
- Check coeliac serology
- Refer for OGD and colonoscopy
- Stool microscopy is advised if recent foreign travel
What is measured in iron studies?
- Serum iron
- Serum ferritin
- Total Iron binding capacity
- Serum soluble transferrin receptors
Iron Deficiency Anaemia - Mx
Address the underlying cause as appropriate – e.g. menorrhagia, GI bleed, etc.
Lifestyle:
=> Advise increased dietary intake of dark green vegetables, fortified bread/cereals, lead red meat, prunes/raisins
Commence oral ferrous sulphate 200 mg t.d.s and before awaiting investigation results
=> Can start with b.d. as may be better tolerated
If ferrous sulphate is not tolerated, consider switching to ferrous gluconate.
Monitor for improvement in Sx and blood parameters after 1 month of Tx
SEs of ferrous sulphate
cramping, bloating, nausea, vomiting, constipation, black stools.
Adverse effects can be decreased if taken with meals
Can offer laxatives for constipation or dose reduction
How long should Tx with iron be continued in IDA?
Tx should be continued for 3 months after blood parameters return to normal, to replenish supplies.
Rule of 10 for anaemia
The maximum rise in Hb concentration is one week is 10 g/L
If more than 10 g/L decline is seen over a week, then blood is being lost.
When transfusing, one bag will raise the Hb concentration by 10 g/L
Anaemia of chronic disease
Can be microcytic or normocytic, therefore can be a differential for IDA.
Ix:
- Serum iron will be decreased
- TIBC will also be decreased
- STR – normal
- Ferritin will be raised
Plummer-Vinson Syndrome
A rare disease characterised by dysphagia, odynophagia, IDA, glossitis, chelitis and oesophageal webs.
Generally occurs in post-menopausal women
Tx:
=> Iron supplementation and mechanical widening of the oesophagus provides a good outcome.
What is thalassaemia?
= Genetic disorders of Hb synthesis
Common in the middle/far East
Caused by deficient alpha or beta chain synthesis, thus resulting in alpha- or beta- thalassaemia.
Beta-Thalassaemia
MINOR (“trait”)
- Carrier state
- Usually asymptomatic
- Gives a mild microcytic anaemia that may worsen in pregnancy
- HbA2 is raised, with slightly raised HbF also
MAJOR (“Cooley’s anaemia”)
- Abnormality in both globin genes
- Presenting within the first year with severe anaemia, hepatosplenomegaly and failure to thrive.
- Extramedullary haematopoiesis results in facial deformities.
- Survival is possible due to HbF
- Blood film – hypochromic microcytic cells, also target cells and nucleated RBCs
- Mx = lifelong blood transfusions
Alpha-thalassaemia
Bart’s hydrops:
- Deletion of all 4 alpha-globin genes
- This form of Hb is physiologically useless and leads to death in utero
Deletion of 3 genes:
- Moderate microcytic anaemia
- Features of haemolysis
Deletion of 2 genes:
- Asymptomatic carrier state, with reduced MCV
Deletion of 1 gene:
- Clinically normal
Anaemia screening before surgery
Anaemia is the most common abnormality seen in pre-op patients:
<60 g/L will require transfusion
<100 g/L may require transfusion depending on cardiac risk and anticipated blood loss.
What is myeloma?
= a malignant clonal proliferation of plasma cells (derived from B-lymphocytes).
Normally, many different plasma cells produce a range of immunoglobulins – i.e. they are polyclonal.
In myeloma, a single clone of plasma cells produces a single immunoglobulin.
=> When you measure the immunoglobulins in a patient with myeloma, one of the type of antibody will be significantly abundant
Myeloma - RFs
Older age (average age of presentation is 70)
Black African ethnicity
FHx
Obesity
Myeloma - presentation
“CRAB” – calcium, renal, anaemia, bone:
Osteolytic bone lesions (due to osteoclast activation)
=> Backache, pathological fractures, hypercalcaemia (bones, stones, moans and groans)
Bone marrow failure
=> Infection, symptoms of anaemia, bleeding
Renal impairment
=> Seen in 20% at diagnosis, due to light chain deposition
Myeloma - complications
Hypercalcaemia,
Spinal cord compression,
Hyper-viscosity,
Acute renal failure.
Myeloma - Ix
FBC – normochromic normocytic anaemia; leucopaenia
Blood film – rouleaux formation
ESR – raised
U&Es – often deranged
Calcium – raised
ALP – normal
Serum/urine electrophoresis
=> Paraprotein monoclonal band seen
Urine Bence-Jones protein – positive
Skeletal XR
=> Punched out lytic lesions
Bone marrow biopsy
=> Increased clonal plasma cells >10%
=> If under 10%, may be termed “monoclonal gammopathy of uncertain significance” (MGUS)
Myeloma - Mx
- Supportive therapy
- Chemotherapy
- Radiotherapy
- Bone marrow stem cell transplants used if <70
Myeloma - prognosis
The original myeloma cell is very resistant, so often returns.
Median survival is 3-4 years.
Death is usually from renal failure/infection.
What is lymphoma?
= malignant proliferation of lymphocytes.
Most commonly accumulate in peripheral lymph nodes, but can accumulate in the peripheral blood or infiltrate organs.
Most are derived from B cells.
Classified as Hodgkin’s or Non-Hodgkin’s
What is Hodgkin’s Lymphoma?
Characterised by Reed-Sternberg cells
=> Binucleate “mirror cells” on biopsy.
Largest peak of incidence is young adults (20-35 years)
Second peak in 50-70-year olds.
Disease is slow growing, usually localised and rarely fatal.
RFs for Hodgkin’s Lymphoma
- Affected sibling
- HIV, EBV
- Autoimmune conditions – e.g. SLE, RA
- FHx
Hodgkin’s Lymphoma - Presentation
Enlarged, non-tender, “rubbery” lymph nodes (typically cervical)
Fatigue, itching
25% will have B-symptoms, with profuse night sweats.
For some patients, alcohol can induce lymph node pain
Mediastinal lymph nodes can have mass effects (SVC/bronchial obstruction)
O/E:
- Lymphadenopathy
- Hepatosplenomegaly in 50%
- Potentially signs of cachexia/anaemia
What is Non-Hodgkin’s Lymphoma?
Includes all lymphomas without the presence of Reed-Sternberg cells.
Peak incidence = 70 years
Can be further classes into high/low grade
=> HIGH grade – divide rapidly, typically present with rapid onset lymphadenopathy; more aggressive but better prognosis if identified and treated.
=> LOW grade – divide slowly, typically present more insidiously and thus tend to be widely disseminated at diagnosis, often incurable.
Non-Hodgkin’s Lymphoma - Presentation
Nodal disease – 75% have superficial lymphadenopathy
Extra-nodal disease – oropharynx, skin, CNS, gut, lung
B-symptoms – weight loss indicates disseminated disease.
Bone marrow failure
Presentation is similar to Hodgkin’s lymphoma and often they can only be differentiated when the lymph node is biopsied.
Lymphoma - Ix
FBC, U&E, LFT, ESR, blood film, Ca2+
LDH
=> Often raised in Hodgkin’s lymphoma but is not specific and can be raised in other cancers and many non-cancerous diseases.
Lymph node biopsy is the key diagnostic test.
=> Reed-Sternberg cells in Hodgkin’s Lymphoma
Staging CT/MRI/PET
Ann Arbor Staging
The staging system used for both Hodgkins and non-Hodgkins lymphoma.
The system puts importance on whether the affected nodes are above or below the diaphragm.
Stage 1: Confined to one region of lymph nodes.
Stage 2: In more than one region but on the same side of the diaphragm (either above or below).
Stage 3: Affects lymph nodes both above and below the diaphragm.
Stage 4: Widespread involvement including non-lymphatic organs such as the lungs or liver.
Lymphoma - Mx
HODGKIN’S
- Chemotherapy
- Radiotherapy
- Chemo-radiotherapy
NON-HODGKIN’S
Involves a combination of treatments depending on the type and staging of the lymphoma:
- Watchful waiting
- Chemotherapy
- Monoclonal antibodies such as rituximab
- Radiotherapy
- Stem cell transplantation
Macrocytic anaemia - Ix
Blood film
=> Hyper segmented neutrophils in B12/folate deficiency
LFTs / TFTs
=> ?Thyroid / hepatic cause
=> Raised bilirubin in B12/folate deficiency
Serum B12 and folate levels
If B12 low:
- Anti-parietal cell antibodies
- Anti-intrinsic factor antibodies
- Schilling test
Bone marrow biopsy:
Megaloblasts suggest B12/folate deficiency (also seen in myelodysplasia)
Deoxyuridine suppression test – can be used to differentiate B12/folate deficiency in vitro after bone marrow biopsy.
What can be a problem with measuring serum folate levels?
Serum folate reflects recent intake, so many labs do red cell folate.
Schilling test
distinguishes between pernicious anaemia and small bowel disease
Radiolabelled B12 given with and without IF
The amount of labelled B12 excreted in the urine then detected.
How does B12/folate deficiency lead to macrocytic anaemia?
B12 acts as a co-enzyme for the conversion of folate (B9) to activated folate.
Activated folate is required for DNA synthesis, and thus if there is a deficiency in either B12 or folate, DNA synthesis malfunctions.
In this case, the DNA fails to stop erythrocyte development, leading to very large cells, which are eventually trapped and destroyed in the reticulo-endothelial system.
B12 absorption
Intrinsic factor is secreted by gastric parietal cells, and binds free B12.
Receptors for the IF-B12 complex are present on the brush border of the terminal ileum, where B12 is absorbed.
IF is generally necessary for B12 ingestion, but even in its complete absence, around 2% of B12 can still be absorbed.
Sources of B12
Humans rely on animal sources of B12 – e.g. meat, fish, eggs and milk.
The liver contains very large stores of B12
=> It is secreted in bile but most of this is normally reabsorbed.
Pernicious Anaemia - Mx
high dose PO B12 supplementation can be enough to treat pernicious anaemia (as ~2% can still be absorbed in the abscence of IF)
Initially patients are often treated with IM B12 on alternate days before switching to PO for maintenance
Causes of B12 deficiency
Chronic low dietary intake – vegans
Impaired binding in the stomach – pernicious anaemia, congenital absence of IF, gastrectomy.
Small bowel disease – resection, Crohn’s/backwash ileitis in UC, bacterial overgrowth.
(Pancreatitis, coeliac disease and metformin can all cause mild impairment of B12 absorption, but not enough to cause significant B12 deficiency. )
Pernicious anaemia
= Autoimmune disease, resulting in severe B12 deficiency
There are 3 autoantibodies that may contribute towards disease:
- Autoantibodies against parietal cells
- Blocking antibodies
- Prevent IF-B12 binding
- Most common abnormality - Binding antibodies:
- Prevent IF binding to ileal receptors
Subacute degeneration of the spinal cord
Simultaneous dorsal column and corticospinal tract loss due to B12 deficiency
=> Gives a combination of UMN and LMN signs.
Initial presentation is with peripheral neuropathy
O/E there is classical triad of extensor plantars, brisk knee jerk reflex but absent ankle jerk reflex
=> Tone and power usually normal
=> Gait may be ataxic
Sources of folate
Folate (folic acid monoglutamate) is not itself present in nature, but occurs as polyglutamates dihydrofolate (DHF) or tetrahydrofolate (THF)
These are found in green vegetables and offal (however cooking causes a loss of up to 90% of the folate).
DHF and THF are converted to folate in the upper GI tract, and folate is absorbed in the jejunum
Causes of folate deficiency
Poor nutritional intake – poor diet, alcohol excess, anorexia.
Malabsorption – coeliac disease
Anti-folate drugs – trimethoprim, methotrexate, anti-convulsants
Excess physiological use – pregnancy, lactation, prematurity.
Excess pathological use – excess erythrocyte production, malignancy, inflammatory diseases
Folate deficiency - Mx
Folic acid 5 mg/day PO for 4 months
Always combined with B12, unless the patient is known to have normal B12 levels.
Approach to normocytic anaemia
Is there acute blood loss?
Is there underlying chronic disease?
Is it haemolytic?
Are other cell lines affected (i.e. bone marrow failure)?
Anaemia of chronic disease
Normochromic or hypochromic, rarely severe.
Seen in chronic infection, malignancy, CKD, rheumatoid disorders.
Pathology involves predominant WBC production in the bone marrow.
Low serum iron, raised ferritin, low TIBC, normal STR.
Bone marrow failure
- investigations
- causes
Hb, reticulocytes, WBC and platelets all equally low.
There will be alterations on the blood film
These patients require bone marrow biopsy.
No abnormal blasts in pancytopaenic marrow = aplastic anaemia (idiopathic or due to drugs).
Other causes will be apparent on marrow examination
=> E.g. haematological malignancies, metastatic disease, myelofibrosis, myelodysplasia.
Parvovirus infection can also cause cessation of marrow erythropoiesis.
Myeloproliferative Disorders
A group of disorders including – myelofibrosis, polycythaemia rubra vera, and essential thrombocytosis.
Clones of haematopoietic stem cells proliferate in the marrow, yet retain the ability to differentiate.
Considered PRE-LEUKAEMIC.
Essential Thrombocytosis
Clonal proliferation of megakaryocytes, leading to persistently raised platelets
=> This is often asymptomatic
=> The platelets have abnormal function
Symptoms:
=> The most common presentation is microvascular occlusion.
=> Other symptoms may be related to bleeding or arterial/venous thrombosis.
Polycythaemia Rubra Vera (PCV)
= Malignant proliferation of a clone derived from one pluripotent marrow cell.
Excess production of RBCs, WBCs and platelets lead to serum hyper-viscosity and thrombotic complications.
Presentation:
- Often asymptomatic
- Arterial/venous thrombosis
- Rarer – vague hyperviscosity symptoms (headache, dizziness, tinnitus, facial swelling, burning sensation in fingers/toes; splenomegaly; gout.
Polycythaemia Rubra Vera - Ix and Mx
Diagnosis:
- Increased red cell mass
- Ix for JAK2 mutation (PCV cells often carry activating mutation in the tyrosine kinase (JAK2) gene)
Key differentials to r/o = hypoxia and renal disease (in these secondary PCV’s only the RBCs are raised).
Treatment:
- Repeated venesection
- Low dose aspirin
Primary Myelofibrosis
= Hyperplasia of megakaryocytes, which produce excess platelet-derived growth factor, leading to marrow fibrosis and metaplasia.
There is secondary haematopoiesis in the liver/spleen, leading to massive hepatosplenomegaly (= most common presentation).
Symptoms:
- B symptoms
- Abdominal discomfort
- Sx of bone marrow failure
Essential thrombocytopaenia and PCV both may progress to myelofibrosis or AML, yet the risk is relatively rare.
Aplastic Anaemia
= A rare stem cell disorder leading to pancytopenia and hypoplastic bone marrow.
Most commonly autoimmune
Triggered by drugs, viruses or irradiation.
Can be inherited (Fanconi anaemia)
Symptoms are of bone marrow failure
Diagnosis is with bone marrow biopsy.
Aplastic Anaemia - Mx
Blood product transfusion
Immunosuppression in autoimmune conditions
In younger patients, allogenic bone marrow transplant may be curative.
What is haemolysis?
Where can it occur?
How does it present?
= the breakdown of RBCs before the end of their normal lifespan (120 days).
Can be:
1. Intravascular
2. Extravascular (reticuloendothelial system of the liver, spleen and bone marrow).
This may be asymptomatic, but haemolytic anaemia develops if the bone marrow does not sufficiently compensate.
Causes of haemolysis
INTRINSIC
Haemoglobinopathies – e.g. sickle cell/thalassaemias
Membranopathies – spherocytosis/elliptocytosis
Enzymeopathies – G6PD/PK deficiency
EXTRINSIC
Autoimmune disease
Alloimmune disease – transfusion/transplant reaction, rhesus disease
Drug-induced – e.g. penicillins
Infection – malaria and some other parasites
Microangiopathic haemolytic anaemias – e.g. DIC
Haemolysis - Ix
Signs suggestive of increased RBC breakdown:
- Anaemia with raised MCV
- Raised bilirubin – unconjugated, pre-hepatic jaundice
- Raised serum LDH (gets released from RBCs)
Signs suggestive of increased RBC production:
- Raised reticulocyte count
BLOOD FILM can give clues as to the cause
Further tests:
- Coomb’s test (DAT) = Identifies RBCs coated with antibodies or complement, indicating an immune cause of haemolysis.
- Hb electrophoresis = Can identify different haemoglobinopathies
- Enzyme assays = If other causes have been excluded
What aspects of a blood film can show the cause of haemolysis?
Hypochromic, microcytic cells – thalassaemia
Sickle cells – SCA
Spherocytes – hereditary spherocytosis or autoimmune haemolytic anaemia
Elliptocytes – hereditary elliptocytosis
Heinz bodies / “bite” cells – G6PD deficiency
Schistocytes – microangiopathic haemolytic anaemia
Glucose-6-phosphate dehydrogenase (G6PD) deficiency - Inheritance and Presentation
X-linked inheritance
=> More common in African and Mediterranean males (females will have mild symptoms).
Presentation:
- Mostly asymptomatic, but susceptible to oxidative crises due to reduced glutathione production.
- These attacks cause rapid anaemia and jaundice with “bite cells” and “blister cells” seen on the blood film.
Attacks may be precipitated by drugs (aspirin, primaquine, sulphonamides), broad bean consumption or illness.
G6PD - Ix and Mx
Diagnosis is with enzyme assay 3 months after initial crisis
BITE CELLS on blood film
Tx:
- Precipitant avoidance (e.g. broad beans)
- Transfusion if severe
- Splenectomy may help with chronic haemolysis
Pyruvate Kinase (PK) Deficiency - Inheritance and presentation
Autosomal recessive condition
Reduced ATP production, shortening the lifespan of RBCs
Homozygotes usually present with neonatal jaundice and later chronic jaundice with hepatosplenomegaly.
Pyruvate Kinase (PK) Deficiency - Ix and Management
Dx = enzyme assay
Tx = Often well tolerated and no specific therapy is needed, although splenectomy may help.
Hereditary Spherocytosis
Autosomal dominant membrane defect => Leading to spherical RBCs
These are less deformable, thus can become trapped in the spleen => leads to haemolysis, splenomegaly and jaundice.
Hereditary Elliptocytosis
Autosomal dominant defect => “elliptocytes”
Mostly asymptomatic
Mx of membranopathies (spherocytosis/elliptocytosis)
Both are treated with folate.
Splenectomy is curative, but reserved for severe disease.
What causes Sickle cell disease?
= Autosomal recessive disorder
Causes abnormal production of beta-globulin chains, due to a single amino acid substitution (glu6val)
This results in the production of HbS rather than HbA
Much more common in patients of African origin
There are two genotypes:
- HbSS – sickle cell anaemia phenotype
- HbAS – sickle cell trait
What causes Sickle cell disease?
= Autosomal recessive disorder
Causes abnormal production of beta-globulin chains, due to a single amino acid substitution (glu6val)
This results in the production of HbS rather than HbA
Much more common in patients of African origin
There are two genotypes:
- HbSS – sickle cell anaemia phenotype
- HbAS – sickle cell trait
HbS polymerises when deoxygenated, causing RBCs to form “sickle cells” which are fragile and haemolyse, and can also block small vessels
HbAS – sickle cell trait
HbAS confers protection from falciparum malaria
rarely symptomatic
=> BUT vaso-occlusive events may occur in hypoxia – e.g. when flying or under anaesthesia
Sickle cell disease - Ix
Usually on the newborn bloodspot screening
Sickle cells can be seen on blood film
Hb electrophoresis can confirm diagnosis and also distinguish variants.
Sickle Cell disease - Presentation
Often presents in the first few months of life, with anaemia developing as HbF levels fall.
Acute haemolytic crises occur, causing bone infarcts and painful dactylitis
Untreated, there is:
- Splenic infarction, leading to hyposplenism
- Renal infarction, causing CKD
- Cerebrovascular accidents
In adulthood, there is normally a chronic haemolytic anaemia (60-90 g/L) but this is well tolerated unless there is a crisis.
Complications of sickle cell disease
Hyposplenism,
CKD,
Bone necrosis,
Chronic leg ulcers,
Iron overload (if multiple transfusions)
Long-term pulmonary damage
Sickle cell disease - Long-term Tx
Lifelong folate supplementation
Pneumococcal vaccination and prophylactic penicillin (due to hyposplenism)
Hydroxycarbamide (hydroxyurea) can help by increasing HbF production and is advised if there are frequent crises.
Regular life-long transfusions (2-4 weekly), with iron chelators to prevent overload.
Bone marrow transplantation is curative – but limited by availability of matched donors.
Sickle-cell - Vaso-occlusive Crises
PAINFUL CRISES
Occur due to micro-vascular occlusion, often affecting the bone marrow, causing severe pain.
Can be precipitated by cold, infection, dehydration or hypoxia.
