Pathology Flashcards
Disc prolapse reason
Degeneration of annulus fibrosus -> nucleus pulposus forced out
Why is spinal cord injury serious (pathological changes)
1) neuron regeneration impossible 2) primary injury will lead to secondary injury due to hemorrhage, oedema and accumulation of necrotic cells ——— 1) Neuronal and glial cell death (1º & 2º) 2) Axontomy and intrinsic changes of injured neurons 3) Demyelination 4) Glial Scars 5) Inhibit molecules 6) Poor blood supply
Occlusion of PICA
Lateral medullary syndrome (Wallenberg syndrome) 1) Spinal trigeminal nucleus -> ipsilateral facial analgesia and thermoanesthesia 2) Spinothalamic tract -> contralateral analgesia and thermoanesthesia below neck 3) nucleus ambiguus -> dysphagia, hoarseness of voice; ipsilateral paralysis of palatal and laryngeal muscles 4) sympathetic nerve -> Horner’s syndrome
Wallenberg syndrome
PICA occlusion: Lateral medullary syndrome (Wallenberg syndrome) 1) Spinal trigeminal nucleus -> ipsilateral facial analgesia and thermoanesthesia 2) Spinothalamic tract -> contralateral analgesia and thermoanesthesia below neck 3) nucleus ambiguus -> dysphagia, hoarseness of voice; ipsilateral paralysis of palatal and laryngeal muscles 4) sympathetic nerve -> Horner’s syndrome
Occlusion of vertebral artery or ASA
Medial medullary syndrome 1) medial lemniscus -> contralateral impaired sensation of position and movement and tactile discrimination 2) corticospinal tract -> contralateral hemiparesis 3) CN XII -> ipsilateral tongue paralysis; deviation to ipsilateral side when protrude
Reticular formation lesion
Loss of life function -> death Interrupt ARAS -> sleep and coma
Brown-séquard syndrome
Hemisection of spinal cord 1) ipsilateral loss of discriminative touch and proprioceptive sense below lesion (DC/ML pathway) 2) contralateral analgesia and thermoanesthesia below lesion (spinothalamic pathway) 3) loss of all sensation at the lesion level 4) ipsilateral UMN sign below lesion (corticospinal tract) 5) ipsilateral LMN sign at lesion level
Pathological manifestation of cerebellar dysfunctions
1) Ataxia and unsteady gait 2) Error in movement range and force (intention tremor, past-pointing, dysmetria) 3) Error in movement rate and regularity (dyssynergia, dysdiadochokinesia) 4) nystagmus (normally purkinje cells exert inhibitory influence to VOR neural network) 5) Delay in initiating responses 6) hypotonus
Horner’s syndrome
Lesion of spinal cord above T1 -> sympathetic ganglion damage PAM Ptosis Anhidrosis Miosis
definition of raises ICP
Elevation of mean CSF pressure above 15mmHg when measured in lateral decubitus position
Raised ICP signs
Headache (meningeal stretching) Vomiting (brainstem distortion) Cushing’s reflex (irregular respiration, bradycardia, hypertension) Unilateral mydriasis (CN III lesion) —- Infant: separation of sutures Long term: skull bone erosion, brain atrophy
Brain herniation types
1) Subfalcine/ supra callosal 2) transtentorial/ uncal 3) reverse tentorial 4) cerebellar tonsil herniation (coning) 5) transcalvarial/ fungus
Raised ICP effect consideration
1) Age 2) stage of spatial compensation 3) rate of development 4) pressure gradient
Transtentorial herniation effects
1) compress ipsilateral CN III -> mydriasis, ophalmplegia (downward outward) 2) optic nerve and retinal vein compression -> papilloedema 2) compress aqueduct of sylvius -> hydrocephalus 3) compress vital structure - midbrain and pontine infarction and haemorrhage (loss of consciousness, bradycardia, respiration changes, hypertension) 4) contralateral cerebral peduncle pushed against tentorium -> ipsilateral hemiplegia (false localising sign) 5) compress posterior cerebral artery -> ipsilateral occipital cortex infarction -> cortical blindness
Tonsillar herniation effects
Displacement of cerebellar tonsils through foramen magnum: - compression and distortion of medulla -> apnoea
Hydrocephalus definition
CSF increase in ventricles and/or subarachnoid space
Brain swelling causes