Other presentations are mesenteric ischaemia (mimicking acute abdomen), cerebral infarctions or priapism
Sickle cell - aplastic crises
Due to parvovirus B19
Causes a sudden reduction in marrow production (particularly RBCs)
Usually self-limiting, but transfusion may be required.
Sickle cell - sequestration crises
Mainly affects children as spleen has not yet undergone atrophy.
Pooling of blood in the spleen +/- liver, with organomegaly, severe anaemia and shock
Urgent transfusions are required.
Sickle cell - haemolytic crises
Rarer
Hb falls due to haemolysis
Mx of sickle cell crises
A-E resuscitation – high flow oxygen and IV fluids
Strong analgesia within 30 minutes
FBC, reticulocytes, XM blood
Screen for signs of infection (culture, MSU, CXR) & treat early.
Prophylactic enoxaparin should be given
Fully cross-matched blood transfusion if Hb/reticulocytes fall sharply.
Exchange transfusion if rapidly deteriorating.
Autoimmune Haemolytic Anaemia
Autoantibodies lead to extravascular haemolysis and spherocytosis
Most commonly idiopathic, but can be secondary to lymphoproliferative diseases or other autoimmune diseases.
Classified according to the optimal temperature at which antibodies bind to RBCs in vitro:
- Warm AHA – IgG mediated; optimal binding 37 degrees
=> Treated with steroids or immunosuppresants +/- splenectomy - Cold AHA – IgM mediated; optimal binding below 4 degrees
=> Often associated with raynaud’s
=> Treated with cold-avoidance +/- chlorambucil
Drug-induced Haemolysis
Penicillin-based drugs can cause formation of RBC antibodies
Drugs such as quinine cause production of immune complexes
Microangiopathic Anaemia
= Mechanical haemolysis caused by physical trauma in the circulation, due to:
- Malignant HTN / pre-eclampsia
- Haemolytic Uraemic syndrome
- Thrombotic thrombocytopaenic purpura
- Vasculitis (e.g. SLE)
- DIC
- Mechanical heart valves
The blood film will show schistocytes irregular, asymmetrical cells).
Alloimmune Reactions/Haemolysis
Transplant/transfusion/rhesus reactions
Immune-mediated, yet Coomb’s negative.
Types of WBC and their purpose
NEUTROPHILS – ingest and kill bacteria, fungi & cellular debris
LYMPHOCYTES – produce antibodies for cell-mediated immunity.
EOSINOPHILS – play a role in allergic reactions and defence against parasitic infection.
MONOCYTES – precursor of tissue macrophages
BASOPHILS – release histamine in inflammatory reactions
Neutrophilia - causes
Bacterial infection
Inflammatory reactions
Disseminated malignancy
Stress – e.g. surgery, burns
Myeloproliferative conditions
Corticosteroid therapy.
Neutropaenia - causes
Viral infections
Severe sepsis
Neutrophil antibodies – e.g. SLE
Bone marrow failure
Hypersplenism – e.g. Felty’s
Cytotoxic drugs
Agranulocytosis
= A complete absence of circulating neutrophils
Can be caused by drugs such as carbimazole/clozapine/etc.
Lymphocytosis - causes
Viral infections
Chronic infections (TB, hepatitis)
Myeloproliferative conditions
Lymphopaenia - causes
Bone marrow failure
Corticosteroid therapy
SLE
Uraemia
HIV Infection
Cytotoxic drugs
What is Disseminated Intravascular Coagulation (DIC)?
Systemic activation of the coagulation pathways, leading to extensive intravascular coagulation and fibrin clot development.
There is thrombotic occlusion of the arterial microvasculature
The simultaneous depletion of clotting factors and consumption of platelets leads to haemorrhage.
Eventually organ failure develops.
Causes of DIC
Infection
Trauma
Malignancy
Obstetric complications (amniotic fluid emboli, pre-eclampsia)
Severe liver failure
Tissue destruction (pancreatitis/ burns)
Toxic / immunogenic stimuli
DIC - clinical features
Bruising
Excessive bleeding from any sites
Renal failure
DIC - Ix
Low platelets, low fibrinogen
Raised PT & APTT
Raised D-dimer
Blood-film – broken RBCs (schistocytes)
DIC - Tx
Treat the cause
Aggressive resuscitation, replacing platelets, coagulation factors (FFP) and fibrinogen (cryoprecipitate).
Protein C – reduces mortality in multi-organ failure / severe sepsis.
Haematopoiesis
The haematopoietic stem cell first divides into the common myeloid or lymphoid progenitor cell.
COMMON MYELOID PROGENITOR cell then subdivides to form
- Erythrocytes
- Mast cell
- Megakaryocytes (go on to form platelets)
- Myeloblasts (go on to form monocytes, basophils, neutrophils, and eosinophils)
COMMON LYMPHOID PROGENITOR cell subdivides to form:
- NK cells
- T and B lymphocytes
Acute Lymphoblastic Leukaemia (ALL)
= Malignancy of lymphoid cells (of either B or T cell lineages), leading to uncontrolled proliferation of immature blast cells.
Leads to eventual bone marrow failure and tissue infiltration
Most common malignancy of childhood; it is rare in adults (“L for little”)
More common in certain genetic syndromes – e.g. Down’s
Prognosis of ALL
Prognosis is good in children under 10
Poor prognosis suggested by:
- older age of presentation,
- male sex,
- B-cell disease,
- presence of Philadelphia chromosome (9:22 translocation).
Acute Myeloid Leukaemia (AML)
= Malignancy of blast cells from the marrow myeloid elements.
It can arise de novo, or on a background of myeloproliferative conditions/ previous chemotherapy/ ionising radiation/ genetic syndromes.
Can occur at any age (median age of presentation = 65 years) – “M for mature”
AML - prognosis
Rapidly progressive
=> Only 20% 3-year survival after chemotherapy.
Acute leukaemias - presentation
Regardless of subtype, acute leukaemias generally present with:
B-symptoms
=> Fatigue, weight loss, night sweats, fevers, pruritis
Bone pain from marrow infiltration
Symptoms related to bone marrow failure
=> Anaemia (SoB on exertion, weakness)
=> Leucopaenia** (recurrent infections)
=> Thrombocytopaenia – bleeding/bruising (more common in AML)
Hepatomegaly/ splenomegaly.
** Although presenting with leucocytosis, the cells are immature and non-functioning blast cells, thus symptoms of leucopaenia are seen.
Acute leukaemias - Ix
FBC
Blood film
=> Blasts are diagnostic
=> Lineage identified morphologically and confirmed with immunophenotyping
CXR – T-cell ALL classically shows mediastinal widening
Bone marrow aspiration – to confirm diagnosis and confirm lineage.
PET scanning – to check for metastatic disease
U&Es, LFTs and cardiac function testing (ECG/ echo) are essential for planning therapy.
Acute leukaemias - general Mx
Supportive care:
- Barrier nursing
- Hickman line for venous access
- High-calorie diet
- Frequent blood and platelet transfusions
- Allopurinol to prevent tumour lysis syndrome due to chemotherapy.
- Check frequent bloods and observations for sign of infection
Antibiotics
=> If temperature is >38oC on 2 occasions greater than an hour apart, assume sepsis and start broad spectrum ABX until afebrile for 72 hours.
ALL - Management
High-dose chemotherapy to induce remission
=> Then 2 years of maintenance therapy
Consider marrow transplant if poor prognosis or relapse.
Transplant is necessary to cure those with the Philadelphia chromosome
AML - Management
Intensive chemotherapy
In disease with poor prognosis – allogenic marrow transplant from HLA-matched siblings is indicated after the first round of chemotherapy.
=> This then allows further high-dose chemotherapy
In intermediate prognosis disease, autologous marrow transplants may be used (cells grown from own bone marrow)
=> Further chemotherapy must be at lower doses.
Chronic Myeloid Leukaemia (CML) - presentation
Rare in childhood, most common in people age 40-60
Philadelphia chromosome is present in 95% with CML
Symptoms:
- 30% are detected by chance
- Insidious B symptoms are the most common presentation
- Gout, due to purine breakdown
- Abdominal discomfort due to splenic enlargement
O/E:
- Massive splenomegaly / hepatomegaly
- Signs of anaemia/thrombocytopaenia.
CML - Ix
FBC
=> WCC very high (raised across whole spectrum of myeloid cells)
Blood film – spectrum of myeloid cells
Bone marrow biopsy – hypercellular
CT/PET
Cytogenic analysis of blood/marrow for Philadelphia chromosome.
CML - Mx
Imatinib chemotherapy is 1st line
Stem cell transplant is the only treatment that may achieve remission, but carries significant mortality/morbidity.
CML - prognosis
Median survival 6 years.
There are 3 phases:
1. Chronic phase – few symptoms, lasts for years
2. Accelerated phase – increasing symptoms, difficulty controlling counts
3. Blast transformation – features of acute leukaemia, eventual death.
Chronic Lymphocytic Leukaemia (CLL) - pathophysiology and presentation
= Most common leukaemia
Median age at presentation = 70 years.
Accumulation of mature B-cells that have escaped apoptosis, and this increasing mass of immune-incompetent cells leads to bone marrow failure.
Presentation:
- Often asymptomatic, found on routine FBC
- May be anaemia or infection-prone
- If severe, there can be B-symptoms
O/E:
- Enlarged non-tender lymph nodes
- Hepatosplenomegaly
CLL - Ix
FBC
- Markedly raised lymphocytes
- May be signs of bone marrow failure
- Autoimmune haemolysis develops later
Blood film – predominant SMUDGE cells (small mature lymphocytes).
CLL - Mx
Without treatment:
- 1/3rd never progress
- 1/3rd will eventually progress
- 1/3rd actively progress from diagnosis.
Treatment is thus only indicated if symptomatic, or there are cytogenic markers of poor prognosis.
Treatment can be with chemotherapy or radiotherapy.
CLL - prognosis
prognosis depends on Rai stage (stage 0 - 4)
Death is usually due to infection, or transformation to an aggressive lymphoma (Richter’s syndrome).
Phaeochromocytoma
= catecholamine secreting tumours, arising from sympathetic paraganglionic cells (known as chromaffin cells).
PCC - location
usually located in adrenal medulla
10% are extra-adrenal
10% are bilateral
10% are familial
=> MEN 2a/2b
=> Neurofibromatosis
=> Von Hippel-Lindau Syndrome
PCC - presentation
Usually severe/episodic HTN, unresponsive to medical treatment.
Also often vague episodic symptoms:
- General – sweating, heat intolerance, pallor or flushing
- Neurological – headaches, visual disturbances, seizures
- CV – palpitations, chest tightness, dyspnoea, postural hypertension
- GI – abdominal pain, nausea, constipation
Symptoms may be worsened by stress, exercise or drugs.
PCC - diagnosis
3x 24-hour urine collections for raised free metadrenaline and nor-metadrenaline.
MRI/CT/functional imaging to locate the tumour
PCC - Mx
Alpha blockade with phenoxybenzamine.
Beta-blockers AFTER alpha blockade is established
=> Used if significant tachycardia remains after alpha blockade.
Surgical excision
What is important to remember with using beta-blockers in phaeochromocytoma?
Should only be initiated after alpha-blockade.
=> can induce life-threatening hypertensive episodes in patients without adequate alpha blockade.
What is Addison’s disease?
= Primary Adrenal Insufficiency
Destruction of the entire adrenal cortex, leading to deficiencies in:
1. Glucocorticoid (cortisol)
2. Mineralocorticoid (aldosterone)
3. Sex steroids
How does Addison’s differ from hypothalamic-pituitary-adrenal disease?
HPA disease generally spares mineralocorticoid production, which is stimulated by ATII.
Causes of Addison’s disease
- Autoimmune (most common in UK)
- TB (most common worldwide)
- Overwhelming sepsis
- Metastatic cancer – lung/breast
- Lymphoma
- Adrenal Haemorrhage (Waterhouse-Friedrichsen syndrome)
Addison’s disease - presentation
Symptoms:
- Often vague and non-specific
- Weight loss, malaise, weakness, myalgia
- Syncope
- Depression
Signs:
- Pigmentation, especially of new scars and palmar creases.
- Postural hypotension
- Signs of dehydration
- Loss of body hair (particularly axillary/pubic)
Addison’s disease - Investigations
Bloods:
- U&Es – low sodium, high potassium (due to mineralocorticoid insufficiency).
- Calcium – raised
- Glucose – low, due to lack of cortisol
Short ACTH stimulation test / Synacthen Test
- Measure plasma cortisol before, and 30 mins after.
- A 2nd value >550nmol/L excludes Addison’s
9am ACTH/cortisol
=> Raised ACTH and low/normal cortisol confirms Addison’s
Investigations for cause:
- 21-hydroxylase adrenal autoantibodies – autoimmune
- CXR – TB
- Adrenal CT – to look for TB/metastatic disease
How is a Short ACTH stimulation test / Synacthen Test performed?
- Give tetracosactide IM (ACTH analogue).
- Measure plasma cortisol before, and 30 mins after.
- A 2nd value >550nmol/L excludes Addison’s
Addison’s Disease - Mx
Long-term glucocorticoid cover:
=> 15-25mg HYDROCORTISONE daily, in 3 divided doses (mimic diurnal variation)
=> Avoid giving late in the day, as can cause insomnia.
Long-term mineralocorticoid cover:
=> Required if postural hypotension
=> FLUDROCORTISONE 50-200 micrograms daily.
Patient education:
- Steroids should never be abruptly stopped
- Extra doses of steroid are needed for strenuous exercise, surgery, febrile illness, or trauma.
- Patient should have a steroid card/bracelet and should carry IM hydrocortisone in case of Addisonian Crisis.
Addisonian Crisis
Severely inadequate levels of cortisol, occurring either as a first presentation of adrenal disease or triggered by physiological stress.
Presents with:
- Fever, N&V
- Shock
- Hypoglycaemia
- Hyponatraemia and hyperkalaemia
Treat with IV fluids and IV hydrocortisone as part of resuscitation.
What is Congenital Adrenal Hyperplasia?
Due to congenital deficiency in 21-alpha-hydroxylase
=> This enzyme is necessary for the production of mineralocorticoids and glucocorticoids (but not sex hormones)
Autosomal recessive.
Aldosterone and cortisol levels decrease, and thus ACTH rises.
=> Precursors such as progesterone build-up and go down the alternative pathway to form sex hormones => testosterone levels raised
CAH - presentation
Virilisation of the external genitalia in females
=> Clitoral hypertrophy (resembling a penis) and variable fusion of the labia (resembling a scrotum).
Enlarged penis and pigmented scrotum is seen in males (but rarely noticed).
Presents with salt-losing crisis in 80% of males at 1-3 weeks of age (failure to thrive, and potentially fatal hypovolemia and shock)
In the non-salt-losing males, presents as hyper-virilisation (early pubarche, adult body odour, muscular build).
CAH - Investigations
17-alpha-hydroxyprogesterone levels = markedly raised => this is diagnostic
Other features may be:
- Low sodium
- High potassium
- Metabolic acidosis
CAH - Mx
Steroid cover, as per Addison’s disease.
Also at risk of Addisonian crisis.
What is Conn’s Syndrome?
Adrenal adenoma, leading to primary hyperaldosteronism
Most common in young females.
Hyperaldosteronism leads to sodium and water retention.
Conn’s syndrome - presentation
Mostly asymptomatic
HTN (resistant to Tx)
Features of hypokalaemia (Cramps, weakness, tetany, polyuria)
Conn’s syndrome - Investigations
Biochemical features:
=> Hypernatraemia, Hypokalaemia
=> Elevated plasma aldosterone:renin ratio
=> Plasma aldosterone levels will not be suppressed by fludrocortisone administration.
Further Investigations:
=> Once primary hyperaldosteronism is confirmed, adrenal CT is indicated
=> Adrenal scintography is alternative method (Unilateral uptake of the isotope in Conn’s)
Conn’s - Mx
Laparoscopic adrenalectomy to remove adenoma
Spironolactone pre-op to control HTN/hypokalaemia.
RFs for DVT
= anything causing blood stasis or hypercoagulability
- Age/immobility
- Pregnancy/OCP
- Malignancy
- Obesity
- Surgery (typically occur 2 weeks post-surgery)
- Previous DVT
DVT - presentation
Most DVTs are silent
Classical Clinical features:
- Calf tenderness & firmness
- Oedema
- Erythema & calor
- Distension of superficial veins
- Superficial thrombophlebitis
Atypical Presentation:
- Ilio-femoral thrombosis can present with severe pain, but few physical signs.
- Complete occlusion of a large vein can lead to cyanotic discolouration.
DVT - Ix
Calculate Well’s Score – by risk stratifying to low risk (Wells’ Score <2) and a negative d-dimer the clinician can exclude the need for ultrasound (US) to rule out DVT.
D-dimer
= Highly sensitive, not specific for DVT (also increased in infection, pregnancy, malignancy, post-op etc.)
=> If pre-test probability is low and D-dimer is negative – can r/o DVT
=> If D-Dimer is positive or high/intermediate pre-test probability, do compression USS.
Compression USS:
=> Non-collapsing veins indicate presence of DVTs
Thrombophilia screen
=> Ensure this is done prior to commencing anticoagulant therapy if there are no pre-disposing factors.
Preventing post-surgical DVT
Stop COCP 4 weeks pre-op
Mobilise as early as possible
Immobile patients should be heparinised
At risk patients should have TEDs/intermittent pneumatic pressure until 16 hours post-op.
Treating proven DVT
LMWH to prevent propagation of the clot
Warfarin started simultaneously
=> LMWH can be stopped when INR = 2-3
Length of warfarin treatment:
- 3 months for post-op DVT
- 6 months if there was no precipitating cause
- Lifelong if known thrombophilia/recurrent DVT
PE - presentation
Classically present with:
- Sudden-onset breathlessness
- Pleuritic pain
- Haemoptysis
However, PE should be included in almost any respiratory differential as they are so common and variable in presentation.
Possible Signs:
- Evidence of a DVT
- Raised JVP
- Cyanosis if embolus is large
Massive PE
~5% of PEs
> 60% of the pulmonary circulation is blocked
Leads to rapid cardiovascular collapse
Major PE
~10% of PEs
Middle-sized pulmonary arteries are blocked
Leads to breathlessness, pleuritic chest pain and haemoptysis
Minor PE
~85% of PEs
Small peripheral vessels are blocked
Patients may be asymptomatic or classical presentation.
Massive PE may ensue following minor PE (known as premonitory embolus)
PE - Investigations
FBC, U&E, clotting, D-dimer
ABG – T1RF
CXR
=> Often normal
-> May see dilated pulmonary artery or wedge-shaped opacities
ECG:
=> Tachycardia, RBBB, RV strain
=> Classical SIQIIITIII is rare
Echo:
=> Can confirm right heart strain
CTPA = gold-standard
=> V/Q if this is unavailable, but less accurate
SI QIII TIII ECG pattern
Large S wave in lead I
Q-wave in lead III
T wave inversion in lead III
Rare; but sometimes seen in PE (sign of right-heart strain)
PE - Management
Major/minor PE should be managed as per DVT.
Massive PE:
- Emergency A-E resuscitation
- IV morphine + antiemetic
- Heparin therapy – LMWH/UH
If SBP >90mmHg – commence anticoagulant therapy
If SBP <90mmHg – start vasopressors (noradrenaline) before commencing thrombolytic therapy.
Causes of CKD
- Diabetes mellitus (20-40%)
- HTN
- Chronic glomerulonephritis
- Chronic pyelonephritis
- Obstructive uropathy
- Renovascular disease
- Drugs (e.g. long-term NSAIDs)
- PKD
CKD - symptoms
Often asymptomatic until very advanced – may be some vague fatigue and anorexia.
- Polyuria/nocturia
- Restless leg syndrome
- Sexual dysfunction
- Nausea & Pruritis (early uraemia)
- Yellow pigmentation, encephalopathy and pericarditis (severe uraemia)
- Pedal oedema & pulmonary oedema.
CKD - signs
- Pallor – due to anaemia
- Excoriations – due to pruritis
- Hypertension/fluid overload signs
- Pericardial rub (rare)
- Proteinuria
Diagnosis of CKD
diagnosed when any two tests, 3 months apart show reduced eGFR and can be stages 1-5 depending on the level of reduction.
(in some situations a 24-hour urinary creatinine may be collected to calculate true creatinine clearance)
CKD Stage 1
eGFR >90
Normal eGFR but urine findings/structural abnormalities/ genetic traits suggest CKD.
Asymptomatic
CKD Stage 2
GFR 60-89
Mildly reduced eGFR and other findings (as for stage 1) point to CKD
Asymptomatic
CKD Stage 3A
eGFR 45-59
= Moderate CKD
Usually asymptomatic
CKD Stage 3B
eGFR 30-44
= Moderate – severe CKD
Pts are often anaemic
CKD Stage 4
eGFR 15-29
= Severe CKD
Symptoms often at eGFR <20
Electrolyte disturbances
CKD Stage 5
eGFR <15 / dialysis
= End-stage renal failure (ESRF)
Significant complications and symptoms
Dialysis usually at eGFR <10
CKD - Investigations
Bloods:
=> FBC, U&Es, LFTs, calcium, phosphate, PTH levels, Glucose
Urinalysis:
- Any blood?
- Quantify proteinuria
- Exclude infection
- May do 24-hour urinary protein / creatinine clearance
- To assess severity / for nephrotic syndrome
CXR – ?pulmonary oedema.
ECG – if hyperkalaemia
Renal USS:
- To exclude obstruction
- Can look for polycystic kidneys
Further Ix:
- Renal biopsy – if cause unclear
- Renal DTPA scan – investigate vascular supply
- Bone imaging – screen for renal bone disease
CKD - Management
Treat reversible causes – e.g. obstruction, nephrotoxic drugs
1st line = BP control/diabetic control
=> BP controlled to <130/80
=> If proteinuric, BP <125/75 (ACEi 1st line)
Primary CV prevention is also important (statin and low-dose aspirin)
2nd line = control of complications
=> Recombinant EPO for anaemia
=> Calcium/vitamin D supplementation for bone disease
=> K+ restriction for hyperkalaemia
Renal replacement therapy is indicated in those with ESRD = dialysis or transplantation
=> Any symptomatic CKD stage 5 patient
Complications of CKD
Renal Anaemia
Renal Bone disease
Secondary HTN
Electrolyte disturbances
Myopathy
Peripheral neuropathy
Increased risk of infection
GI – Anorexia, N&V
Pericarditis
Depression is common – particularly in later stages/dialysis
Renal Anaemia
In CKD, the kidney partly loses its secretory EPO function, leading to anaemia.
=> Correlates with the severity of renal disease
Recombinant EPO can be given to those on dialysis with ESRD as part of renal replacement therapy to combat this anaemia
Target Hb 100-120
Renal Bone Disease
- cause
- investigation results
- treatment
In CKD the kidneys produce less 1-alpha-hydroxylase and excrete less phosphate
=> low VitD, low Calcium, hyperparathyroidism
=> Ultimately osteopaenia and osteoporosis
Tx:
- Restriction of dietary phosphate,
- Phosphate binders (calcichew)
- AdCal (calcium and vitD supplementation).
Indications for Renal Replacement Therapy
ESRF is not a clear cut line, and RRT may be required at different levels in different individuals, but general indications are:
A intractable acidosis
E electrolyte disturbance (hyperkalaemia, hyponatraemia, hypercalcaemia)
I Intoxicants
O intractable fluid overload
U uraemia symptoms
Haemodialysis
Diffusion of solutes between blood and dialysate, which flow in opposite directions with a semi-permeable membrane between.
Vascular access is most commonly achieved by:
1. AVF (at the wrist / cubital fossa)
2. Double lumen arterial lines (vascath / permcath)
Dialysis must occur for 4 hours, three times weekly.
- Normally occurs at hospital
- Home treatment is available, but requires support and training in dialysis unit.
The main issue is haemodynamic instability during dialysis
How is Peritoneal Dialysis performed?
What is the main risk?
Continuous ambulatory peritoneal dialysis patients instil up to 2 litres of isotonic/ hypertonic solution into the peritoneal cavity.
This then equilibrates with the blood in peritoneal capillaries.
The fluid is then drained out after 2 hours.
This is performed 3-4 times daily at home
Main risk is peritonitis
Which is preferable - haemodialysis or peritoneal dialysis?
There is no difference in clinical outcomes between peritoneal and haemodialysis.
Renal Transplantation - process and prognosis
Patient assessment:
- Virology / TB status – active infection is a CI due to risks of immunosuppression
- Blood group / HLA matching
- Full systemic examination – comorbid disease is a CI.
Prognosis is good
=> 1 year graft survival rate of 90-95% depending on extent of HLA match
Complications of kidney transplant
Operative – bleed, thrombosis, infection, urinary leaks.
Rejection – risk highest in 1st 3 months; need lifelong immunosuppression
Ciclosporin / Tacrolimus toxicity
Infection / malignancy due to immunosuppression (typically skin cancer, anal cancer, lymphoma).
Kidney anatomy
Lie in the retroperitoneum of the abdomen.
Typically extend from T12 to L3.
=> The right kidney is generally lower than the left due to the liver.
The kidney parenchyma consists of two main regions, covered with a fibrous capsule:
1. inner medulla
2. outer cortex
Components of nephron and their function
RENAL CORPUSCLE - site of initial filtration
PCT - reabsorption of ions and solutes; regulation of pH by secreting bicarbonate
LOOP OF HENLE - Ascending limb aims to create a strong osmotic gradient for absorption of large amounts of water from the descending limb
DCT - Secretion of ions, acids, drugs and toxins; Variable reabsorption of water/sodium under the control of aldosterone.
COLLECTING DUCT - Variable reabsorption of water under the control of ADH
Renin-Aldosterone-Angiotensin System
The juxtaglomerular cells of the kidneys are stretch receptors:
1. Decrease in blood volume => reduced stretch
2. Leads to the release of renin.
3. Renin is involved in the cleavage of angiotensinogen to form AI
4. AI undergoes conversion by ACE to form AII
Angiotensin II causes:
- Vasoconstriction (of afferent arteriole)
=> BP increases until it returns to normal
- Release of aldosterone from the adrenal cortex
=> Enhances reabsorption of sodium and water (and increases secretion of K+ and H+), thereby increasing blood volume.
Causes of hyperkalaemia
Pseudo-hyperkalaemia (Haemolysis, Incorrect order of blood draw, Sample taken from drip arm)
AKI / CKD
Drugs:
=> Supplements, K+-sparing diuretics, ACEis, NSAIDs
Acidosis (including DKA)
Addison’s disease
Tumour-lysis syndrome
Burns
Symptoms of hyperkalaemia
Often asymptomatic if mild/moderate
Muscle weakness, numbness, tingling,
N&V
Palpitations (=> arrythmias if untreated)
Hyperkalaemia - Ix
Raised K+ on U&Es / blood gas
ECG signs:
- Tall, peaked T waves
- Widened QRS complexes
- Flattened P-waves / prolonged P-R interval
If it goes untreated, ventricular fibrillation / tachycardia can develop.
Hyperkalaemia - aims of Tx
Aims of Tx:
1. Stabilise the Heart – Calcium Gluconate
2. Drive potassium intracellularly – insulin & dextrose / salbutamol
3. Tackle the underlying issue to reduce total body potassium
Hyperkalaemia - Mx
If potassium >6.5 mmol/L or there are ECG changes, initiate emergency management:
- Start continuous ECG monitoring
- 10ml of 10% Calcium gluconate IV to stabilise the heart
=> Repeat at 5 min intervals until a max of 3 doses or ECG normal - 50ml 50% glucose with 10 units Actrapid Insulin into a large vein over 30 minutes to decrease K+ concentration
=> Onset 1-4 hours, consider BM - Consider 10mg Salbutamol neb
- If pH <7.2, consider sodium bicarbonate IV (if advised by renal registrar)
- Recheck K+ after 2 hours
- Consider potassium binders
- Ensure the underlying cause is being treated.
What is AKI?
= a sudden deterioration in kidney function occurring over hours or days, as measured by serum urea and creatinine.
This results in a failure to maintain fluid, electrolyte and acid-base homeostasis.
Can be PRE-RENAL, RENAL or POST-RENAL
Pre-renal AKI
Occurs when renal perfusion is interrupted
Main causes:
1. Shock – hypovolaemic, cardiogenic, distributive.
2. Renovascular obstruction:
- AAA,
- Renal artery stenosis (and ACEis given in bilateral renal artery stenosis),
- Renal vein thrombosis
If interruption in the blood supply is prolonged, there will be acute tubular necrosis (ATN)
Post-Renal AKI
Occurs when there is obstruction of the urinary tract
Blockage is often in the ureters – e.g. stones, strictures, clots, external/internal malignancy.
Can also be due to bladder outlet obstruction – e.g. prostatic enlargement, urethral strictures, paraphimosis.
Intrinsic/ Renal AKI
If there is no pre-renal or post-renal cause of AKI, then intrinsic cause should be suspected
Injury or damage to the renal parenchyma, by 3 mechanisms:
- Acute Tubular Injury (85%)
- Interstitial Nephritis (10%)
- Glomerular Disease (5%)
AKI - acute tubular injury
Renal causes are due to drugs/toxins damaging the tubular cells (rather than ischaemia, which is pre-renal).
Drugs – aminoglycosides, cephalosporins, radiological contrast mediums, NSAIDs.
Toxins – heavy metal poisoning, myoglobinuria, haemolytic uraemic syndrome (HUS).
Myoglobinuria
Follows an episode of rhabdomyolysis (muscle breakdown from trauma, strenuous exercise or medications), releasing myoglobin which is readily filtered by the glomerulus.
Gives the classical dark urine, but in high quantities will precipitate out within the tubules to cause damage.
Causes ACUTE TUBULAR INJURY & thus AKI
haemolytic uraemic syndrome
Occurs in children following diarrhoeal illness caused by verotoxin-producing E. coli O157, or following a URTI in adults.
Thrombocytopaenia, haemolysis and ACUTE TUBULAR INJURY (=> AKI).
Children recover within a few weeks, prognosis for adults is poor.
Treatment is supportive, including dialysis.
AKI - Interstitial Nephritis
Damage is not limited to tubular cells (as in ATN) and bypasses the basement membrane to cause damage to the interstitium.
Most commonly caused by drugs (especially antibiotics, but also diuretics, NSAIDs allopurinol and PPIs).
Can be caused by infection, auto-immune mechanism or lymphoma.
Normally responds to withdrawal of the drugs and a short course of oral steroids.
AKI - Glomerular Disease
Glomerulonephritis, thrombosis, HUS, IgA nephropathy
AKI - Presentation
Symptoms:
- Reduced urine output
- Nausea and vomiting
- Dehydration
- Confusion
- Fatigue
Signs - Dependent on the underlying cause – look for:
- Fluid overload
- Hypotension in pre-renal causes, HTN in CKD
- Palpable abdominal mass
- Associated features of vasculitis – petechiae, skin changes, bruising, etc.
Approach to patient with reduced urine output / raised creatinine / decreased GFR
- Is it AKI or CKD?
=> Suspect CKD if history of comorbidities (HTN, DM) and long duration of Sx (confirm with USS showing small kidneys) - If it is AKI, is it pre-renal / renal / post-renal?
=> Pre-renal – look for signs of shock and treat appropriately; listen for renal bruits and take vascular Hx
=> Post-renal – order abdominal or KUB USS; examine prostate in older males.
=> Renal – drug history, Hx of recent infections / joint pains/ rashes; urine dip (?blood / protein); any red cell casts on microscopy
Diagnosis of AKI
NICE recommends using any of the following criteria:
- A rise of serum creatinine >26 micromol/L in 48 hours
- A 50% or greater rise in serum creatinine over the past 7 days
- A fall in urine output to <0.5mL/kg/hour for > 6 hours
AKI Stage 1
SERUM CREATININE
150-200% increase OR >25 micromol/L increase in 48h
URINE OUTPUT
<0.5 mL/kg/hour for 6h
AKI Stage 2
SERUM CREATININE
200-300% increase
URINE OUTPUT
<0.5 mL/kg/hour for 12h
AKI Stage 3
SERUM CREATININE
>300% increase OR >350 micromol/L increase in 48h
URINE OUTPUT
<0.3 mL/kg/h for 24h OR Anuria for 12h
How should oliguria/anuria be confirmed in patients with suspected AKI?
In order to confirm oliguria/anuria, the patient first needs to be volume replaced to ensure they are euvolaemic.
AKI - Investigations
BEDSIDE
Urine dip and MC&S
Observations
Glucose
ECG – ?hyperkalaemia
BLOODS
FBC, U&E, LFTs, clotting, CRP
ABG/VBG – ?acid-base imbalance
Nephritic Screen if cause unclear
Creatine Kinase (if indicated)
IMAGING
Renal USS to rule out obstruction
CXR if pulmonary oedema
CT KUB if obstruction
Nephritic Screen
ANCA & anti-GBM – Rapidly progressive glomerulonephritis (RPGN)
ANA, dsDNA & complement – SLE
Immunoglobulins, serum electrophoresis – myeloma
Rheumatoid Factor – RA-associated GN
Hepatitis B/C screen – Mesangiocapillary glomerulonephritis (MCGN)
ASO – post-streptococcal
AKI - Management
A – E assessment (with correction of any hypoxia)
Hold any potentially damaging drugs
Restrict potassium intake
Then manage cause:
PRE-RENAL
= Treat shock
RENAL
= Assess fluid status
Volume replacement (normal saline) to match losses (fluid balance chart)
If there is urine output after fluid replacement, continue large quantities of fluid +/- diuretics – furosemide stress test
If there is no urine output / there are complications – nephrologist input
POST-RENAL
= Refer to urology
AKI - complications
Hyperkalaemia
Hypernatraemia (unless pre-renal cause)
Metabolic acidosis
Rapidly progressive Uraemia
Volume overload => pulmonary oedema
CKD and End-stage renal disease
What is lymphoedema?
= swelling which results from an increased quantity of fluid in the interstitial space of soft tissues, due to failure of lymphatic drainage.
Can be PRIMARY or SECONDARY
It causes chronic, non-pitting oedema – commonly affecting the legs and progressing with age
Primary lymphoedema
Presents in early life
Due to an inherited deficiency of lymphatic vessels (e.g. Milroy’s disease)
Secondary Lymphoedema
Due to obstruction of lymphatic vessels (e.g. filarial infection, repeated cellulitis, malignancy, post-op).
Lymphoedema - Ix
Lymphoscintography can be used to confirm diagnosis, after other causes of oedema have been excluded (CCF, renal disease, deep venous insufficiency).
Lymphoedema - Mx
Elevation
Compression stockings
Physical massage
Long-term ABX if recurrent cellulitis (each episode further damages lymphatic drainage).
Raynaud’s Phenomenon vs Raunaud’s Syndrome
Phenomenon = general term describing episodic digital vasospasm in the absence of an identifiable associated disorder.
Syndrome = Raynaud’s phenomenon occurring secondary to another condition
Secondary causes of Raynaud’s
Connective Tissue Disease :
- Systemic Sclerosis
- Mixed connective tissue disease
- SLE
- Sjogren’s syndrome
- Polyarteritis Nodosa
Macrovascular Disease:
- Atherosclerosis
- Thoracic Outlet Obstruction
- Buerger’s disease
Occupational Trauma
- Vibration white finger
- Repeated extreme cold or chemical exposure
Drugs
- Beta-blockers
- Cytotoxic drugs
Others
- Malignancy
- AVF
Raynaud’s - presentation
Common triggers = cold exposure or emotional stress.
There are 3 phases:
1. Pallor – due to digital artery spasm
2. Cyanosis – due to accumulation of deoxygenated blood
3. Rubor – erythema due to reactive hyperaemia.
As the fingers return to normal, there may be numbness or a burning sensation and severe pain.
Attacks are usually <45 minutes; but can last for hours.
=> Very severe cases can involve tissue infarction and loss of digits.
Raynaud’s - Investigations
Primary Raynaud’s does not require further investigation.
if any features suggesting secondary cause:
- FBC, U&E, coagulation, glucose
- TFTs
- ANA/RF/APA – autoimmune screen if suspecting secondary cause.
Raynaud’s - Management
Keep extremities warm
Smoking cessation
Stop exacerbating drugs – e.g. beta-blockers, OCP
1st line medical therapy = nifedipine
=> Losartan/prazosin/fluoxetine = 2nd line
Sympathectomy may help those with severe disease, but may be short lived.
Paracetamol overdose - pathophysiology
Paracetamol = intrinsic hepatotoxin
- It is conjugated with glucuronide and sulphate at therapeutic doses.
- A small amount is metabolised by mixed function oxidase systems to form NAPQI
- NAPQI is immediately conjugated with glutathione due to its toxicity.
- In overdose, the normal conjugation pathways become saturated
- Large amounts of NAPQI are created.
- This overwhelms the liver glutathione stores to cause cellular damage.
Severity is dose-related, however those who are malnourished/low weight or with high alcohol intake appear to be more susceptible.
Paracetamol overdose - Presentation
Most remain asymptomatic for 24 hours – or at most develop anorexia, nausea and vomiting.
Symptoms/signs start to develop after 24 hours:
- RUQ pain
- Metabolic acidosis
- Hypotension
- Hypoglycaemia
- Pancreatitis
- Arrythmias
Liver damage is not detectable on blood tests until 18 hours after ingestion.
=> Damage peaks at 72-96 hours post-ingestion (deranged ALT/ALP and INR)
Without Tx, some develop fulminant liver failure.
Renal failure due to acute tubular necrosis can also occur.
Paracetamol overdose - Tx
A-E approach
Lavage if >12g (>150mg/kg) taken within 1 hour.
Give activated charcoal if <1 hour since ingestion.
Take a full set of bloods at 4 hours post ingestion
- Including INR, ABG, LFTs, U&Es, glucose, blood salicylate and paracetamol level
If <8 hours after ingestion – give IV acetylcysteine if blood levels above the treatment line on the hospital protocol.
If >8 hours after ingestion – treat immediately with N-acetylcysteine if >150mg/kg has been ingested.
=> Discontinue if plasma levels return below the treatment line, and the patient is asymptomatic with normal biochemistry.
If the patient continues to deteriorate then discuss with the liver team.
Discharge only after mental health team review.
Why is paracetamol level not measured until 4 hours after overdose ingestion?
Paracetamol level is unreliable before the 4-hour mark due to continuing absorption/distribution
N-acetylcysteine
Replenishes cellular glutathione stores and may repair oxidative damage.
Potential SEs:
- Rash, oedema, hypotension, bronchospasm (rarely serious; treated with IV chlorphenamine).
- Only stop the infusion in true anaphylaxis
Causes of splenomegaly
Infection
=> E.g. IE, bacterial sepsis, EBV, TB, malaria, schistosomiasis.
Inflammation
=> E.g. RA, SLE, sarcoidosis
Portal HTN
Haematological disease
=> Haemolytic anaemia, leukaemia, lymphoma, myeloproliferative disorders
–
MASSIVE splenomegaly (palpable in the RIF) can be seen in myelofibrosis, CML, lymphoma, malaria, leishmaniasis or Gaucher’s disease.
Hypersplenism
Splenomegaly of any cause can lead to hypersplenism, which results in:
- Pancytopaenia
- Increased plasma volume
- Haemolysis
What is the function of the spleen?
= largest lymphoid organ in the body
functions to break down erythrocytes and for immunological defence
Splenic Rupture
Most commonly caused by blunt trauma, occasionally by penetrating injuries.
Pre-existing illness can markedly increase the risks of splenic injury
Presentation:
- Immediate massive bleeding
- Peritonism from progressive blood loss
- Eventually shock
Rupture can occur hours-days after the initial trauma, due to expanding haematoma beneath the capsule (asymptomatic interval).
3 main routes of bacterial infection of the liver
- Ascending spread from cholangitis
- Portal spread from a focus of sepsis in the abdomen
- Systemic bloodstream spread in septicaemia
Pyogenic Liver Abscess - cause and presentation
Most common organisms:
- E. coli
- Strep. Milleri
- Anaerobes
Presentation:
- Patients are often not acutely unwell, may just have a long history of malaise.
- Can present acutely unwell with abdominal sepsis and a tender enlarged liver.
- May be pleural effusion in the right lower chest.
Pyogenic Liver Abscess - Investigations
USS/CT can detect a liver abscess.
CXR may show elevation of the right hemidiaphragm +/- pleural effusion
Pyogenic Liver Abscess - Management
Aspiration under USS guidance.
IV ABX
Treat underlying cause
Amoebic Liver Abscess - causes and presentation
Consider in patients with a Hx of travel.
Faeco-oral spread of entamoeba histolytica.
Presentation:
- May be asymptomatic
- Can get profuse/bloody diarrhoea
- Swinging high fever, RUQ pain and tenderness
Amoebic Liver Abscess - Investigations
Stool microscopy will show offending organism, blood and pus.
USS/CT to visualise the abscess
Amoebic Liver Abscess - Mx
Metronidazole for 5 days = Tx for amoebic dysentery
USS drainage may also be required.
Liver Hyatid Cyst - cause and presentation
Caused by echinococcus granulosis (dog tapeworm).
Infects humans coming into contact with infected dogs or food/water contaminated with dog faeces.
Thick-walled, slow-growing cyst
Either Asymptomatic or dull ache in RUQ
Liver Hyatid Cyst - Investigations
Positive hyatid complement fixation test/haemagglutination, eosiniphilia.
AXR – may show calcification of cyst wall
USS/CT – shows cyst
Liver Hyatid Cyst - Management
Albendazole and FNA under USS guidance
Deworming of pet dogs.