1) cerebral oedema (vasogenic, cytotoxic, hydrocephalic) 2) congestive brain swelling due to vasodilation alone (in hypoxia, hypercapnia, loss of vasomotor tone)
UNN vs LMN lesion
Location: CNS vs CNS/PNS Structure: cortex/corticospinal tract/ corticobulbar tract vs alpha motor neurons/ motor fibres in cranial or spinal nerves Distribution: groups of muscles vs segmental muscle fibres Spastic paralysis vs flaccid paralysis Hyperreflexia vs hyporeflexia Mild disuse muscle atrophy vs pronounced muscle atrophy Babinski sign vs none
Common sites of metastatic intracranial tumour
~25% Lung, breast, kidney and malignant melanoma Metastatic choriocarcinoma common in Chinese female
Primary intracranial carcinoma classified by origin
- Neuroectodermal tumours a. Glial cells (gliomas) - astrocytoma - ependymoma - oligodendroglioma - etc b. Neurons and primitive cells - neuroblastoma - medulloblastoma 2. Other structure tumours E.g. Meningioma, schwannoma, pituitary adenoma, carniopharngioma, haemangioblastomas
Supratentorial intracranial tumours
CEREBRAL LOBE AND DEEP HEMISPHERE - astrocytoma - glioblastoma - meningioma - metastatic tumours SELLA TURCICA - pituitary adenoma - carniopharyngioma
Intracranial tumours in ventricular system
Ependymoma Choroid plexus papilloma
Sites of cerebral astrocytoma, glioblastoma and oligodendroglioma
Commonly in frontal and temporal lobe; uncommon in occipital lobe
Biological malignancy of intracranial tumours
1) while histologically well differentiated, neuroectodermal tumours are rarely encapsulated and diffusely infiltrate tissues 2) may be in inoperable sites e.g medulla, pons, midbrain or deep hemisphere 3) may become histologically malignant with years, esp astrocytoma to glioblastomas multiforme
Spread of poorly differentiated neuroectodermal tumours
Spread within brain and spinal cord, by direct infiltration or CSF spread Rarely metastasise outside CNS
Most common site for adult intracranial tumour
Supratentorial in the cerebral lobes (70%)
Common CNS tumour and site in children
70% infratentorial Posterior fossa in midline, usually: - Cerebellum (astrocytoma, medulloblastoma) - brainstem (astrocytoma, ependymoma)
Astrocytoma histological types
Protoplasmic Pilocytic Gemistocytic Fibrillary
Astrocytoma grading
1 to 4 Grade 2: Nuclear pleomorphism (astrocytoma grade 2) Grade 3: mitotic activity (anaplastic astrocytoma) Grade 4: necrosis, endothelial hyperplasia (glioblastoma multiforme)
Astrocytoma gross appearance
Diffuse infiltration thus no clear border Cerebral astrocytoma: diffuse enlargement of region Cerebellar astrocytoma: cystic with proteinaceous fluid
Glioblastoma multiforme histology
- Variable histology - pseudo palisade - central necrosis zone surrounded by degenerate tumour with extensive cytoplasmic pleomorphism - endothelial hyperplasia
Oligodendroglioma gross and histo
Grossly well differentiated with little necrosis Histo: box like cells with clear halo Well marked cell border Calcification common
Ependymoma gross and histo
Gross: mass protruding into ventricles, encapsulated Histo: - rosette (cuboidal tumour cells around central lumen) - pseudo rosette (pink Fibrillary halo around vessels) - spindle cells - blepharoplasts
Medulloblastoma histo
Good radiotherapy response Histo: - small cells - densely stained ovoid nuclei - little cytoplasm - rosette formation with Central Fibrillary extension
Meningioma Gross and histo
Well circumscribed and lobulated Histo: - cellular whorls - psammoma bodies Site: parasagittal, fall cerebri, base of skull, inner surface of calvaria
Schwannoma sites
Most commonly cranial nerve roots: - Vestibulocochlear nerve - Trigeminal nerve Can be in spinal nerve root or peripheral nerve
Schwannoma histo
Antoni type A & B (Read)
Xerostomia definition and cause
Def: USF reduce by 50% Cause: 1) water or electrolyte loss 2) damage to salivary gland 3）interference with neural transmission
Rhinitis classifications
Allergic rhinitis Infectious rhinitis Occupational rhinitis Drug induced rhinitis
Sinusitis radiological finding
X Ray: -air fluid level -sinus opacification
Sinusitis complication
Extension of infection to: Orbital cellulitis Orbital abscess Cavernous sinus thrombosis
Sinusitis pathogenesis
Anatomical or functional obstruction of normal mucociliary clearance of sinuses -> Fluid accumulation in sinus or ostemeatal complex -> Infection
Otitis media pathogensis
Ear canal skin inflammation Swelling blocking rapid cell turnover More dead skin produced, which allow germ breed Pus filled ear canal Tympanic membrane bulge outwards, leading to pain, fever, hearing loss (AOM) Tympanic membrane bursts and perforation, discharge of pus (active CSOM) Perforation persists, discharge stops (inactive CSOM)
Otitis media complications
TM rupture with pus discharge Mastoid abscess if pus moves in Facial nerve palsy or CN VI Brain abscess
Otitis media pathogens
Viral or bacteria (S pneumoniae, HI)
Tonsillitis pathogen
Bacterial: s pyogenes, Staphylococci, S pneumoniae, HI Viral: rhinovirus, adenovirus, EBV Others: diphtheria, syphilis, TB, candida
Clinical features of tonsillitis
Fever Sore throat Odynophagia Otalgia Trismus Red swollen tonsils Throat redness Swollen uvula Gary furry tongue Whitish spots ALWAYS BILATERAL
Sialoadenitis pathogensis
1) ascending duct infection related to dehydration and debilitation e.g. Old age –> thicker more mucous salvia that stuck in ducts –> infection OR 2) secondary to ductal obstruction e.g. Stones (submandibular duct most likely)
Sialoadenitis pathogen
Viral: Mumps Coxsackievirus HIV Echovirus Bacterial: Staphylococcus TB Syphilis No infectious: Sjogren’s
Acute epiglottitis presentation
Children 2-4 yo Fever Severe sore throat Stridor Dysphonia Drooling Laryngoscopy: cherry red epiglottis XR neck: thumb sign Blood culture: HIB
HI microbiology
Gram negative Beta lacamase producing Coccibacilli Factor V and X for growth Type a to f, b most invasive
Epiglottitis management
Airway protection Antibiotic (amoxiclav) Rifampicin prophylaxis HIB vaccination
Quinsy presentation
Adolescents and young adults Low grade fever Severe sore throat Stridor (if bilateral) Dysphagia Medial deviation of tonsils
Epiglottitis pathogen
HiB
Quinsy pathogen
GAS (strep pyogenes) Mixed oropharyngeal organisms: anaerobes, viridans streptococcus
GAS microbiology
Beta hemolytic Lancefield group A Bacitracin sensitive
Strep pneumoniae microbiology
Alpha hemolytic Optochin sensitive Bile soluble
Croup (laryngotracheobronchitis) presentation
Young children of 3 months to 3 yo Fever Barking cough Tripod position Hoarseness Stridor XR neck: subglottic swelling - hourglass or steeple sign Nasopharyngeal aspirated (NPA) - viral antigens
Quinsy management
Airway protection Antibiotic Abscess drainage
Croup pathogen
Viral mainly: Parainfluenza Influenza Respiratory syncytial Adenovirus Rhinovirus Mycoplasma
Croup management
Airway protection Racemic adrenaline +- steroid
Deep oropharyngeal fascial space infections
1) submandibular and sublingual space (Ludwig’s agina) 2) lateral pharyngeal space 3) retropharyngeal space
Ludwig’s angina presentation
Board like floor swelling High fever Systemic toxicity Dysphagia Often with dental root abscess
Ludwig’s angina management
Airway protection Antibiotic Soft tissue decompression Dental assessment
Lateral pharyngeal space infection presentation
Fever Sore throat Dysphagia Neck stiffness Jaw angle swelling Great pain and trismus (if ant) Great dyspnea (if post) CT/MRI to see extension Blood culture Pus culture
Lateral pharyngeal space infection complications
Jugular venous thrombophlebitis Carotid artery erosion
Lateral pharyngeal space infection management
Airway protection Antibiotic Surgical drainage (if abscess) Treat primary infective focus
Prothrombin time
Extrinsic and common pathway -> I, II, V VII X
APTT
Activated partial thromboplastin time Intrinsic and common pathway -> all factors except VII and XIII
Thrombin time
Fibrinogen deficiency or dysfunction Thrombin inhibition e.g by heparin
Bleeding disorder lab tests
PT APTT TT fibrinogen level Platelet tests -> platelet count, platelet function test by aggregometry, skin bleeding time