Liver Mets
90% of liver tumours are secondary metastases.
Primaries commonly in the lung/stomach/colon/breast/uterus.
Management = investigation to find the primary
Hepatocellular Carcinoma - causes
= Malignant tumour of hepatocytes – accounts for the majority of primary liver cancers.
Common in China and Sub-Saharan Africa (rare in the west)
Causes:
- Chronic hepatitis / cirrhosis
- Metabolic liver diseases
- Aspergillus aflatoxin
- Parasites
- Anabolic steroids
Hepatocellular Carcinoma - presentation
Symptoms:
- Non-specific fever, malaise, weight loss.
- RUQ pain
Signs:
- Hepatomegaly (may be smooth or hard/irregular)
- Signs of chronic liver disease / decompensation
- Abdominal mass / bruit over liver
- Jaundice is late presentation
Hepatocellular Carcinoma - Ix
Bloods – FBC, LFTs, clotting, hepatitis serology, AFP (raised in >50% of HCC)
USS/CT to identify lesions and guide biopsy
MRI to distinguish between benign/malignant lesions
ERCP/biopsy if cholangiocarcinoma suspected
Hepatocellular Carcinoma - Mx
Surgery for solitary HCCs <3cm, but high risk of recurrence
Liver transplantation if there are small tumours due to cirrhosis
=> Resection in cirrhosis can lead to decompensation
Benign liver tumours
Most commonly haemangiomas (incidental finding on CT/USS)
If the patient is a young woman on the OCP, it may be more likely to be a liver cell adenoma.
A benign liver tumour should only be treated if large/symptomatic
Jaundice
= yellow discolouration of the sclera, skin and mucous membranes secondary to hyperbilirubinaemia
Generally, the bilirubin needs to be around 2x the upper limit to be clinically visible
Bilirubin Metabolism
- Bilirubin is a product of haemoglobin breakdown. When a red cell is broken down (typically in the spleen), this releases unconjugated bilirubin (UCB).
- UCB is binds to albumin before being transported to the hepatocytes of the liver.
- In the liver it is conjugated by a hepatic enzyme. This conjugated bilirubin (CB) is then stored in the gallbladder as part of bile.
- Bile is released during digestion, where the CB is then broken down in the small intestine into Urobilinogen.
- Urobilinogen then takes 1 of 3 paths:
- Converted to stercobilin in the gut and excreted in the stool
- Absorbed into blood before being excreted by the kidney in the urine.
- Recycled back to the liver to be re-excreted in bile.
Stercobilin and Urobilinogen
Stercobilin gives stools their dark colour
Urobilinogen in the urine is oxidised to urobilin when exposed to air, eventually giving the urine a dark colour (as opposed to immediate dark urine of cholestasis, which is caused by conjugated bilirubin).
What are the 3 sub-types of jaundice?
- Pre-hepatic – Increased RBC breakdown
- Hepatic – Dysfunction of hepatocytes
- Post-hepatic – Cholestasis due to obstruction
Pre-hepatic Jaundice
Occurs due to increased breakdown of RBCs leads to increased UCB – this overwhelms the capacity of the hepatocytes to conjugate it
There will be leftover UCB in the bloodstream and results in jaundice.
Causes = anything causing haemolysis.
Hepatic Jaundice - causes
Hepatitis (Viral, autoimmune, alcoholic)
Cirrhosis
Drug-induced liver injury
Wilson’s Disease
Jaundice occurs due to:
- UCB not conjugated at a sufficient rate, leading to increased circulating UCB.
- A degree of obstruction means that CB not being transported into biliary ducts, CB builds up in the hepatocytes and ends up in the bloodstream (increased circulating CB).
ISOLATED unconjugated hyperbilirubinaemia
= hyperbilirubinaemia with no other blood test abnormalities (i.e. LFTs and reticulocytes)
DUE TO GILBERT’S SYNDROME
Gilbert’s Syndrome
Autosomal recessive inherited condition
Leads to defective gene encoding for the hepatic conjugation enzyme.
Intermittent jaundice in the absence of haemolysis or underlying liver disease.
Will see isolated elevated UCB on investigation
=> Normal LFTs and reticulocytes
Benign and self-limiting condition
Hepatic Jaundice - stool/urine colour
Urinary urobilinogen may be raised (due to inability of the liver to re-excrete what is reabsorbed)
If conjugated bilirubin levels are high enough => dark urine.
Stools could be paler than usual (due to a decrease in the ability to conjugate bilirubin and excrete it into the gut)
Pre-hepatic Jaundice - stool/urine colour
Large amounts of bilirubin excreted into the gut => normal stools
Urinary urobilinogen also raised (but no clinically dark urine as takes time to oxidise).
UCB cannot be excreted in urine
Post-hepatic jaundice - causes
Due to obstruction of bile outflow from the liver – leading to cholestasis.
Obstruction can be INTRA or EXTRA-HEPATIC
=> Pressure backs up bile between hepatocytes back to vasculature and CB is pushed back into the bloodstream (conjugated hyperbilirubinaemia).
Causes of intra-hepatic bile outflow obstruction
Hepatitis
Cirrhosis
Neoplasm
Drugs (chlorpromazine, flucloxacillin, isoniazid, OCP)
Pregnancy
Causes of extra-hepatic bile outflow obstruction
Gallstones
Cholangiocarcinoma
Primary sclerosing cholangitis
Congenital atresia of CBD
Pancreatitis
Tumour of pancreatic head
Post-hepatic jaundice - stool/urine colour
Pale stools – very little/no bilirubin reaching the GI tract.
Dark urine – conjugated bilirubin reaches the kidneys through the blood.
Jaundice - Investigations
Bloods:
=> FBC, reticulocytes, LFTs, U&Es, clotting, glucose, bilirubin levels.
Urinary urobilinogen/bilirubin
Further Investigations:
- Blood films / Coomb’s test – if ?haemolysis
- Viral serology/autoantibodies – if ?hepatitis
- USS - ?dilated duct system
- CT/MRI - intrahepatic / pancreatic lesions
ERCP if ductal system dilated on USS
Acute causes of hepatitis
Viral infections (Hep A-E or non-Hep infections)
Autoimmune
Drug reactions
Alcohol
Chronic causes of hepatitis
Hepatitis B +/- D virus
Hepatitis C virus
Autoimmune hepatitis
Alcohol
Hyperlipidaemia (NAFLD)
Drugs (methyldopa, nitrofurantoin)
Metabolic disorders (Wilson’s, alpha1-antitrypsin deficiency, haemochromatosis)
Liver screen
Done in any patient with suspected hepatitis / liver pathology of unknown origin
Microbiology – viral screen
Clinical chemistry:
- Ferritin / transferrin
- Lipids
- Caeruloplasmin
- AFP
- Alpha-1 antitrypsin
Immunology – autoantibodies
Abdominal USS
Hepatitis A
Transmitted faeco-orally
Notifiable disease
Does not lead to chronic liver disease, thus there are no carriers.
No specific treatment
Hepatitis E
Transmitted faeco-orally
Clinically similar to HepA infection:
- Causing epidemics of acute, self-limiting hepatitis
- No progression to chronic disease
Common in indo-china, so consider if recent travel.
Can cause severe disease in pregnant women
Which hepatitis viruses are spread faeco-orally ?
A
E
Hepatitis B
transmitted in blood/semen/saliva via skin breaks or mucous membranes
Vertical transmission = common worldwide
Around 10% of those infected will develop chronic disease
1% will develop fulminant liver disease
Which hepatitis viruses are spread via bodily fluids?
B
C
D
RFs for hepatitis B infection
Unprotected sex with multiple partners / someone who is infected
Sharing needles
MSM
Living with someone with chronic HBV
Infant born to infected mother
Job that exposes you to human blood
Travel to regions with high infection rates of HBV, such as Asia, the Pacific Islands, Africa and Eastern Europe
Hepatitis D
= Incomplete RNA virus
Can only cause infection in the presence of Hep B (as it requires the HepB virus for its own assembly).
Also transmitted by bodily fluids
Can be both acute and chronic
It can be acquired simultaneously with Hep B, or occur later.
Patients with Hep D superadded to HepB infection are more likely to develop fulminant liver disease.
Hepatitis C
clinically similar to HepB infection
Transmitted via bodily fluids
Particularly common in IVDUs
Vertical transmission is rare, and sexual transmission is uncommon
About 85% become chronically infected
30% get cirrhosis in 20 years.
Pathophysiology of Acute Hepatitis
Pathological changes are the same, regardless of cause.
Hepatocytes undergo degenerative changes (swelling & vacuolation) before necrosis and rapid removal.
Extent can vary from scattered necrosis to multiacinar necrosis leading to fulminant hepatic failure.
Pathophysiology of chronic hepatitis
= Defined as any hepatitis lasting more than 6 months.
Chronic inflammatory cell infiltrates are present in the portal tracts.
There may be loss of definition, necrosis and fibrosis.
This eventually leads to cirrhosis
The overall severity is judged by the degree of inflammation (grading) and the extend of fibrosis/cirrhosis (staging).
=> Using various scoring systems such as the Child-Pugh Score.
HBsAg
Hep B surface Antigen
Marker of viral replication and thus ACTIVE infection.
Appears within 6 weeks of infection
Disappears by 3 months after
HBsAb
Anti-HepB surface antibody
Marker of previously cleared infection OR vaccination
HBeAg
Hep B E Antigen
Marker of a high degree of viral replication (infectivity)
HBeAb
Anti-HepB E Antibody
Marker of natural immunity to Hep B
HBcAb IgG
Anti-HepB core IgG Antibody
Non-specific marker of current / previous infection
HBcAb IgM
Anti-HepB core IgM Antibody
Infection within the last 6 months
Hep B Virus PCR
= The best marker of viraemia
Immune tolerance phase (i.e. incubation) of hep B
HBsAg / HBeAg & PCR positive
Liver Transaminases negative (transaminases will be raised in any active disease)
Evidence of Hep B vaccination
Vaccination involves injecting the hepatitis B surface antigen.
Therefore there should only be evidence of surface antigen immunity (HBsAb)
Acute Viral Hepatitis - Presentation
PRE-ICTERIC PHASE:
- 1-2 week prodrome – malaise, arthralgia, headache, anorexia
- Classic aversion to cigarette smoke
- Vague RUQ pain
ICTERIC PHASE:
- Patient becomes jaundiced – with associated pale stools and dark urine (intrahepatic cholestatic jaundice)
- Pruritis
- May be associated with lymphadenopathy and hepato-splenomegaly.
Hep A and C often cause very mild or no symptoms
Extra-hepatic features are more common in Hep B
Acute Alcoholic Hepatitis - Presentation
Presents after a binge with jaundice, RUQ pain and systemic upset.
May be signs of chronic liver disease (acute on chronic presentation)
Bilirubin, prothrombin time and hepatic encephalopathy predict survival (combined to form the “discriminant function”)
AST:ALT ratio >2.0 suggests alcoholic liver disease.
Autoimmune Hepatitis - presentation
Most commonly presents as chronic hepatitis, but up to 40% of patients get acute hepatitis with jaundice.
The chronic form presents insidiously:
- Generally in women with non-specific symptoms of fatigue, arthralgia, fevers and weight loss.
Age peaks are at 15-25 or perimenopausal years.
Associated with other autoimmune conditions
- Most commonly primary biliary cirrhosis
- Primary sclerosing cholangitis
- IBD
Autoimmune hepatitis - Ix
High transaminases and IgG levels
Negative viral serology
High tires of autoantibodies (non specific – e.g. ANA)
Final diagnosis is with a liver biopsy.
Presentation of chronic hepatitis
Often asymptomatic unless complications (e.g. cirrhosis) develop
Can only be diagnosed when serum ALT levels are elevated for >6 months
=> E.g. on follow-up from acute viral hepatitis diagnosis.
Autoimmune Hepatitis - Mx
Start prednisolone 30mg OD
Add Azathioprine 1mg/kg/day after TPMT assays
If there are falls in transaminases, gradually reduce the prednisolone dose to maintain the fall.
Long-term therapy with low-dose prednisolone (5-10mg) and azathioprine is then recommended
=> Bone protection plus monitoring required
Hepatitis B - Mx
Have a low threshold for screening patients with RFs for acquiring HBV
Notify Public Health (it is a notifiable disease)
Refer to gastroenterology, hepatology or infectious diseases for specialist management
Lifestyle:
- Stop smoking and alcohol
- Education about reducing transmission and informing potential at risk contacts
The acute episode is treated with supportive therapy and alcohol avoidance (95% will recover and develop immunity)
1st line management of chronic hepatitis is with SC peginterferon alfa-2a for 48 weeks.
Hepatitis C - Mx
Very specialist area of management – Refer to gastroenterology, hepatology or infectious diseases
There are new drugs on the market that have replaced PEG interferons
Indications for liver biopsy
- Chronic hepatitis
- Cirrhosis
- Suspected neoplastic disease
- Storage diseases
- Unexplained hepatomegaly
Liver biopsy - contraindications
- Prolonged PT
- Platelet count <80
- Ascites
- Extrahepatic cholestasis
Alternatives to liver biopsy
A newer alternative = fibroscan (transient elastography), which allows the liver “stiffness” to be measured non-invasively.
Other non-invasive tests exist = MR elastography, serum biomarker tests.
Spirometry - FEV1
= volume that has been exhaled at the end of the 1st second of forced expiration
(Typically, over 70-80% of the FVC will be expired in the first second)
Spirometry - FVC
= forced vital capacity; the volume that has been exhaled after a maximal expiration following a full inspiration.
(usually around 5L)
Spirometry - TV
= Tidal Volume; the volume of air entering and leaving the lung with each normal breath
Spirometry - Kco / TLco
Both measures of gas transfer
KCO = Diffusion capacity of the lung per unit area for CO.
TLCO = Diffusion capacity of the total lung capacity for CO.
Decreased TLCO /KCO indicate an issue with gas exchange, which can be due to either ALVEOLAR disease or VASCULAR disease.
=> This rules out chest wall/ diaphragm pathology.
Spirometry - obstructive pattern
Normal (or increased FVC)
Reduced FEV1/FVC
Spirometry - restrictive pattern
Reduced FVC
Normal (or increased) FEV1/FVC
What is bronchiectasis?
= chronic dilation of the airways, leading to chronic inflammation/infection.
Bronchiectasis - presentation
SYMPTOMS:
* Recurrent cough, with copious amounts of infected sputum.
* Intermittent haemoptysis (can be the only symptom).
* Persistent halitosis
* Dyspnoea
* Recurrent febrile episodes and episodes of pneumonia
SIGNS
* Clubbing
* Coarse inspiratory crackles over infected areas (typically bibasal)
* Wheeze
* Often low BMI, due to high energy demands
Bronchiectasis - causes
Idiopathic = most common
Otherwise:
- Post-infective – TB, measles, pertussis, pneumonia
- CF
- Bronchial obstruction – tumour/FB
- Allergic broncho-pulmonary aspergillosis
- Ciliary dyskinetic syndromes – Kartagener’s syndrome, Young’s syndrome
- Immune deficiency – IgA, hypogammaglobulinaemia
- CTDs – 1/3rd of RA patients develop bronchiectasis.
Bronchiectasis - Pathophysiology
Any bronchi may be involved, but most commonly at the lung bases.
Airways are dilated, with purulent secretions and chronic inflammation in the wall with inflammatory granulation tissue
=> Granulation tissue can bleed, leading to haemoptysis.
With repeated exacerbations, there can be fibrous scarring, leading to respiratory failure.
Bronchiectasis - Ix
Sputum culture
=> Atypical organisms
CXR - Cystic shadowing
CT
=> To assess distribution of disease;
=> Can see dilated airways with “signet ring” sign.
Spirometry
=> Obstructive pattern
=> Reversibility should be assessed.
Other tests to look for cause
=> E.g. serum immunoglobulins, CF sweat test, aspergillus precipitins
What organisms are often seen in bronchiectasis
Atypical organisms
Most common organism is haemophilus
Pseudomonas, Klebsiella and Strep pneumoniae are also common
Bronchiectasis - Mx
Assess for rare but treatable causes (e.g. immune deficiencies)
Smoking cessation
Chest Physiotherapy
=> Inspiratory muscle training
Postural drainage – twice daily
ABX for exacerbations
=> According to known sensitivities
=> Constant rotating ABX in severe disease
Immunisations
Bronchodilators can be useful in some cases
Surgery is rarely indicated (as the disease is rarely confined to one lobe).
=> Lobectomy used to be common
Indications for Lobectomy
Lung cancer
Previously Bronchiectasis (less common now)
Chronic lung abscess / TB
Fungal infections – life-threatening haemoptysis due to aspergillus.
Sarcoidosis
= Systemic non-caseating granulomatous disease.
Most commonly affects the lungs, mediastinal lymph nodes, and skin.
Typically occurs in females, aged 20-40
Presents as subacute illness, with non-specific features of malaise, arthralgia, etc.
Pulmonary manifestations lead to fibrosis.
Sarcoidosis can also lead to glomerulonephritis, cardiomyopathy, arthritis, cranial nerve lesions and erythema nodosum.
Sarcoidosis - Mx
The acute form is usually self-limiting (2 months to 2 years) but it can present as a chronic insidious disease, with progressive dyspnoea.
Tx:
- Simple analgesia and NSAIDs
- Occasional corticosteroid courses if there is progressive lung fibrosis.
How can aspergillus fungus affect the lungs?
- Asthma
- Extrinsic Allergic Alveolitis (EAA) – malt worker’s lung
- Allergic Bronchopulmonary aspergillosis
- Aspergilloma
- Invasive Aspergillosis
Allergic Bronchopulmonary aspergillosis
More common in asthmatics and CF patients
Type I and II reaction, giving asthma-like symptoms with a productive cough
Needs steroid Tx
Aspergilloma
= fungal ball formation within pre-existing lung cavities (e.g. TB)
May be asymptomatic, cause general malaise/weight loss or torrential haemoptysis.
Tx = Single lesions may be resected.
Invasive Aspergillosis
Affects immunocompromised individuals
Needs aggressive Tx with antifungals
Mortality is high
Cystic Fibrosis - inheritance
Autosomal recessive inheritance
Caucasians have a carrier frequency of 1 in 25
Due to a mutation in the cystic fibrosis transmembrane conductance regulator (CTFR) gene on chromosome 7, position 508.
Genetic screening is available for the 4 most common mutations, and this identifies 90% of CF cases.
What is the most common mutation causing CF?
point deletion (DF508)
This codes for a cAMP-regulated chloride cannel present on multiple epithelial surfaces (predominantly in the pancreas and respiratory tract).
CF - pathophysiology
mutation in the CTFR gene leads to abnormally thick secretions, this leading to pancreatic insufficiency and recurrent chest infections.
CF - pulmonary effects
Recurrent childhood chest infections
FTT
Breathlessness and haemoptysis develop in later years as progressive bronchiectasis develops.
Spontaneous PTX is common
Most will have chronic sinusitis and many will have nasal polyps
Respiratory failure and cor pulmonale can eventually develop due to scarring of the pulmonary vasculature.
Pathogens involved in chest infections in CF
initially mainly caused by S. aureus, Haemophilus influenza and gram-negative bacilli.
Later, pseudomonas predominates (this is associated with poor prognosis).
CF - GI effects
Meconium ileus is common at birth
Steatorrhoea due to pancreatic dysfunction, associated with malabsorption
Increased frequency of gallstones & peptic ulceration.
Cirrhosis sometimes develops in older patients.
CF - other effects (non-GI/pulmonary)
Clubbing
Infertility in most males (congenital absence of vas deferens rather than increased viscosity)
Subfertility in females
DM
Rickets/osteomalacia (due to vitD deficiency)
CF - Ix
Bloods:
- FBC, U&Es, LFTs, clotting
Sodium sweat test
- Levels >70 mmol/L are characteristic
Annual diabetes screening
Sputum cultures
CXR
=> Hyperinflation, evidence of bronchiectasis.
Abdo USS
=> Fatty liver/cirrhosis
=> Chronic pancreatitis
Spirometry
=> Obstructive deficits
CF - Mx
CHEST
- Two parenteral ABX are used for exacerbations (to decrease resistance, often one with pseudomonal cover).
- Experts may decide whether to employ regular ABX prophylaxis
- Mucolytics (e.g DNase daily nebulisers)
- Airway clearance devices (E.g. acapella)
- Lung transplant (if resp. failure develops).
GI
- Pancreatic enzyme replacement (Creon)
- Fat soluble vitamin supplementation (ADEK)
- Liver transplantation for advanced cirrhosis
OTHER
- Tx of diabetes
- Fertility treatment
- Genetic counselling.
+ disease modifying drugs?
Disease modifying drugs in CF
Orkambi:
- Used for patients with homozygous DF508
- Lumacaftor increases the number of CFTR proteins transported to the cell surface
- Ivacaftor potentiates those already at the cell surface to increase the probability that the channel will be open
Symkevi:
- Can also be used for heterozygous DF508 patients.