Platelet disorder presentation and classes
All present with mucocutaneous bleeding Autoimmune thrombocytopenia Alloimmune thrombocytopenia -neonatal allo TP -post transfusion purpura -platelet refactoriness Inherited -Bernard-soulier syndrome -grey platelet syndrome -storage pool disease -glanzmann’s thrombasthenia DIC dilutional (eg after massive transfusion)
Haemophilia A gene linkage
Long arm of X chromosome -> x linked Maternal side 1/3 are due to spontaneous mutation
Haemophilia A and B problem
Haemarthrosis -> recurrent bleeding in major joints leading to progressive joint deformity Inhibitor to infused factor concentrate -> replacement therapy less effective High cost of treatment Transfusion transmitted infection (esp viral HIV HBV HCV) Carrier female detection
VWD genetic
Short arm of chromosome 12
VWD lab test
Increased APTT Increased bleeding time VWF antigen assay Ristocetin assay Collagen binding assay Factor VIII assay
Other hereditary coagulation disorder
Deficiency of VII XII X fibrinogen Autosomal recessive
Vit K deficiency causes
Obstructive jaundice Malabsorption Post oral broad spectrum antibiotics that killed intestinal flora
Haemorrhagic disease of newborn
Immature liver that cannot perform K dependent post translation gamma carboxylate on of glutamic acid on II VII IX X C S sterile gut with no intestinal flora for K production Low vit K in breast milk
INR
International normalised ratio INR = (PT/ mean normal PT)^ ISI ISI is international sensitivity index Used for monitoring oral anticoagulant so no vitamin K antagonism occur
Vitamin antagonism
Result of oral anticoagulant usage Competitive inhibitor of vitamin K epoxide reductase needed for recycling vitamin k during gamma carboxylation
Liver disease and bleeding aetiology
Reduced hepatic synthesis of clotting factors and inhibitors (except VIII and VWF) Reduced vit K absorption due to cholestasis -> further decrease clotting factor production Failure of reticuloendothelial cells to clear activated products and intermediates of coagulation and fibrinolysis -> interfere with platelet function and fibrin formation Portal hypertension -> hypersplenism -> platelet sequestration Acquired dysfibrinogenaemia -> abnormal fibrinogen synthesis
Liver induced coagulation disease treatment
Parenteral vit K replacement Clotting factor replacement via FFP
Uraemia and bleeding tendency aetiology
Defect in platelet function (inhibition by nitric oxide) Low haematocrit -> Platelet-vessel wall interaction
How to treat uraemia bleeding tendency
Increase haematocrit by red cell transfusion erythropoietin therapy Peritoneal or haemodialysis DDA VP administration Cryoprecipitate transfusion
DIC pathogenesis
Entry of tissue thromboplastin into blood stream Direct activation of coagulation Severe endothelial injury Direct activation of platelet Thrombin activation which convert fibrinogen to fibrin, activating secondary fibrinolysis Widespread coagulation —> intravascular fibrin formation —> micro thrombotic occlusion of small vessels —> tissue ischaemia and multi organ dysfunction Widespread coagulation and fibrinolysis depletes clotting factors, platelets and coagulation inhibitors —> severe bleeding
Causes of DIC
Infection (septicaemia and viral infection) Trauma (serious tissue injury, fat embolism, extensive burns) Cancers (acute promyelochtic leukemia, metastatic carcinoma) Obstetric condition (septic abortion, amniotic fluid embolism, abruptio placentiae) Immunological (haemolytic blood transfusion reaction eg ABO incompat; organ transplant rejection)
DIC diagnosis
Underlying related condition Increase PT APTT TT Reduced fibrinogen level, low antithrombin Thrombocytopenia Increase fibrin degradation product namely D-dimers from secondary fibrinolysis Microangiopathic change in blood film as RBC damaged when passing through clots
DIC. Management
Platelet transfusion FFP to replenish clotting factors Anticoagulants (to overt thromboembolism or extensive fibrin deposition) Antithrombin concentrate *** treat precipitating trigger first!!
IPEX
Autoimmune disease X linked single gene deletion Immune dysfunction Polyendocrinopathy Enteropathy X linked Deletion in foxp3 transcription regulator -> loss of Treg cells (Cd4 Cd25 foxp3)
Autoimmune aetiology
Lack of Treg cells (IPEX) Release of sequestrated antigens (sympathetic ophthalmia, vasectomy) Induction of MHC II antigen on non-APC (interferon gamma on thyroid epithelial cells) Cross reaction between microbial antigen and similar autoantigen (rheumatic heart disease)
Autoimmune disease factors
Genetic Hormonal Environmental (infective, drug)
Genetic factors in autoimmune
Demonstrates familial clustering and higher concordance rate in identical twins No clear mandelian traits Multiple genes involve with low penetrance Genetic heterogeneity MHC gene esp associated -> HLA-DR4 and rheumatoid arthritis; HLA-DR3/4 and IDDM
Hormonal factors in autoimmune
Sex preponderance in many SLE female:male = 9:1 (admin of male sex hormone and female castration helps with SLE in mice)
Infective factor and autoimmune
IDDM and rubella or enterovirus infection
Drug induced autoimmune
SLE - hydrallazine, penicillamine Hemolytic anaemia - methyldopa
Environment factor and autoimmune
Drug, infection SLE -> Sun exposure
Neutrophilia causes
1) infection (bacterial fungal) 2) Acute inflammation 3) tissue damage/ infarction 4) MPN 5) drugs eg corticosteroids
Neutropenia causes
Infection (neonate) Leukemia, metastases Aplastic anaemia Drugs Myelofibrosis Cyclical
Lymphopenia causes
HIV AIDS Drugs eg corticosteroid
Lymphocytosis causes
Children: Viral infection (CMV), sometimes bacterial (pertussis) Adolescent: Viral (EBV) Adult: Chronic lymphocytic leukemia, acute stress
Eosinophilia causes
Allergy Parasitic infection Drug hypersensitivity Autoimmune Neoplasm
Basophilia causes
Chronic myelogenous leukemia (CML) Acute leukemia
Monocytosis
Chronic infection eg TB chronic inflammation Neoplasm: CML, other MPN MDS
Crude Haematological findings in AML ALL CML CLL and MDS
AML -> presence of blast cells; auer rods ALL -> blast cells CML -> basophilia, mature and immature CLL -> abnormal mature looking lymphoid cells MDS -> funny looking white and red cells; abnormal nucleus shape
Functional white cells disorders
Lazy leukocyte syndrome -> defect in chemotaxis Opsonin deficient -> defect in phagocytosis Chronic granulomatous disease, myeloperoxidase deficiency -> defect in killing or digestion
WBC disease investigations
1) PBS, CBC 2) Bone marrow - BMA or - touch imprints - trephine biopsy 3) cytochemistry staining - non specific esterase (AML) - myeloperoxidase (AML) - PAS (ALL) 4) flow cytometry 5) lymph node / other tissue biopsy 6) cytogenetic karyotypin 7) FISH 8) PCR
Both quality and quantity abnormality WBC disorder
B cell - X linked agammaglobulinaemia - severe combined immunodeficiency T cells - DiGeorge syndrome - MHC class II deficiency
Multiple myeloma (presentation, diagnosis)
Plasma cell neoplasm Present as: Anaemia Bone pain Recurrent infection Renal failure PBS-> rouleaux formation; no abnormal white cells Bone marrow-> plasma cells 30% and clinal Urine/ serum -> monoclonal protein
BMA usage in WBC disorder diagnosis
Assessment of BM cellularity and differential counts Identification of abnormal cells Stain with Wright-Giemsa stain
BM trephine biopsy usage in WBC disorder diagnosis
Assess BM cellularity Identification of abnormal cells Assess architecture and topographic relationship of cells in BM staging of lymphoma
Cytogenetic karyotyping limitations
There might be no metaphase cells
What is a blood cancer
Malignancy arising from haematopoietic system or lymphpoietic system
Lymphoma definition
Clonal malignancy of lymphoid system (ie from lineage B cells T cells NK cells)
Aetiology of lymphoma