Bundle Branch Block
In BBB, the depolarisation wave reaches the septum normally, so the PR interval is normal (in contrast to complete heart block).
Delayed depolarisation of the ventricles thus leads to wide QRS (>120ms or 3 small squares)
Right Bundle Branch Block
The septum is depolarised from the left side as normal
As it takes longer for excitation to reach the right ventricle, this depolarises after the left, causing a second R wave.
RBBB is best seen in V1 with an “RSR pattern”
Delayed overall conduction time to the RV extends the QRS duration to > 120 ms
No specific Tx is needed for RBBB, but consider underlying ASD / PE.
Left Bundle Branch Block
conduction delay means that impulses travel first via the right bundle branch to the RV, and then to the LV via the septum
Delayed overall conduction time to the LV extends the QRS duration to > 120 ms
The overall depolarisation vector from the right to left ventricle produces tall R waves in lateral leads (I, V5-6) and deep S waves in the right precordial leads (V1-3).
The delay between activation of the RV and LV produces the characteristic “M-shaped” R wave seen in lateral leads
–
If LBBB is present, no further interpretation of the ECG is possible.
=> If asymptomatic, consider aortic stenosis.
=> If chest pain, LBBB = STEMI as you cannot prove otherwise
What is heart block?
= abnormal conduction from the SAN to the ventricles.
1st Degree Heart block
= Fixed, prolonged PR-interval (>5 small squares or 1 big square)
The prolongation remains fixed in length, and P-waves remain associated with QRS complexes
1st degree Heart Block is not itself pathological, but it can indicate:
- Coronary artery disease
- Acute rheumatic fever
- Electrolyte disturbances
- Digoxin toxicity.
2nd Degree Heart Block – Mobitz I (Wenckebach)
Excitation intermittently fails to pass through the AVN or bundle of His.
PR-interval progressively elongates, eventually culminating in the non-conduction of one P-wave, before the cycle begins again with a minimally-prolonged/normal PR interval.
Often no specific treatment needed for this type.
2nd Degree Heart Block – Mobitz II (Hay)
Excitation intermittently fails to pass through the AVN or bundle of His.
Intermittent conduction and non-conduction of P waves without PR-interval prolongation (can be no pattern, or fixed ratio e.g. “2:1”, “3:1”, etc. )
This type of block will need permanent pacing due to high risk of asystole.
3rd Degree Heart Block
= complete heart block
There will be total dissociation between atrial and ventricular activity
=> NO conduction between atria and ventricles
=> ventricles are excited by a slow escape mechanism randomly
Can occur acutely following MI, or be a chronic state.
Tx –> Pacing is generally always required due to high risk of asystole.
Sinus arrythmia
Occurs in young people where heart rate changes with respiration – R-R interval changes progressively on a beat-beat basis.
Sinus Bradycardia
HR <60
Can be associated with athletic training, fainting attacks, hypothermia, hypothyroidism.
Can also occur immediately after MI
Sinus tachycardia
HR >100
Can be associated with exercise, fear, pain, haemorrhage or thyrotoxicosis
supraventricular rhythms
QRS complex is normal – depolarisation spreads to the ventricles in the usual way via the bundles.
Sinus rhythms give a normal P wave
Atrial rhythms give an abnormal P wave
Junctional rhythms (AVN) will not show P waves.
Ventricular rhythms
wide (slower spread of depolarisation through the ventricles) and abnormal QRS complexes.
Ventricular escape rhythm
A slow, protective rhythm initiated by a focus in the ventricles
if the SAN fails or conduction is completely blocked
~20 - 40 bpm
Bradycardia - Mx
A-E, treat reversible causes
Assess for adverse features and risk of asystole
=> Adverse features – shock, syncope, heart failure, myocardial ischaemia
=> Risk of asystole – recent asystole, Mobitz II or complete heart block
If none of these features are present, continue to observe and monitor.
If any of these features are present, initiate treatment and seek expert help
=> Atropine 500 mcg IV; repeated up to a maximum of 3mg.
Cardiology may then initiate transcutaneous pacing prior to more definitive pacing of the heart.
Extrasystoles
If any part of the heart depolarises quicker than it should, and this is accompanied by an extra heartbeat, this is called an extrasystole.
Atrial extrasystoles have an abnormal P wave
Junctional extrasystoles have no P wave
=> Normal QRS complexes in both
Ventricular extrasystoles have a wide QRS that can take virtually any shape.
These are common and usually of no importance, however, if they occur early in the T wave of a preceding beat, they can induce a ventricular fibrillation.
What is Supraventricular Tachycardia?
the atria depolarise faster than 150/min
=> P waves are often superimposed on the previous T waves.
The AV node can only conduct atrial discharge rates of up to 200/min, so above this “atrioventricular block” occurs and some P waves are not followed by QRS complexes.
Supraventricular tachycardia - Mx
A-E resuscitation, asses for adverse features.
=> Synchronised DC cardioversion if any adverse features.
If irregular rhythm / atrial flutter – treat as AF
If regular, first attempt vagal manoeuvres:
=> Carotid sinus massage / Valsalva manoeuvre
=> These lead to vagal stimulation of the SAN/AVN, causing decreased SAN discharge and increased AVN delay.
If unsuccessful, IV adenosine.
=> 6mg initially, 12mg if no effect, then another 12 mg bolus.
Electrical cardioversion if this is not successful.
Secondary prevention is indicated with beta-blockers
Vagal manoeuvres in SVT
Carotid sinus massage / Valsalva manoeuvre
=> These lead to vagal stimulation of the SAN/AVN, causing decreased SAN discharge and increased AVN delay.
Ventricular tachycardia
Wide, abnormal QRS seen in all 12 leads.
Potential to transform to VF, so requires urgent treatment
Management:
- If systolic BP <90mmHg, chest pain, heart failure or rate >150 – immediate electrical cardioversion
- If absence of these signs – amiodarone 300mg loading dose over 30 minutes
=> Electrical cardioversion if this fails
Ventricular fibrillation
No QRS can be identified and the ECG is totally disorganised
The patient will usually have lost consciousness
Manage as per the cardiac arrest protocol.
Atrial Fibrillation
Irregular baseline with no P waves
The AVN is bombarded and thus will depolarise irregularly, leading to ventricular contraction at an irregular rate.
=> Usually 450-600 atrial contractions / minute
=> Normal QRS as conduction from the AVN is not abnormal
AF can be asymptomatic, or present with dyspnoea, palpitations, syncope, chest pain or stroke / TIA
If no abnormalities are seen on ECG, 24-hour ambulatory ECG monitoring or an event recorder can be used to detect paroxysmal AF.
AF - management
If presenting symptomatic with haemodynamic instability – emergency electrical cardioversion and immediate anticoagulation.
If haemodynamically stable:
1. Rate control
2. Rhythm control
3. Anticoagulation
AF management - rate control
Generally 1st line
Beta-blocker (bisoprolol) or RL CCB (verapamil / diltiazem) are the agents used.
=> CCBs are CI’d in heart failure;
=> Beta-blockers are CI’d in asthma
Therapeutic target is 60-80 bpm at rest
If the symptoms are not controlled with one drug, combination therapy can be used.
AF management - rhythm control
May be indicated in younger patients with new onset AF (<48h) and evidence of a reversible cause (e.g. chest infection), or the AF is causing heart failure.
Cardioversion can be pharmacological or electrical
Pharmacological options include flecanide and amiodarone.
Cardiologist referral is generally required.
AF management - anticoagulation
Heparin at initial presentation (if no contraindications / not already anti-coagulated)
Then assessment of the need for long-term anticoagulation using the CHA2Ds2VAsc tool to assess stroke risk
=> Anticoagulation should be considered for anybody with a score of 2 or more
=> The HASBLED tool should be used to assess the risk of major bleeding.
Either warfarin or a DOAC can be used according to patient preference (target INR 2-3)
If an anticoagulant is contraindicated, offer DAPT (aspirin and clopidogrel), as one antiplatelet alone is not sufficient.
Causes of AF
Cardiac – HTN, valvular heart disease, heart failure, ischaemic heart disease.
Respiratory – chest infections, PE, lung cancer
Systemic – excessive alcohol intake, thyrotoxicosis, electrolyte depletion, infections, DM.
Consider assessment for these with FBC, TFTs, U&Es, glucose, ECG (old infarction), echo and CXR.
Atrial Flutter
If the atrial rate is above 250 / min and no flat baseline between P waves exists, atrial flutter is present.
=> Classic “sawtooth” baseline.
Can be thought of as similar to AF, in that the normal coordination of the atria are lost, however some element of synchronicity still exists.
Generally treated as per AF.
Wolff-Parkinson White Syndrome
Some people have an accessory conduction pathway, causing the action potential to bypass the AVN.
This triggers early depolarisation of part of the ventricle (seen as a Delta Wave on the ECG)
The second part of the QRS is normal as the bundle of His conduction catches up
The ECG s in sinus rhythm but there is right axis deviation, short PR interval and widened QRS with a delta wave of pre-excitation.
The only clinical importance is that it can cause paroxysmal tachycardia
Right Atrium
Receives deoxygenated venous blood from the SVC, IVC and coronary sinus.
Pumps blood though the right atrioventricular orifice (guarded by the tricuspid valve) separates the RA and RV.
Forms the right border of the heart.
Right Ventricle
Receives deoxygenated blood from the right atrium
Pumps blood through the pulmonary orifice (guarded by the pulmonary valve), into the pulmonary artery.
It forms the majority of the anterior border of the heart.
Left Atrium
Receives oxygenated blood from the four pulmonary veins
Pumps blood through the left atrioventricular orifice (guarded by the mitral valve) into the left ventricle
The left atrium forms the posterior border (base) of the heart
Left Ventricle
Receives oxygenated blood from the left atrium
Pumps blood through the aortic orifice (guarded by the aortic valve) into the aorta.
Left Coronary Artery
Initially branches to yield the left anterior descending (LAD) artery (also “anterior interventricular artery”)
Also gives off the left marginal artery (LMA) and the left circumflex artery (Cx).
In ~20-25% of individuals, the left circumflex artery contributes to the posterior interventricular artery (PIv).
Typically supplies:
- The left atrium
- Most of the left ventricle
- Part of the right ventricle
- Most of the IV septum – usually anterior two thirds (including AV bundle)
- The SA node – approx. 40% of people
Right Coronary Artery
Branches to form the right marginal artery (RMA) anteriorly.
In 80-85% of individuals, it also branches into the posterior interventricular artery (PIv) posteriorly.
Typically supplies:
- The right atrium
- Most of the right ventricle
- Part of the left ventricle
- Part of the IV septum – usually posterior third
- SA Node – approx. 60% of people
- AV Node – approx. 80% of people
Coronary veins
The coronary sinus runs from left to right in the posterior part of the coronary sulcus.
The coronary sinus receives the great cardiac vein at its left end and the middle and small cardiac veins at its right end
ECG - P-wave
represents atrial depolarisation
Normally <3 small squares
ECG - PR interval
= the distance between the start of the P wave and the start of the QRS complex
it represents atrial depolaristation and the delay at the AV Node.
Normal duration = 3-5 small squares
ECG - QRS Complex
represents ventricular depolarisation.
Normal duration – <3 small squares
Normally positive in I, II, V4-V6; negative in aVR, V1 and V2
ECG - QT interval
represents the whole ventricular action potential
normal to be slightly longer in women
This needs rate-correcting (QTc)
approach to ECG interpretation
- Patient identification + indication for ECG + calibration
- General Impression
- Rate
- Rhythm
- Axis
- P-waves (present / absent)
- P-R Interval (normal / prolonged / shortened)
- QRS complexes (narrow / broad)
- ST segments
- T waves
- QT Interval
ECG - cardiac axis
- Normal Axis => I, II and III all point up
- Left axis deviation (“leaving”) => I up, II and III down
- often associated with essential hypertension or valvular heart disease - Right axis deviation (“reaching”) => I down, II and III up
- often associated with COPD and pulmonary hypertension.
ECG - ST elevation
Is the J-point of the ST segment elevated?
must be by at least:
* 1mm in the limb leads
* 2mm in the chest leads
must occur in 2+ adjacent leads
=> indicates STEMI
ECG - ST depression
Any depression >0.5mm in 2+ leads is abnormal
Indicates ischaemia.
“tall and tented” T waves
Tall – at least ½ the amplitude of the preceding QRS complex
Tented – look as if they’ve been pinched from above - i.e. a pointed peak, narrow base
Caused by hyperkalaemia.
inverted T waves
This is normal in Lead aVR (where everything should be negative)
can be a normal variant in Leads V1 and III
T-wave Inversion in other leads is a non-specific sign for Ischaemia, BBBs, PE, Hypertrophic Cardiomyopathy (HCM) etc.
flattened T waves
a non-specific sign of ischaemia or of electrolyte imbalance (e.g. Hypokalaemia)
polycystic kidney disease - inheritance
Can be either:
- autosomal dominant (more common, less severe)
- autosomal recessive.
Autosomal dominant PKD
Both kidneys are gradually replaced by enlarging fluid-filled cysts, compressing the parenchyma out of existence.
Presentation:
- Systemic HTN
- CKD
- Abdominal swelling (due to very large kidneys bilaterally)
Renal failure generally occurs later in life, after the genes are passed on.
Cysts also occur in the liver, lungs, pancreas (but without symptoms).
Autosomal recessive PKD
Rarer
Earlier in onset
Runs a more malignant course, with chronic renal failure earlier in life.
Cysts in the liver lead to portal HTN and fibrosis
PKD - Management
As for CKD, but with screening for berry aneurysms.
Glomerulus structure
The glomerulus creates three layers for substances to pass through:
- Fenestrated capillary epithelium
- Basement membrane
- Visceral layer – formed by interdigitating podocytes.
This creates a “sieve” that allows small, charged ions through, yet will not allow the transport of proteins or blood.
Glomerulonephritis - pathophysiology
injury to the glomerulus, caused by an immunological attack, by an antibody or T cell attacking an antigen in the glomerulus.
This may be primary or secondary (acquired/deposited)
Capillary
- Endothelial cell proliferation => bigger fenestra
- Capillary wall necrosis
- Glomerulosclerosis – scarring in the mesangium leading to fenestra and capillaries being pulled apart.
Basement Membrane
- Thickened membrane – leading to structural distortion and thus becomes more permeable.
Tubules
- Deposition of cells in Bowman’s space.
Secondary factors causing deposition of antigens in the glomerulus (“NSAID HSP”)
N – neoplasm
S – SLE
A – amyloid
I – Infection
D – Diabetes
HSP – Henoch Schoenlein Purpura
Potential histological changes in glomerulonephritis
GLOBAL – whole glomerulus is diseased
SEGMENTAL – small patches of one glomerulus are damaged in a “patchy” fashion
DIFFUSE – affecting >50% of glomeruli
FOCAL – affecting <50% of glomeruli
Nephrotic Syndrome - triad of symptoms
- Proteinuria (at least 3.5 g/day)
- Hypoalbuminaemia (<30g/L)
- Oedema (due to decreased oncotic pressure and water retention).
=> Oedema typically occurs peri-orbitally and peripherally in limbs.
Nephrotic Syndrome - Mx
Investigate as per any suspected glomerulonephritis
Tx:
Diuretics, salt/water restriction and ACEIs to reduce proteinuria
Anticoagulation if immobile, due to risk of thrombosis
Treat the cause.
Nephrotic Syndrome - causes
most common primary causes:
- Minimal change nephropathy
- Membranous glomerulonephritis
- Proliferative glomerulonephritis
Secondary causes may be bacterial/viral infection, drugs, neoplasm.
How does nephrotic syndrome cause venous thrombosis?
Renal loss of thrombo-regulatory proteins or lipo-regulatory proteins may lead to hyperlipidaemia or venous thrombosis.
Nephritic Syndrome - tetrad of symptoms
Tetrad of:
1. Haematuria + red cell casts (can be microscopic)
2. Oliguria
3. Proteinuria (can be less than 3.5g)
4. HTN
Is nephrotic or nephritic syndrome proliferative?
NEPHROTIC - non-proliferative
NEPHRITIC - proliferative (increased cell numbers as well as damage to the basement membrane)
Nephritic syndrome - causes
Common primary causes:
- IgA nephropathy
- Goodpasture’s disease
Secondary causes are commonly SLE/HSP.
Glomerulonephritis - Ix
Bloods – FBC, U&E, CRP, culture
Urine dip to r/o infection
Urine MCS for red cells/red cell casts/ Bence-jones protein
Urine protein/creatinine ratio to quantify protein loss.
Nephritic screen to look for causes.
Renal USS
Renal biopsy to confirm the cause in all adults
Urine protein:creatinine ratio
generally used instead of 24-hour urinary protein estimation, as it is more convenient and equally accurate.
The amount of protein in mg per mmol of creatinine equates to the amount of protein excreted in over 24 hours
Random protein:creatinine ratios >300mg/mmol are considered “nephrotic range”
Ratios of 50-100 mg/mmol are considered significant proteinuria and should be repeated with an early morning sample.
Glomerulonephritis - Buerger’s Disease
= IgA nephropathy
presents with nephritic syndrome
Renal biopsy demonstrates IgA/C3 deposits
Mx:
- Supportive
- 20% progress to ESRD over 20 years – steroids may slow the decline in renal function.
Glomerulonephritis - Minimal Change Nephropathy
The most common cause of glomerulonephritis in children (75%)
Characterised by normal light microscopy and negative immunofluorescence
Electro-microscopy will show fusion of podocyte foot processes.
Tx:
- Oral steroids
- Cyclophosphamide if relapsing.
- 99% of cases resolve in 4-6 weeks if treated with steroids (adults may need longer courses).
Glomerulonephritis - Membranous Nephropathy
Mostly idiopathic
Diagnosed on biopsy
=> Global diffuse glomerulonephritis with IgG and C3 deposits
Focal Segmental Glomerulosclerosis
Idiopathic areas of segmental sclerosis, with IgM and C3 deposits
Response to treatment is poor.
Membranoproliferative Glomerulonephritis
Presents with nephrotic or mixed nephrotic / nephritic syndrome
Biopsy shows large glomeruli with a “double basement membrane” due to mesangial proliferation, giving a tramline appearance
50% develop ESRF in 10 years, and there is a high recurrence rate in transplants.
Post-streptococcal Glomerulonephritis
Patients present with nephritic syndrome 1-2 weeks following a sore throat / skin infection
Biopsy shows a diffuse proliferative GN with IgG and C3 deposits, although there is no need to biopsy in typical cases.
Bloods:
- Raised ASOT / anti DNAase B
- Reduced complement levels
What is Henoch Schoenlein Purpura (HSP)?
Typically in children aged 3-15
Present with symptoms of a systemic small vessel vasculitis (IgA deposition) and nephritic syndrome following an URTI
HSP - Investigations
Diagnosis is usually clinical, confirmed with positive immunofluorescence in skin/renal biopsy (IgA).
HSP - presentation
Purpuric rash on extensor surfaces
Polyarthritis
Abdominal pain (due to GI bleeding)
Scrotal/scalp swelling
Glomerulonephritis (indistinguishable from IgA nephropathy).
HSP - management
Attacks are usually self-limiting
If there are relapses/evidence of progressive renal involvement, then corticosteroids are indicated.
Goodpasture’s Syndrome
Anti-glomerular basement membrane (anti-GBM) antibodies recognise an epitope on type IV collagen, present in the glomerular basement membrane.
Presents with:
- Haematuria and a rapidly progressive glomerulonephritis
- Pulmonary haemorrhage leading to haemoptysis and breathlessness.
Goodpasture’s Syndrome - Ix
CXR will show pulmonary shadowing
Renal biopsy will show linear IgG deposition along the glomerular basement membrane.
Goodpasture’s syndrome - Mx
= plasma exchange and corticosteroids +/- cytotoxics.
Glomerulonephritis - systemic vasculitis
Leads to focal segmental glomerulonephritis, with appearance overlapping with IgA nephropathy
They are often ANCA positive.
Rapidly Progressive Glomerulonephritis
= Glomerulonephritis rapidly leading to ESRF, presenting with signs of renal failure and systemic disease.
Causes:
- Immune complex diseas (e.g. SLE / endocarditis / IgA nephropathy).
- Vasculitis (e.g. HSP, Wegener’s, Churg-strauss syndrome, etc.)
- Goodpasture’s disease
Management:
- Aggressive immunosuppression (high dose steroids and cyclophosphamide).
- Prognosis depends on how early treatment is initiated.
Spinal cord - ascending tracts
The tracts by which sensory information from a peripheral nerve is transmitted to the cerebral cortex.
Consists of:
- Dorsal columns
- Lateral Spinothalamic Tract
- Ventral spinothalamic tract
Spinothalamic Tracts
Transmit pain, temperature, and light touch to the thalamus.
Decussates at the spinal level.
Dorsal Columns
Transmit deep touch, proprioception, and vibration to the parietal cortex.
Decussates in the brainstem.
Corticospinal Tracts
Transmits motor axons from the motor cerebral cortex to the spinal cord.
Decussates in the brainstem.
General Approach to spinal cord trauma
A to E
=> High C-spine lesions can lead to a total/partial loss of respiratory function.
Determine the mechanism of injury
Physical Examination:
=> Vision, palpation of vertebral column, neurological exam.
Imaging
Imaging choice in spinal cord trauma
AP / lateral/ C2 open mouth (peg view) XR (if the C-spine cannot be cleared clinically)
CT C-spine if
- Already having head/other body CT
- If X-Rays are suspicious
- If intubated/rapid diagnosis required.
Whole spinal X-ray if one spinal fracture identified.
Spinal trauma - Unconscious Patients
Any trauma patients with LoC need C-spine stabilisation
If there are signs of neurological deterioration, urgent CT head to T4/5 should be performed.
If there are not – cervical, thoracic and lumbar spine XR is required.
Spinal precautions can be ceased if a consultant radiologist reviews the above imaging and there are no signs of an abnormality; as well as no clinical signs suggestive of a spinal cord injury.
Spinal trauma - Conscious Patients
If GCS is 15 and the patient is stable, follow the “Canadian C-spine Rules” if spinal injury is a concern.
If the patient is >65, has paraesthesia in the extremities or there was a dangerous mechanism => radiography.
If not, then there are 5 factors which will allow attempt to clinically clear the C-spine.
1. Simple rear-end RTA
2. Sitting position in ED
3. Walking at any time
4. Delayed onset of neck pain
5. Absence of C-spine tenderness
If none of these factors are present, then radiography is required.
If one or more of these criteria are satisfied, attempt to clear clinically:
* Ask the patient to rotate neck 45o to left and right
* If the patient can do this, the C-spine can be considered “cleared” without radiology.
If there is clinical uncertainty, it is always better to err on the side of caution and get radiology input.
Cord Transection at C3
- Neurogenic shock
- Respiratory insufficiency
- Quadriplegia
- Anaesthesia below affected level
- Loss of bladder/bowel sphincter tone
- Sexual dysfunction
- Horner’s syndrome may also be present
Cord Transection at T10
- Paraplegia
- Anaesthesia below affected level
- Loss of rectal/bladder sphincter tone.
- Sexual dysfunction
Cord Hemi-section (Brown-Sequard Syndrome)
A unilateral lesion of the spinal cord will cause Brown-Sequard Syndrome:
=> Ipsilateral reduced power (CST) / vibration & proprioception (DC)
=> Contralateral reduced pain/temperature/light touch (STT)
This can occur in trauma or transverse myelitis (MS)
Posterior Cord Lesion (= loss of dorsal tract)
Tingling, numbness, electric-shock like syndromes
Clumsiness
O/E:
- Sensory ataxia
- Loss of proprioception,
- Loss of vibration sense
- Loss of 2-point discrimination below the level of the lesion.
Causes of Posterior Cord Lesion
Demyelinating disease – e.g. MS, B12 deficiency, etc.
External compression – e.g. tumours, mechanical degeneration of cervical spine.
Occlusion of posterior spinal artery.
What is normal ICP?
Normal ICP is 0-10 mmHg.
Causes of increased ICP
Vasogenic – increased capillary permeability
=> Tumour, trauma, ischaemia, infection
Cytotoxic – cell death
Interstitial – obstructive hydrocephalus
Raised ICP - symptoms
Headache
- Dull persistent ache,
- Worse on lying,
- Present on waking,
- Worse by coughing/straining
Vomiting
Seizures
Irritability
Raised ICP - signs
GCS deterioration
Progressive dilation of the pupil on the affected side
Cushing’s reflex
Cheyne-Stokes respiration
(Papilloedema is NOT an acute sign of raised ICP, it takes weeks to occur)
Raised ICP - Mx
Elevate the head of the bed to 30-40 degrees
If intubated, hyperventilate to reduce PaCO2
=> Almost immediate reduction in ICP
Mannitol
=> 0.2g/kg 20% IV over 15 minutes
=> Clinical effect after 20 minutes
=> Useful as a temporary measure prior to definitive management
Corticosteroids:
=> Only useful for oedema around tumours
Fluid restriction
Consider monitoring ICP (surgically implanted extradural catheter)
Make diagnosis and treat the cause
Methods to reduce ICP
Hyperventilation if intubated
Mannitol
Controlled hypothermia,
CSF drainage
Barbiturates.
Positioning the patient for an LP
The patient lies on their side, curled forward with knees to their chest (opens lumbar interspinous spaces).
Alternative position = sitting forward, curled into a pillow (especially useful in obese patients).
However, the opening pressure can only be measured if the head is at the same level as the lumbar spine (i.e. in lateral recumbent position).
Performing a Lumbar Puncture
The spine of L4 is identified.
=> Found at the level of the tops of the iliac crest.
A LP needle is introduced obliquely above L4, parallel to the place of the spine, though the interspinous ligament.
There is a slight “give” as the needle pierces the dura-arachnoid mater to enter the subarachnoid space.
The cord has ended, so rare to pierce the dura mater of the cauda equina and cause nerve damage.
LP - indications
Diagnosis of meningitis/encephalitis
Diagnosis of SAH
=> If clinically suspected but no abnormalities on CT
Measurements of CSF pressure
=> Idiopathic intracranial HTN
Therapeutic removal of CSF:
=> Idiopathic intracranial HTN
Intrathecal drug administration
Diagnosis of various conditions:
=> MS, neurosyphilis, Behcet’s disease
LP - complications
Post-LP headache
Dry tap (correct position of needle but no CSF comes out)
Infection
Damage to spinal nerves – causing weakness/paraesthesia
Coning of cerebellar tonsils.
Post-LP headache
Occurs in 30%
Onset within 24 hours, resolution over 2 weeks.
Constant bilateral dull ache.
Worse when upright
Treat with analgesics +/- blood patch (re-injection of the patient’s own blood to form a clot).
LP - contraindications
Suspicion of intracranial / spinal cord mass, or raised ICP.
=> This can lead to coning of the cerebellar tonsils
=> Any unconscious patient must have a CT prior to LP
Overlying/local infection
Congenital lesions in the area (e.g. meningomyelocele)
Problems with haemostasis
Haemodynamic instability.
CSF xanthochromia
Xanthochromia = yellow-ish colour of the CSF.
Caused by bilirubin from RBC breakdown
=> RBCs in the CSF indicates there has been a SAH
If the RBCs in the CSF are due to bleeding at the LP site, they will not have been degraded to bilirubin, so CSF will not be xanthochromic.
CSF findings in MS
Moderately raised protein levels – less than 1 g/L
Up to 50 lymphocytes / mm3
Oligoclonal IgG bands on electrophoresis.
What is Guillain Barre Syndrome ?
= a rapid-onset muscle weakness caused by the immune system damaging the peripheral nervous system.
Thought to be auto-immune process
- Symptoms occur 1-3 weeks after an infection
- Infection may be trivial and unidentified
- Campylobacter and CMV infections are well-recognised causes of severe GBS
Guillain Barre Syndrome - Presentation
Ascending paralysis, with loss of tendon reflexes
Sensory loss is rare
Usually affects the lower limbs initially
Ascends and progresses over several days to weeks.
Proximal muscle involvement is common – e.g. cranial nerves, respiratory muscles.
Other complications:
- VTE
- Autonomic involvement – leading to BP lability / arrythmias
Guillain Barre Syndrome - Diagnosis
Supported by nerve conduction studies (showing slowed conduction)
CSF protein is often also raised.
Guillain Barre Syndrome - Mx
Severe cases progress rapidly over hours to days.
Admit to HDU
Some patients will require ventilator support.
s.c. Heparin plus TED stockings
High dose IV immunoglobulin (IVIG) within the first 2 weeks.
=> Reduce duration and severity of paralysis
=> Corticosteroids are of no use.
Guillain Barre Syndrome - Prognosis
In mild cases, there is little disability before spontaneous recovery.
Complete recovery occurs over months in 80-90%
=> Some may be left with residual weakness
Mortality is very high in the acute phase – up to 10%
What is motor neurone disease?
= degenerative disease of UMNs and LMNs in the spinal cord, cranial nerve motor nuclei and the cortex.
There is NO sensory involvement.
It is sporadic, with the cause unknown (although there are rare genetic forms).
Peak onset is age 50-70
What are the 4 broad patterns of MND?
Amyotrophic Lateral Sclerosis
Progressive Muscular Atrophy
Primary Lateral Sclerosis
Bulbar Presentation
MND Amyotrophic Lateral Sclerosis - presentation
Loss of spinal and brainstem LMNs, and cortical UMNS (giving both UMN and LMN signs)
Progressive spastic tetraparesis and added LMN signs such as wasting and fasciculation.
May be associated with fronto-temporal dementia
Presentation:
- LMN weakness – starting in the hands and progressing to upper arms/legs
- UMN spastic weakness – starting in the legs and progressing to the arms
- Bulbar palsy / pseudobulbar palsy
O/E:
=> The classical sign is muscle wasting and fasciculation with brisk reflexes and up-going plantars. Sensory examination is normal
MND Progressive Muscular Atrophy - presentation
Loss restricted to spinal LMNs, giving purely LMN signs
Painless wasting begins in the small muscles of the hands, and spreads.
O/E – wasting and fasciculation is seen
MND Primary Lateral Sclerosis - presentation
Rare form of MND
Disease confined to cortical UMNs, giving purely UMN signs
Progressive tetraparesis
MND - Bulbar Presentation
Bulbar symptoms with preservation of limb function in early stages.
Poor prognosis due to early respiratory involvement
Guillain Barre Syndrome - diagnosis
Diagnosis can be clinical in the presence of mixed UMN / LMN signs in multiple limbs, but investigations are usually useful to establish the diagnosis:
- Bloods – r/o differentials
- Spinal cord MRI – r/o myelopathy
- EMG – evidence of denervation, can be diagnostic.
Guillain Barre Syndrome - Mx
Should be managed by a specialist MDT
Social and carer assessments are important
Disease modifying therapy:
=> Riluzole – increases pre-synaptic glutamate release, can increase survival in ALS patients by an average of 3-4 months.
Nutritional Support
Respiratory Support
=> Overnight NIPPV if respiratory weakness is an issue (biggest prognostic benefit)
Tx of complications (as per MS)
MND - prognosis
Remission of MND is not known
Death is eventually from bronchopneumonia or ventilatory failure due to weakness of the respiratory muscles.
What do LMNs innervate?
What are the signs of a LMN lesion?
LMNs innervate ipsilateral muscles
Signs:
- Weakness
- Wasting
- Fasciculation
- Hypotonia
- Hyporeflexia
What do UMNs innervate?
What are the signs of an UMN lesion?
UMNs innervate contralateral muscles
SIGNS:
- Weakness (characteristically extensor weakness in UL, flexor weakness in LL)
- No wasting
- Hypertonia, spasticity
- Hyperreflexia
- Loss of fine motor movements
- Pronator drift
- Extensor plantar response
- Clonus
Causes of LMN lesions
Ventral horn pathology (MND, post-polio)
Peripheral nerve pathology
NMJ pathology (MG)
Muscular pathology
Causes of UMN lesions
Vascular – stroke
Inflammatory – MS, MND
Neoplastic – tumour
Degenerative – Parkinson’s
Infective – post-meningitis
Drugs
LMN vs UMN lesions in the face
LMN lesions cause ipsilateral facial weakness of all muscles of facial expression.
UMN lesions cause contralateral facial weakness, but spare frontalis (as this received supranuclear innervation from both hemispheres)
=> Furrowing of the brow, eye closing and blinking are preserved
Cerebrum - Frontal lobe
Separated from the parietal lobe posteriorly by the central sulcus and from the temporal lobe infero-posteriorly by the lateral sulcus
Responsible for:
* Higher intellect,
* Personality,
* Mood,
* Social conduct
* Language (dominant hemisphere side only).
Cerebrum - Parietal lobe
Between the frontal lobe anteriorly and the occipital lobe posteriorly
Separated from these by the central sulcus and parieto-occipital sulcus
Contributes to the control of:
* Language and calculation on the dominant hemisphere side
* Visuospatial functions (e.g. 2-point discrimination) on the non-dominant hemisphere side.
Cerebrum - Temporal lobe
Inferior to the frontal and parietal lobes, from which it is separated by the lateral sulcus.
Involved with:
* Memory
* Language – this includes hearing as it is the location of the primary auditory cortex.
Cerebrum - Occipital lobe
The most posterior part of the cerebrum
Its inferior aspect rests upon the tentorium cerebelli, which segregates the cerebrum from the cerebellum
The parieto-occipital sulcus separates the occipital lobe from the parietal and temporal lobes anteriorly.
The primary visual cortex (V1) is located within the occipital lobe (hence it is responsible for vision)
Cerebellum - location and function
Located at the back of the brain, immediately inferior to the occipital and temporal lobes, and within the posterior cranial fossa.
It lies at the same level of and posterior to the pons, (these are separated by the fourth ventricle)
Plays an important role in motor control.
=> In particular – coordination, precision and timing of movements, as well as in motor learning
Each cerebellar lobe controls movement of ipsilateral limbs.
The vermis (midline structure) maintains midline posture and balance.
Anterior Cerebral Artery
Supplies medial surface of cerebral hemisphere, as far back as the peri-occipital sulcus
Middle Cerebral Artery
Supplies 2/3rd of the lateral surface of the brain
Central branches supply the corpus striatum, thalamus and internal capsule.
Posterior Cerebral Artery
Supplies the corpus callosum and cortex of occipital and temporal lobes.
Central branches supply the optic radiation, subthalamic nucleus and thalamus
What is the blood supply to the brainstem and cerebellum ?
supplied by the vertebral and basilar arteries
CN I
= Olfactory
Special sensory – smell from nasal mucosa
CN II
= Optic
Special sensory – vision from retina
CN III
= Oculomotor
Somatic motor – 4 of 6 extra-ocular muscles, levator palpebrae superioris.
Visceral motor – pupil constriction
CN IV
= Trochlear
Somatic motor – superior oblique muscle
CN V
= Trigeminal
Ophthalmic nerve (V1) – sensory to upper 1/3rd of face and cornea
Maxillary Nerve (V2) – sensory to middle 1/3rd of face
Mandibular Nerve (V3):
- Sensory – lower 1/3rd of face
- Motor – muscles of mastication
CN VI
= Abducens
Somatic motor – lateral rectus muscle
CN VII
= Facial
Somatic motor – muscles of facial expression
Visceral motor – submandibular/sublingual glands; lacrimal gland
Special sensory – taste from the anterior 2/3rd of tongue
General sensory – skin of external acoustic meatus.
CN VIII
= Vestibulocochlear
Special sensory – hearing and balance.
CN IX
= Glossopharyngeal
Somatic motor – swallowing
Visceral motor – parotid gland
Special sensory – posterior 1/3rd of tongue
General sensory – external ear and pharynx
CN X
= Vagus
Somatic motor – swallowing
Visceral motor – parasympathetic innervation to smooth muscle of trachea, bronchi, GI tract and heart.
General sensory – auricle and external acoustic meatus
CN XI
= Spinal Accessory
Motor – SCM and trapezius muscles
CN XII
= Hypoglossal
Motor – intrinsic/extrinsic muscles of tongue
Which cranial nerves arise from the medulla oblongata?
Also the “bulb” => “bulbar palsy”
= CN IX, X, XII
What is hydrocephalus?
= excessive CSF within the cranium.
High pressure then leads to dilation of the lateral ventricles +/- dilation of the 3rd and 4th ventricles.
Can be either COMMUNICATING or NON-COMMUNICATING
(or, very rarely, caused by CSF overproduction)
Non-communicating Hydrocephalus
Most common type
Due to blockage of the CSF pathways from the ventricles to the subarachnoid space.
Communicating Hydrocephalus
Due to impairment of CSF reabsorption at the arachnoid vili along the dural venous sinuses.
Usually precipitated by infection (particularly TB meningitis) or SAH
Risk factors for hydrocephalus
Patients with congenital malformations
=> E.g. stenosis of the aqueduct of Sylvius.
Posterior fossa / brainstem tumours
Post brain insult
=> E.g. SAH, head injury, meningitis
Hydrocephalus - presentation
- Headache
- Vomiting
- Papilloedema
- Cognitive Impairment
- Ataxia
- Bilateral pyramidal signs
Hydrocephalus - Ix
CT to assess size of ventricles
MRI if suspecting malformations / tumour
Hydrocephalus - Mx
MEDICAL = to reduce CSF secretion / increase absorption
- Only role is to delay surgical management
- Acetazolamide, alone or in combination with Furosemide.
SURGICAL:
- Ventriculo-atrial or ventriculo-peritoneal shunting for progressive symptoms (Valves open at certain pressures to release CSF)
- Endoscopic 3rd ventriculostomy is an alternative procedure for obstructive hydrocephalus.
- Neurosurgical removal of tumours if appropriate
Normal Pressure Hydrocephalus
= the syndrome of enlarged lateral ventricles
usually in the elderly
associated with a classic triad:
1. Dementia (despite no signs of cortical atrophy on CT)
2. Urinary incontinence
3. Ataxia
Normal Pressure Hydrocephalus - Ix
Isolated CSF measurements are usually normal, but continuous monitoring may show intermittent periods of raised pressure.
Normal Pressure Hydrocephalus - Mx
Some patients respond to ventriculoperitoneal shunting, only indicated if they respond to trials of lumbar drainage.
What is myasthenia gravis?
= an autoimmune condition that causes muscle weakness that gets progressively worse with activity and improves with rest.
Due to IgG autoantibodies against the ACh receptor located on the post-synaptic membrane of the motor end plates
myasthenia gravis - pathophysiology
IgG autoantibodies against the ACh receptor located on the post-synaptic membrane of the motor end plates
This blocks synaptic transmission at the NMJ and prevents the acetylcholine from being able to stimulate the receptor and trigger muscle contraction
These antibodies also activate the complement system within the neuromuscular junction, leading to damage to cells at the postsynaptic membrane.
(a small % of MG cases are caused by other antibodies against important proteins for the creation and organisation of the acetylcholine receptor)
What can Myasthenia Gravis be associated with?
There is a strong link with thymoma (a tumour of the epithelial cells of the thymus)
~25% with MG have thymoma.
Myasthenia Gravis - Presentation
Weakness and fatiguability that gets worse throughout the day.
Classically affects:
- Proximal limb muscles – fluctuating proximal weakness, more common in the upper limb.
- Extra-ocular muscles – symmetrical diplopia and ptosis
- Bulbar muscles – dysphagia/speech difficulties
- Muscles of facial expression – weakness in facial movements
Wasting and respiratory difficulties may occur after many years.
The heart is not affected.
Tendon reflexes are preserved.
Myasthenia Gravis - Ix
Serum anti-AChR antibody titre
Single fibre electromyography
=> Diagnostic – decreased responses to repeated stimulation
TFTs and CT – for evidence of thymoma
What is an Edrophonium test (Tensilon test)?
Previously used in the diagnosis of MG
Now rarely used due to risk of arrythmia
IV injection of edrophonium (short-acting anticholinesterase) – will produce rapid, transient improvement in features.
Cardiac monitoring and resuscitation should be available.
Myasthenia Gravis - Mx
Avoidance of certain antibiotics that may exacerbate NM blockade – e.g. aminoglycosides
Lifelong long-acting oral ANTICHOLINESTERASES
=> Neostigmine/pyridostigmine.
CORTICOSTEROIDS for relapses:
Starting in hospital, as risk of increasing weakness early on.
Weakness of respiratory muscles can be life-threatening
=> Monitor FVC, May need ventilatory support
=> Severe cases will require IVIG / plasmapheresis
Alternate-day regimen after discharge
=> Azathioprine may be useful as a steroid-sparing agent.
Thymectomy
=> Performed at any age will increase the chance of remission
What % of strokes are haemorrhagic?
~15% of strokes
= either intra-cerebral haemorrhage or SAH
Intracerebral haemorrhage - presentation
As per haemorrhagic stroke
At the bedside there is no reliable way to differentiate.
=> More likely to present with severe headache and coma
Intracerebral Haemorrhage - Ix
CT – haemorrhage will be seen immediately
MRI – very reliable after 2 hours from symptom onset.
Intracerebral Haemorrhage - Mx
Stop and reverse any anticoagulation
Intubate if GCS is 8 or less
Lower BP to <140/90 within 1 hour
=> IV labetalol
Maintaining adequate oxygenation and MAP
Neurosurgical intervention may be required.
SAH - presentation
“Thunderclap” headache
=> Develops over seconds, devastating intensity, often occipital
=> Often comes on during times of transient HTN – such as physical activity or sexual intercourse.
Vomiting:
=> Comes on after developing the headache.
Photophobia
Increasing drowsiness/coma
Focal signs may point to the location of the lesion.
=> However, may just reflect raised ICP (false localising sign) or cerebral vasospasm due to the irritant effect of blood.
O/E:
- Neck stiffness
- Positive Kernig’s sign – takes 6 hours to develop
- Papilloedema (may be present); retinal haemorrhages.
SAH - “sentinel headache”
The patient may have experienced an earlier “sentinel headache” before the thunderclap headache.
due to a small warning lead from the offending aneurysm.
Small bleeds may give few physical signs, but almost always a headache.
SAH - Predisposing Abnormalities
Berry Aneurysms (70%)
Arteriovenous Malformations (10%)
No lesion found (20%)
Berry Aneurysms - locations
Developmental rather than congenital
Develop in circle of Willis and adjacent arteries
ACA = most common
PCA – at bifurcation from ICA
MCA – at bifurcation/trifurcation
RFs for berry aneurysms
- Polycystic kidney disease
- FHx
- Smoking
- HTN
- Connective tissue diseases
PCA berry aneurysm - presentation
MASS EFFECTS => most common cause of painful 3rd CN palsy
HAEMORRHAGE
SAH - AVMs
Congenital collection of abnormal arteries/veins
Have a tendency to rebleed if symptomatic once (10% will rebleed annually)
Can also cause epilepsy
SAH - complications
DEATH – 30% will die immediately
RE-BLEED:
=> Aneurysms – the initial bleed may be fatal, however if vasospasm is sufficient then a clot can form; this usually holds for 3-4 days before re-bleeding.
=> AVMs – generally rebleed within a few years.
HYDROCEPHALUS:
Due to fibrosis in the CSF pathways
CEREBRAL VASOSPASM:
Can be severe, leading to delayed ischaemic damage.
SAH - Ix
Bloods:
- FBC, U&E, LFT, ESR, clotting
CT = initial Ix of choice
- SAH/intraventricular blood usually seen within 48h
LP – if CT normal
- Should be done >12 hours after symptom onset
- CSF will be xanthochromic (visual inspection sufficient for diagnosis).
CT/MRI angiography – in all patients fit for surgery
=> To determine underlying vascular anatomy
SAH - Mx
4 weeks bed rest
HTN control
=> Nimodipine – to prevent vasospasm (reduces mortality) – give to all if BP allows.
IV fluids
Analgesia, anti-emetics
Stool softeners - to prevent straining
Discuss with neurosurgery
=> Aneurysms may need to be coiled by interventional radiology or require neurosurgical clip
=> AVMs may require coiling or other neurosurgical intervention
=> Patients with hydrocephalus may need a shunt.
Subdural haemorrhage
= collection of blood in the subdural space, following the rupture of a vein.
Usually following head injury, but can occur spontaneously.
Patients are often young
ACUTE Subdural haemorrhage - presentation
Patients are often young, post-head injury
Often occurs in severe acceleration-deceleration injuries
Present to hospital with a dilated pupil and NO lucid interval before decreased GCS
SUB-ACUTE / SPONTANEOUS Subdural Haemorrhage - presentation
May occur spontaneously or after minor trauma.
Can be bilateral
Symptoms and signs of raised ICP, developing about 3 weeks after insult or start of bleed and often fluctuant:
=> Headache, drowsiness, confusion, focal neurological signs.
Eventually stupor and coma due to coning.
ACUTE Subdural haemorrhage - Management and outcomes
CT head to confirm
Craniotomy and early evacuation of the clot is required.
These patients are often seriously ill even with early intervention.
=> Require ICU admission with intracranial pressure monitoring.
High incidence of subsequent epilepsy, permanent neurological disability and high mortality.
RFs for subdural haemorrhage
- Head injury (acute)
- Elderly (cortical atrophy stretches brittle veins)
- Alcohol abuse
- Other coagulopathies
SUB-ACUTE / SPONTANEOUS Subdural Haemorrhage - management
CT head to confirm
Chronic subdural haemorrhage may resolve spontaneously.
Progress can be assessed with serial imaging, but neurosurgical input is required.
Subdural haematoma - imaging
CT
Acute SDH:
- Classic CRESCENT-SHAPE with increased density, conforming to the contour of the skull.
- May be accompanying midline shift and compression of ventricles.
Chronic SDH:
- Blood becomes more radiolucent (darker), and assumes a lentiform shape, similar to that of an extrdural haemorrhage.
Extradural haemorrhage
Most common in young patients following minor assault or sporting injury.
Blow is usually to the side of the head, enough to cause a fracture and associated tearing of the middle meningeal artery.
Blood accumulates rapidly over minutes to hours in the extradural space.
Extradural haemorrhage - presentation
Brief duration of unconsciousness, and then a LUCID recovery period.
Progressive hemiparesis and stupor develops due to trans-tentorial coning.
First there is an ipsilateral dilated pupil, then bilateral fixed dilated pupils.
If untreated, there is hemiplegia and respiratory arrest.
Extradural haemorrhage - Ix
CT => characteristic LENTIFORM shape
Midline shift and compression of the ventricles as it enlarges.
EDH vs SDH on CT
EDH = lentiform
SDH = crescent
Extradural haemorrhage - Management
Urgent neurosurgical referral
=> Burr hole to release pressure
=> Prognosis is very good if this is performed early.
If very minor, may be managed conservatively with regular monitoring.
Definition of stroke
= an acute, focal neurological deficit of cerebrovascular origin that persists >24 hours.
What % of strokes are ischaemic?
85%
Either due to:
- Arterial embolus from a distant site
- Arterial thrombosis in atheromatous carotid/vertebral/basilar artery
- Systemic hypoperfusion (general circulatory problem)
RFs for Ischaemic Stroke
MODIFIABLE
HTN
Hypercholesterolaemia
Diabetes
Smoking
Alcohol
Poor diet
Low exercise
Increased weight
Use of oestrogen-containing OCPs
NON-MODIFIABLE
Age
Family History
Hypercoagulable states
Non-white ethnicity
AF
RFs for haemorrhagic stroke
Family History
Uncontrolled HTN
Vascular abnormalities (aneurysms, AVMs, HHT)
Coagulopathies/anticoagulant therapies
Heavy recent alcohol intake.
Illicit drug use (mostly amphetamines and cocaine)
Trauma
Ischaemic stroke - presentation
Facial weakness – sparing forehead.
Contralateral limb weakness/hemiplegia and loss of sensation.
=> At first flaccid, but over time reflexes return and become exaggerated, with extensor plantars.
Higher Dysfunction
Visual Disturbances
Seizures (rare)
Total Anterior Circulation Syndrome (TACS)
= Proximal MCA Occlusion
Affecting the areas of the brain supplied by both the middle and anterior cerebral arteries
Must have all three of:
1. Higher dysfunction (incl. decreased level of consciousness)
2. Homonymous hemianopia
3. Contralateral hemiplegia and/or sensory loss (>2 of face, arm, leg)
Partial Anterior Circulation Syndrome (PACS)
= distal MCA or ACA occlusion
A less severe form of TACS, in which only part of the anterior circulation has been compromised.
Requires 2 of the 3 TACS criteria.
Lacunar Syndrome (LACS)
= occlusion of lacunar branch of MCA leading to subcortical stroke
There is no loss of higher cerebral functions (e.g. dysphasia).
One of the following:
- Pure motor symptoms
- Pure sensory symptoms
- Pure sensorimotor symptoms
- Ataxic hemiparesis
What are possible features of higher dysfunction?
Expressive aphasia
= inability to express language despite intact comprehension
Receptive aphasia
= inability to understand commands, may have fluent but meaningless speech.
Apraxia
= difficulty in performing task, despite intact motor function.
Asterognosis
= inability to identify objects in both hands, despite intact sensation.
Agnosis
= inability to recognise objects/people/sounds/smells despite the specific sense intact and no memory loss.
Inattention (neglect)
= inability to attend to stimuli despite intact senses.
Posterior Circulation Syndrome (POCS)
= PCA occlusion.
There will be damage to the area of the brain supplied by the posterior circulation (e.g. cerebellum, thalamus, and brainstem).
Presents as:
- Cranial nerve palsy AND contralateral motor/sensory deficit.
- Conjugate eye movement problems (e.g. nystagmus, double vision)
- Cerebellar dysfunction
- Isolated homonymous hemianopia
Oxford (Bamford) Classification of stroke
TACS
PACS
LACS
POCS
“Syndrome” describes indeterminate pathogenesis prior to imaging (e.g. TACS)
=> If confirmed infarct = TACI
=> If confirmed haemorrhage = TACH
Stroke - important factors from history
HPC:
- Exact time of onset
- Speed of onset
- Body parts affected
- Seizure at onset?
PMH:
- Previous stroke/MI
- AF
- DM
- Abscess
- Tumour?
DHx:
- Anticoagulants
- OCP
SHx:
- Alcohol abuse, Smoking, Illicit drug use
Stroke - examination
GCS
NIHSS – national institute of health stroke scale:
=> 15-item neurologic examination stroke scale
=> Evaluates level of consciousness, language, neglect, visual field loss, extra-ocular movement, motor strength, ataxia, dysarthria, and sensory loss.
=> Gives rapid insight into location of the stroke and severity – identifying those who may benefit from thrombolysis.
CVS:
=> Murmurs (endocarditis), BP, HR, signs of dissection
Respiratory:
=> SpO2, RR, crackles
Neurological:
=> UMN/LMN signs
=> CNS and cerebellar examination
NIHSS / national institute of health stroke scale
15-item neurologic examination stroke scale
Evaluates level of consciousness, language, neglect, visual field loss, extra-ocular movement, motor strength, ataxia, dysarthria, and sensory loss.
Gives rapid insight into location of the stroke and severity – identifying those who may benefit from thrombolysis.
Stroke - investigations
ADMIT TO STROKE WARD IF POSSIBLE
BLOODS:
=> FBC, U&Es, glucose + HbA1c, lipids, clotting screen, ESR
BRAIN IMAGING:
- MRI = gold-standard due to higher resolution, but less availability.
- CT = rapid and commonly used, mainly used to exclude haemorrhage.
Early signs of infarct can be seen as loss of grey-white differentiation, sulcal effacement, loss of insular ribbon
When is brain imaging within 1 hour indicated in stroke?
within 1 hour if:
- Considering thrombolysis
- Bleeding risk/headache at onset
- Decreased consciousness
- Neck stiffness
Stroke - Immediate Mx
A – E assessment
=> Always check glucose – hypoglycaemia is a common mimic.
Withhold antiplatelet therapy until haemorrhage excluded
=> As soon as excluded, administer aspirin 300mg.
If patient has had symptoms for over 30 minutes, but onset was within 4.5 hours – arrange THROMBOLYSIS.
If thrombolysis is contraindicated – manage supportively on the ward, continuing 300mg aspirin daily for 2 weeks whilst implementing secondary prevention measures.
Stroke Management - thrombolysis
Check for contraindications first (must have lab blood results back)
Alteplase 0.9 mg/kg as per clinical pathway within the hospital
10% bolus over 1 minute, remainder over 60 minutes.
Stroke - ward management
- SALT – swallow assessment ideally within 2 hours
- PT – relieve spasticity and prevent contractures; early mobilisation is vital.
- OT
- Nursing – SSKIN bundle, early nutrition required if NBM
- LMWH anticoagulation started on day 3 post-ischaemic stroke
- Ensure TED stockings are being worn.
Care of a patient after Thrombolysis
Patient is closely monitored over 24 hours via cardiac monitor and has specific observations completed on stroke thrombolysis observation chart.
If the patient develops severe headache, acute HTN, nausea or vomiting hen discontinue infusions and obtain emergency CT.
Avoid catheterisation during the infusion
Avoid aspirin or heparin for 24 hours.
Avoid NG tube insertion for 1st 24 hours.
Stroke - secondary prevention
Identify and tackle lifestyle risk factors.
=> E.g. stop smoking, reduce alcohol, regular exercise, etc.
Antihypertensive therapy = most important factor.
=> Start 2 weeks following stroke if elevated BP
Antiplatelet therapy:
=> Aspirin 300mg for 2 weeks
=> Clopidogrel 75mg lifelong.
Statin:
=> Offer from 48 hours post-stroke, regardless of cholesterol levels.
Manage co-morbidities appropriately:
=> Good AF control / anticoagulation, good diabetes control
=> Carotid USS
Assessment of social care needs (+/- home assessments and modifications)
=> Independent patients can often become more dependent after a stroke
Stroke - impact on driving
Patients with normal license must not drive for 4 weeks following a stroke.
After this period they may return to driving if clinical improvement is satisfactory, without needing to inform the DVLA.
Post-stroke complications
Malignant MCA syndrome
DVT / PE
Aspiration & hydrostatic pneumonia
Pressure sores
Depression
Seizures
Incontinence
Post-stroke pain
Malignant MCA Syndrome
= Rapid neurological deterioration due to the effects of cerebral oedema following MCA territory stroke.
High morbidity / mortality
Mainly occurs in patients <60
Presentation – can be variable, high index of suspicion required:
- Increased agitation / restlessness
- Reducing GCS
- Haemodynamic / thermal instability
- Signs of raised ICP
These patients require decompressive hemi-craniectomy
What is a TIA?
= an acute, focal neurological deficit of cerebrovascular origin that persists <1 hour, without signs of cerebral infarction on MRI scanning.
Only diagnosed after resolution
Can occur in brain, spinal cord or retina
There is a very high risk of stroke within 4 weeks of a TIA.
What is Amaurosis Fugax ?
= sudden, transient loss of vision in one eye.
Often occurs in TIA of the retina, can be the first clinical evidence of ICA stenosis.
Can also occur due to ocular disease or migraine.
TIA - immediate management
Assess the patient’s immediate further stroke risk
Immediate 300mg aspirin
=> Unless contraindicated, patient already anticoagulated or already taking aspirin 75mg daily.
Consider admission if more than one recent TIA (crescendo TIA) or suspected carotid/cardio-embolic source
Otherwise, arrange outpatient specialist TIA clinic assessment within 24 hours.
=> Can be within 7 days if TIA was >1 week ago.
Give all people with suspected TIA and their family/carers information on the recognition of stroke and TIA and advise them to call 999 immediately if symptoms occur.
High risk features for further stroke after a TIA
Recurrent TIAs within a short period of time
AF, or TIA whilst anticoagulated.
Driving advice post-TIA
Advise patient not to drive until seen by specialist in TIA clinic
TIA Management in TIA clinic
Carotid artery doppler – to assess for carotid artery stenosis
If stenosis is >50% on affected side related to symptoms, carotid endarterectomy is offered:
=> Reduced risk of further stroke/TIA by 75%
Alternative = percutaneous luminal angioplasty +/- stenting.
TIA - secondary prevention
As per stroke – will be initiated by secondary clinic
Clopidogrel = antiplatelet of choice.
(Aspirin and dipyridamole if clopidogrel is unsuitable)
What is multiple sclerosis?
= disease involving relapsing episodes of immunologically mediated (T-cell mediated) demyelination in the CNS, leading to neurological degeneration.
Common areas of demyelination in MS
Areas of demyelination are termed plaques (containing chronic inflammatory cells)
Best seen in certain locations:
- Optic nerves
- Angles of the lateral ventricles
- Cerebellar peduncles
- Brainstem
- Dorsal and corticospinal tracts
MS - symptoms
Symptoms are related to the common areas of demyelination:
- Optic nerve => visual disturbances
- Corticospinal tract => UMN deficit
- Dorsal tract => sensory deficit
- Cerebellar peduncles => cerebellar signs
- Brainstem => bladder/bowel/sexual dysfunction
- Cognitive impairment (late)
In all forms of MS, episodes of neurological deficit appear irregularly throughout the CNS in terms of anatomical site and time.
Visual disturbances seen in MS
Optic neuritis is a common presenting feature
Symptoms are:
* blurring of vision over hours to days
* Mild ocular pain (worse on movement)
* Loss of colour vision
O/E:
* Decreased acuity and colour vision
* Pink/swollen optic disc
Diplopia is also common, due to brainstem involvement.
L’Hermitte’s sign
induce tingling sensations shooting down the arms/legs on neck flexion
Due to posterior cervical demyelinating lesions in MS
Uthoff’s Phenomenon
MS symptoms are clinically worse during a fever, hot weather, or after exercise (as central conduction is slowed by increased body temperature)
what can cause of recurrence of MS symptoms?
Recurrence is unpredictable, with no clearly identified precipitating factors
(although pregnancy / intercurrent illness may be implicated)
What are the different clinical patterns of MS?
Primary Progressive MS
=> No clear-cut relapses/remissions
Relapsing/remitting MS (80-90%)
=> Initial episodes resolve completely
=> Subsequent events usually result in some residual disability.
=> Patients eventually develop secondary progressive MS (steady progression without remission)
Fulminating MS
=> Debilitating progressive deterioration from an early stage.
MS - diagnosis
Clinically – two separate MS-like episodes of neurological dysfunction
Diagnosis then conformed with MRI evidence of lesions
MS - Investigations
In primary care – NICE recommend doing:
=> FBC, U&E, LFT, ESR, TFT, glucose, calcium, B12 and HIV serology before referring to a neurologist.
MRI
=> Will show lesions in 85% of patients with clinical disease
=> Lesions are not specific to MS, so clinical features are also required.
CSF Examination:
=> Often unnecessary if MRI is diagnostic
=> Raised cell count and protein.
=> Electrophoresis shows oligoclonal IgG bands in 80% (non-specific)
Visual Evoked Responses (VER):
=> Delayed occipital EEG reactions to visual stimuli are present in 95% of those with MS
=> Useful to demonstrate evidence of previous optic nerve lesions to demonstrate previous subclinical disease.
Acute MS Relapses - Management
- Investigate appropriately to r/o other causes (particularly infection)
- Consider admission if relapse is severe or patient cannot meet their social care needs at home.
- High-dose Corticosteroids:
- Oral methylprednisolone 500mg o.d for 5 days.
- Start as soon as possible in the attack
- May reduce severity of attack, no effect on long-term outcome. - Assess whether any increase in social care is required.
- Patient education
Patient education in an acute MS relapse
Inform that steroids likely to reduce attack severity and duration, but may cause temporary mental health effects (confusion, anxiety, depression, psychosis)
Significant recovery can be expected in 2-3 months, but there may be some residual symptoms.
MS - general management
Patients should be under the care of a specialised MS MDT, with annual review.
Lifestyle advice:
- Regular exercise can be beneficial
- Smoking cessation improves disease course
Prompt recognition and treatment of any co-existing illness
=> Illness/fever can frequently exacerbate MS symptoms
Assess for and appropriately manage complications
Disease modifying therapy (initiated by specialist).
MS - prognosis
Average life expectancy from diagnosis = 20-30 years
There may be a long latent period (15-30 years) from an episode of optic neuritis before further Sx occur
Poor prognostic factors:
- Increased age of presentation
- Early cerebellar involvement
- Loss of mental functions
Visual Defect in Macula lesion
= Central Scotoma
Visual Defect in Optic Nerve lesion
= Ipsilateral Monocular Vision Loss
Visual Defect in Optic Chiasm lesion
= Bitemporal Hemianopia / Quadrantanopia
Can get superior bitemporal quadrantanopia due to pressure from below the chiasm
=> E.g. pituitary tumour.
Inferior bitemporal quadrantanopia is due to pressure from above the chiasm
=> E.g. craniopharyngioma, carotid aneurysm, meningioma.
Visual Defect in Optic tract lesion
= Contralateral Homonymous Hemianopia
Visual Defect - Optic radiation lesion
= Contralateral Homonymous Quadrantanopia
Temporal lesions = inferior fibres (superior retina) => superior homonymous hemianopia
Parietal lesions = superior fibres (inferior retina) => inferior homonymous hemianopia
Visual Defect - visual cortex due to PCA lesion
Homonymous hemianopia / quadrantanopia with Macular Sparing
(macula gets blood supply from both PCA and MCA).
Broca’s Area
Motor speech function
Located in inferior frontal gyrus, areas 44 + 45
Wernicke’s Area
Involved in understanding of the spoken word
Located in superior temporal gyrus, area 22
Broca’s Aphasia
= expressive aphasia, loss of ability to produce speech.
Non-fluent – verbal output reduced
Comprehension is good, repetition is poor
Wernicke’s Aphasia
= receptive aphasia, loss of ability to understand speech
Fluent – normal production of incorrect words
Poor comprehension, poor repetition.
Global Aphasia
= Both expressive and receptive dysphasia
What is dysarthria?
= disordered articulation / slurred speech, language remains intact
Causes of dysarthria
Bulbar palsy
=> LMN, high-pitched nasal speech
Pseudobulbar palsy
=> UMN, “Donald duck” gravelly speech
Cerebellar lesion
=> Slow, jerky/staccato, slurred speech
Extrapyramidal lesions
=> Soft, indistinct, monotonous speech
Myasthenia Gravis
=> Speech fatigues and dies away
What causes Horner’s Syndrome?
What are the triad of signs?
= oculo-sympathetic palsy, caused by interruption of the sympathetic chain.
- Unilateral pupillary constriction (miosis).
- Partial ptosis
=> Loss of Muller’s muscle, only slight LPS intact - Anhidrosis
In congenital/long-standing lesions, heterochromia will develop
Causes of Horner’s Syndrome
Due to the interruption of the sympathetic chain in the level of the first, second or third order neurone:
First order:
=> Brainstem disease – tumour, stroke, MS, syphilis
Second order:
=> Intrathoracic lesions – Pancoast tumour, cervical rib, TB
=> Neck lesions – lymphadenopathy, trauma, thyroid surgery
Third order:
=> ICA aneurysm
=> Migraine (transient)
=> Idiopathic
RFs for venous sinus thrombosis
Pro-thrombotic risk factors:
- Oral contraceptives
- Pregnancy / puerperium
- Malignancy
- Genetic thrombophilia
Head injury
Recent LP
Infection
Venous sinus thrombosis - pathology
Venous infarction leads to vascular congestion.
Eventually there is haemorrhagic necrosis
It can be split into cortical venous thrombosis and dural venous sinus thrombosis
Cortical Venous Thrombosis - presentation
Ocular pain, worse on movement
Proptosis and chemosis
Ophthalmoplegia
Papilloedema
Fever
Dural venous Sinus Thrombosis - presentation
Signs of raised ICP (headache, vomiting, fever, papilloedema, seizures).
Venous sinus thrombosis - Ix
CT – often normal
LP – raised ICP
CT/MRI venography may be required for diagnosis
Suspect venous sinus thrombosis if there is thunderclap headache and raised ICP, with no signs of meningitis and no changes on CT.
What is shingles?
How does it typically present?
= reactivation of varicella zoster infection within the dorsal root ganglia.
Most commonly occurs in the lower thoracic dermatomes:
- Pain and paraesthesia for several days
- Erythema and a dermatomal eruption of vesicles
- Increased burning and itching
- Vesicles become pustular 2-3 days later and may separate 3 weeks later.
Ophthalmic Shingles
Infection of the 1st division of the 5th nerve.
Can lead to uveitis, corneal scarring and secondary pan-ophthalmitis
Ramsey-Hunt Syndrome - presentation
VZV infection of the geniculate ganglion.
Clinical features:
- Facial palsy (often severe and irreversible)
- Facial/ear pain
- Vesicles in the ear canal, pinna and soft palate.
May also be sensorineural deafness and vertigo and neuropathy of nerves 5, 9 & 10.
Ramsey-Hunt Syndrome - Mx
5-7 days oral acyclovir
Paracetamol and amitriptyline for pain
Post-herpetic Neuralgia
Pain in previous shingles zone, occurring in 10%
Burning, continuous pain
Responds poorly to analgesia
Amitriptyline is commonly used, plus topical capsaicin
Associated with depression
Gradual recovery over ~2 years
Intracerebral space occupying lesion - presentation
Presentation is dependent on the location of the tumour and its rate of growth:
Signs/symptoms of raised ICP
=> Headache (morning/lying down), N&V, papilloedema
Epileptic Seizures
=> Adults with an epileptic fit have a brain tumour until proven otherwise.
Progressive neurological deterioration:
- Increasing weakness
- Sensory loss
- Cranial nerve palsies
- Dysphasia (if involving the dominant hemisphere)
Intracerebral space occupying lesion - Ix
These patients need urgent admission for investigation:
- Early CT with contrast
- MRI if no mass can be seen on CT
Intracerebral space occupying lesion - Mx
Dexamethasone 4-6mg QDS if any neurological deterioration/drowsiness
Anticonvulsants – if presented with epilepsy
Refer to neuro-oncology MDT
=> Neurosurgical intervention if accessible, often with adjunctive radiotherapy.
What is paraneoplastic syndrome?
= a cluster of symptoms that occur in patients with cancer, that cannot be explained by the tumour/metastases or hormones normally secreted by the primary tissue from which the tumour arose.
Seen in ~10% of patients with advanced malignant disease.
What paraneoplastic syndromes involve the nervous system ?
Myasthenia Gravis
Lambert-Eaton Myasthenic syndrome
Paraneoplastic sensory neuropathy
Paraneoplastic cerebellar degeneration
Paraneoplastic cerebellar degeneration
- Presentation
- Associated conditions
=> Gives classic cerebellar signs – e.g. ataxic gait, dizziness, dysarthria
=> Frequently associated with Hodgkin’s Lymphoma, breast cancer, small cell lung cancer and ovarian cancer.
What are the 3 most common adult primary brain tumours?
malignant glioma, meningioma, and astrocytoma
Malignant Glioma
Most common adult primary malignancy, originating from astrocytes.
Rapidly growing, thus present with signs of raised ICP
Poor prognosis, with death often within 6 months of diagnosis
Meningioma
Generally benign, slow growing tumours arising from the meninges
Surgical excision and debulking is undertaken wherever possible.
Good prognosis following surgical excision.
Astrocytoma
Benign, slow-growing tumour that occur in young people.
Can turn malignant in later life.
Ependymoma
Originate from the ependymal cells lining the ventricles
Most common in young people/children
Usually malignant, but do not tend to recur after removal
Acoustic Neuroma (Schwannoma)
Arise from the Schwann cells of the acoustic nerve
More common in neurofibromatosis type II
Presents with progressive unilateral sensorineural deafness, tinnitus, vertigo, facial nerve palsy.
Tumour growth can cause cerebellar symptoms or bulbar palsy.
Brain mets - most common primary tumour locations
- Bronchus
- Breast
- Kidney
- Colon
- Thyroid
- Malignant melanoma
Vasovagal/cardiogenic syncope
= “simple faint”
Due to sudden reflex bradycardia and peripheral vasodilation
Occurs in response to standing, fear, venesection or pain.
Patient is unconscious for less than 2 minutes.
Recovery is rapid
Treatment is not necessary
Causes of syncope
Vasovagal
Postural hypotension
Post-prandial hypotension
Carotid sinus syncope (excessive vagal response – e.g. wearing tight collars).
Anaemic syncope
Micturition syncope (in men, due to parasympathetic overactivity).
Coughing or exertion syncope.
Definition of postural hypotension
Drop in SBP of 20mmHg or more on standing from a sitting/lying position.
=> Measure sitting, and then at 1, 2 and 3 minutes after standing up.
Occurs due to blood pooling in the legs due to the influence of gravity
Postural hypotension - RFs
- Fluid depletion
- Age-related autonomic dysfunction
- Polypharmacy (vasodilating/diuretic drugs).
Definition of post-prandial hypotension
Drop in SBP of 20mmHg (or DBP of 10mmHg) after eating, due to pooling of blood in the splanchnic vasculature.
Thought to be even more common than postural hypotension.
Seizure vs syncope
This is a clinical differentiation:
=> Witnessed jerking movements, incontinence, post-episode confusion and amnesia highly suggestive of a seizure.
Cardiac evaluation can detect RFs for syncope (arrythmias, mechanical issues, etc.)
Investigations for recurrent syncope
Advise patient against driving whilst undergoing investigation for the cause.
Investigations:
- Bloods – FBC, U&E, glucose
- L/S BP or tilt table tests
- ECG / 24-hour tape (heart block , arrythmias, long QT)
- EEG/ sleep EEG
- Echo
- CT head
What are the 3 types of muscle diseases?
- Muscular Dystrophies
- Genetically determined diseases that result in progressive deterioration. - Myopathies:
- Diverse group of conditions that are grouped due to their predominant effect on muscle. - Neurogenic disease:
- Disease of peripheral nerves or motor neurones that cause secondary skeletal muscle atrophy.
Muscular Dystrophies
Duchenne Muscular Dystrophy
Becker Muscular Dystrophy
Myotonic Dystrophy
What is Duchenne Muscular Dystrophy?
Most common muscular dystrophy
X-linked recessive, seen exclusively in males.
=> Can be spontaneous mutations
Caused by a mutation in the dystrophin gene, making muscle fibres liable to break down with repeated contraction.
Duchenne Muscular Dystrophy - Presentation
Onset in early childhood:
- Global muscle weakness
- Calf pseudohypertrophy – due to fatty replacement of muscle.
- Gower’s sign – uses hands to climb up to standing.
Prognosis is poor – patients usually die in late teens due to respiratory failure and cardiomyopathy
Duchenne Muscular Dystrophy - investigations
- Raised CK
- Genetic testing / muscle biopsy can confirm Dx
What is Becker Muscular Dystrophy ?
Less common, producing partially functioning dystrophin
As such, symptoms are milder and prognosis is better than Duchenne
Patients generally survive until mid-40s.
Myotonic Dystrophy - inheritance
Autosomal dominant condition, caused by a chloride channelopathy
Shows “anticipation”, with symptoms more severe in each generation
=> Due to expansion of CTG repeat
Myotonic Dystrophy - presentation
Characterised by muscle weakness and myotonia
=> Inability to relax muscles
Usually becomes apparent in adolescence, with facial and lower limb weakness.
Also associated with non-muscular features:
=> Cataracts, frontal baldness, mental impairment, cardiac abnormalities.
Muscle Disorders - investigations
Serum muscle enzymes – Creatine Kinase
=> Raised in muscular dystrophies and inflammatory muscle disorders
=> Normal in MG
Electromyography:
=> Classical trace for myopathy, denervation, myotonic discharges and in MG.
Muscle biopsy:
=> Can differentiate between denervation and muscular disease.
Management of a patient with impaired motor function
manage as per the REPAIR mnemonic.
Spasticity:
- Physical Mx
=> PT, gait retraining, removal of exacerbating stimuli (e.g. constipation, UTI, pressure ulcers).
- Surgical Mx:
=> Tendon lengthening, releases for fixed deformities, electrostimulation therapy. - Medical Mx:
=> Baclofen, dantrolene, benzodiazepines, botox injections.
Contractures:
- Aim to prevent development with good management of spasticity
- If contractures are present, orthopaedic referral may be appropriate.
- PT and aids are also appropriate.
Causes of delirium
Drugs/dehydration
=> Drugs – withdrawal/new/toxicity
=> including opiates, antihistamines, BZDs, antipsychotics, antimuscarinics, alcohol.
Electrolyte imbalance
Level of pain
Infection/inflammation
Respiratory failure / Reduced sensory input
Impaction of faeces / Intracranial
Urinary retention
Metabolic / MI
Symptoms of delirium
Symptoms depend on the type.
HYPERACTIVE:
* Abnormally alert, Agitation/restlessness, disorientation, hallucinations, aggression, wandering, inappropriate behaviour.
* Tx – delirium pathway
HYPOACTIVE:
* More common
* Often unrecognised (so increased mortality), presents similar to depression.
* Withdrawn, not eating/drinking, drowsy, disorganised.
Can also have a mixed delirium.
Delirium - Investigations
Collateral Hx (establish baseline cognition).
Physical examination (conscious level, infection, neurology).
Confusion Bloods
=> FBC, CRP, U&Es, LFTs, TFTs, glucose, Ca, B12, folate
Urinalysis
CXR, ECG, CT/MRI
Assess nutritional status
Medication review
Delirium - Mx
Treat the underlying cause (if ignored => high mortality).
Reduce medications – avoid opiates, anticholinergics.
Reassure and keep orientated, active, hydrated, nourished.
Optimise senses and promote good sleep hygiene.
Only use drugs if other interventions have failed and patient is a risk to themselves or others.
- Haloperidol 0.5mg = 1st line
- Lorazepam 0.5mg (if haloperidol is contraindicated – Parkinson’s, LB dementia).
- Only use short-term (usually 1 week or less).
What is the classical triad of Parkinsonism?
- Tremor
- Rigidity
- Bradykinesia
Parkinsonism - tremor
4 – 7 Hz
Characteristic “pill-rolling” movement between thumb and finger
Occurs at rest
Decreases with action (e.g. on finger-to-nose test)
Increases with anxiety/anger/excitement
Positive glabellar tap sign (tap smooth part of the forehead above the nose and between the eyebrows)
=> Leads to excessive blinking
Parkinsonism - rigidity
Increased tone throughout the range of limb movement
It is equal in opposing muscle groups, giving “lead pipe” rigidity
Patient may have problems getting up from a chair
Parkinsonism - bradykinesia
Difficulty initiating movement
Progressive reduction in speed/amplitude of repetitive actions
Spontaneous blinking rate is reduced.
Facial immobility gives mask-like face => hypomimia.
Combined with hypersalivation => drooling
Causes of parkinsonism
Idiopathic = Parkinson’s disease
Drug-induced:
=> Neuroleptics, prochlorperazine, metoclopramide, TCAs, methyldopa
Vascular:
=> Multiple cerebral infarcts
Toxin induced
=> Wilson’s disease
Post-encephalopathy
Parkinson’s-plus Syndromes
What are the Parkinson’s plus syndromes?
= Rare alternative causes that should be screened for before diagnosing with Parkinson’s disease.
- Progressive Supranuclear Palsy
- Multiple system atrophy
- Lewy Body Dementia
- Vascular Parkinsonism
- Cortico-basal degeneration
Parkinson’s Plus - Progressive Supranuclear Palsy
- Symmetrical onset, tremor is unusual
- Early postural instability (falls)
- Dementia develops early
- Vertical gaze palsy ( = limitation of movement in down gaze)
Parkinson’s Plus - Multiple system atrophy
Early autonomic features
* Postural hypotension, bladder dysfunction, excess sweating
Cerebellar signs also present
* Nystagmus in horizontal gaze
Pyramidal (UMN) signs present
* Extensor plantars, hyperreflexia
Parkinson’s Plus - Lewy Body Dementia
Early dementia, with fluctuating cognition and visual hallucinations.
Symmetrical motor signs
Parkinson’s Plus - Vascular Parkinsonism
Strokes affecting basal ganglia
Symptoms worse in legs than arms
Pyramidal signs present
Parkinson’s Plus - Cortico-basal degeneration
Akinetic rigidity involving one limb
Cortical sensory loss – e.g. asterognosis
Idiopathic Parkinson’s Disease - pathology
= A neurodegenerative disorder
Caused by a loss of the dopamine producing cells in the Substantia Nigra.
The results in REDUCED DOPAMINE ACTIVITY within the corpus striatum of the basal ganglia, leading to Parkinsonism.
60% of nigrostriatal neurones have to be lost before symptoms appear.
=> Surviving neurones increase dopamine production
=> Target striatal neurones increase receptor number.
Idiopathic Parkinson’s Disease - Presentation
Onset is typically asymmetrical and there is persistent asymmetry in the severity of the classical triad of Parkinsonism.
Motor and Non-motor symptoms
Parkinson’s Disease - MOTOR symptoms
- Bradykinesia
- Rigidity
- Postural instability
- Resting tremor
- Freezing
=> Narrow/confined spaces
=> Changing direction - Dystonia (painful cramping in feet/legs) - worse at night
- Dysphagia
- “Classic Parkinson’s Gait” – shuffling/small steps, stooped over, reduced arm swings.
Parkinson’s Disease - NON-MOTOR symptoms
- Masked face
- Hypophonia (deep, soft, monotonous voice)
- Micrographia (progressively smaller handwriting)
- Depression/anxiety
- Psychosis
- Anosmia
- Insomnia/REM sleep disorder/restless legs
- Fatigue
- Constipation/urinary incontinence
- Seborrhoeic dermatitis
- Cognitive impairment
Parkinson’s Disease - Diagnosis
Diagnosis is clinical, after ruling out other causes of Parkinsonism.
Parkinson’s Disease - Mx
There is no cure.
Care should be under a specialist MDT, including a Parkinson’s nurse.
- Levodopa Monotherapy
- Dopamine Receptor Agonists
- Levodopa Dual Therapy – Dopamine Metabolism inhibitor
- Non-pharmacological
- Patient education – advice to minimise “freezing”
- Comprehensive Geriatric Assessment
- Social support
- Physio/OT - Treatment of Non-motor Symptoms
- Constipation – dietary fibre, water, mild osmotic laxatives.
- Urinary incontinence – timed voids, bladder antispasmodics.
- Sleep – make sleeping environment safer.
- Orthostatic hypotension – reduce/stop antihypertensives or diuretics, possibly fludrocortisone/midodrine.
Levodopa Monotherapy in management of Parkinson’s
A dopamine precursor (dopamine itself cannot cross the BBB).
Acts to increase synaptic dopamine.
Combined with carbidopa to prevent peripheral metabolism to dopamine (but cannot cross the BBB so allows action of L-dopa in the CNS).
Usual maximum dose 600-1000mg / day
Complications may arise after 4-6 years and efficacy reduces (narrowed therapeutic window).
SEs – dyskinesia (uncontrollable wriggling), confusion, depression, insomnia.
Dopamine Receptor Agonists in management of Parkinson’s
e.g. Ropinirole, Rotigotine (patch), bromocriptine
Activates post-synaptic receptors.
Can be used as monotherapy in early disease to delay the use of L-dopa, or can be used as an adjunct to L-dopa.
Generally less effective, but cause fewer unwanted dyskinesias.
SEs – confusion, hallucinations, impulsive control disorder (gambling, hypersexuality).
Levodopa Dual Therapy in management of Parkinson’s
[1] Dopamine Metabolism inhibitors:
MAO-B inhibitors (selegiline/rasagiline)
* Can increase duration of response to L-dopa.
* SE – postural hypotension
[2] COMT inhibitors (entacapone)
* Block L-dopa metabolism
* SEs – sleepiness, hallucinations, impulsiveness.
[3] Amantadine – useful if prominent dyskinesias.
What is Radiculopathy?
= Process affecting nerve roots
What is Neuropathy ?
= Pathological process affecting a peripheral nerve(s)
What is Mononeuropathy ?
= Process affecting a single nerve
What is Mononeuropathy ?
= Process affecting a single nerve
What is Mononeuritis Multiplex?
= Process affecting several individual nerves
What is Polyneuropathy / peripheral neuropathy ?
Diffuse, symmetrical disease, usually beginning peripherally.
Can be motor/sensory/autonomic or combinations of these
Can be broadly classified into demyelinating or axonal types.
Widespread loss of tendon reflexes is usual, as well as “glove and stocking” sensory loss.
What drugs can cause peripheral neuropathy?
Amiodarone, statins, hydralazine, phenytoin, ABX
What are the 4 most common causes of peripheral neuropathy?
DM,
Carcinomatous neuropathy (myeloma/paraneoplastic syndrome)
B-vitamin deficiency
Drugs.
Demyelinating vs axonal neuropathy
Can be separated by nerve conduction studies
DEMYELINATING:
- Damage spares axons, but affects Schwann cells, more common in immune-mediated disease such as GBS
- Inferred by decreased conduction velocity
- Schwann cells can regrow, so will improve with Tx
AXONAL:
- Nerve cell bodies are unable to maintain long axonal processes, leading to degeneration that starts at the periphery, progressing upwards to the neuronal cell.
- Inferred by reduced amplitude of nerve impulses
- Axons cannot regrow, thus treatment outcomes are poor.
At what rate can nerves regenerate?
Providing the cell bodies are intact, the nerves are able to regenerate at a rate of up to 1mm per day.
Peripheral Neuropathy - Ix
Bloods:
- FBC, U&E, LFTs, HbA1c, B12/folate
- ANCA, VDRL (syphilis), autoantibodies
Nerve conduction studies
=> Demyelinating or axonal?
LP:
=> Raised protein in GBS / CIDP
Peripheral nerve biopsy if diagnosis uncertain.
How is non-alcoholic fatty liver disease (NAFLD) diagnosed?
Diagnosis involves:
1) ruling out other causes of hepatomegaly (such as alcoholism, viral hepatitis, and auto-immune liver disease)
2) evidence of of hepatic steatosis (liver biopsy or radiology)
Causes of transient or spurious non-visible haematuria
urinary tract infection
menstruation
vigorous exercise (this normally settles after around 3 days)
sexual intercourse
Causes of persistent non-visible haematuria
cancer (bladder, renal, prostate)
stones
benign prostatic hyperplasia
prostatitis
urethritis e.g. Chlamydia
renal causes: IgA nephropathy, thin basement membrane disease
Sick euthyroid syndrome
low T3/T4 levels alongside an inappropriately normal TSH in the context of an acutely unwell patient
Changes are reversible upon recovery from the systemic illness and hence no treatment is usually needed.
ALARMS 55 Symptoms
- Anaemia (iron deficient)
- Loss of weight
- Anorexia
- Recent onset, progressive symptoms
- Melaena or haematemesis
- Swallowing difficulties.
- > 55 years of age
How should a patient be counselled for risks of antithyroid medications?
AGRANULOCYTOSIS - Advise (including in writing) to see their GP immediately if they develop any signs of mouth ulceration, sore throat or fever.