Increase with age Related to viral infection - EBV, HIV HTLV human T cell lymphoproliferative virus
Lymphoma manifestation
1) enlargement of nodal (lymph node) or extranodal tissues 2) A symptoms -> asymptomatic 3) B symptoms -> systemic, eg Fever, night sweats, loss of body weight
Lymphoma classifications
Hodgkin lymphoma B cell lymphoma T cell lymphoma NK cell lymphoma
Lymphoma metastasis
Via lymphatics (Hodgkin) Hematogenous spread in other types of lymphoma Local infiltration to different organs
B cell lymphoma treatment
1) R-CHOP chemotherapy + targeted therapy Rituximab anti CD20 cyclophosphamide, hydroxydaunorubicin, vincristine [Oncovin], prednisone (Purine analogue containing regimen for low grade; mab for maintenance treatment) 2) HSCT autologous HSCT for relapses lymphoma (Source from peripheral blood, BM) If there is BM involvement, then allogenic HSCT
Hodgkin lymphoma treatment
1) chemotherapy with/wo radiotherapy 2) Mab against CD30 for relapse 3) autologous HSCT for relapse
NK lymphoma treatment
1) chemotherapy, esp L-asparaginase containing regimen 2) otherwise similar to B cell
T cell lymphoma treatment
Similar to B cell lymphoma 1) early use of autologous HSCT may be useful
Hodgkin lymphoma nature
Less common in Chinese Good prognosis; most patients curable
NK cell lymphoma nature
Found mainly in Asians (ninja!) Nose affected as main site EBV related Highly aggressive with poor prognosis
T cell lymphoma nature
Uncommon Variable prognosis Related to HTLV-1 (Japan and TW)
Lymphoma prognosis
1) International prognostic index -tumour stage - serum LDH - extranodal sites - age -performance 2) Histology types -lineage - high/low grade 3) chemotherapy intensity
AML clinical features
-adults -myelosuppresion -> anaemia and thrombocytopenia -leucocytosis with >20% blasts in BM and blood -associated with toxic exposure, toxic drugs and antecedent myelodysplastic syndrome - Auer rods
AML treatment
Induction of remission Consolidation of remission with high doses of chemotherapy Maintenance of remission usually not given HSCT for relapse or high risk cases All trans retinoids acid and arsenic trioxide for acute promyelocytic leukemia
ALL clinical features
-mainly adults, sometimes children - leucocytosis -myelosuppresion -> anaemia and thrombocytopenia -enlargement of lymph nodes, liver and spleen as lymphoblastic cells return to origin - CNS involvement -not obviously associated with toxic exposure B cell origin?
ALL treatment
Induction of remission Consolidation chemotherapy Maintenance treatment for 2 years CNS prophylaxis HCST transplant in relapse or high risk
CML clinical features
-adults; incidence increase with age -leucocytosis with mature and immature cells, basophilia -enlarged liver and spleen -associated with irradiation exposure eg atomic bomb -triphasic if untreated: 1) chronic 3-4y 2) acceleration <6m 3) blastic crisis 1-2 months -Philadelphia gene - BCR-ABL 9-22 translocation (cytogenetic karyotyping or FISH or PCR)
CML treatment
Chemotherapy ineffective Targeted therapy with tyrosine kinase inhibitors (eg imatinib dasatinib bosutinib I’m da boss) Hydroxyurea for symptomatic treatment HSCT for blastic transformation patient or not responding to TKI
CLL clinical features
-elderly, never in childhood -uncommon in Chinese -late stage myelosuppresion -> anaemia and thrombocytopenia -lymph node enlargement, late stage liver and spleen enlargement -leucocytosis with mature cells -associated with toxic exposure, toxic drugs and antecedent myelodysplastic syndrome
CLL treatment
No early stage treatment Chemotherapy with Purine analogue (oral alkylation agent not preferred in <50
MDS clinical features
Pancytopenia Hyper cellular BM Myelodysplastic blood cells in blood or BM BM abnormal karyotyping Increased blasts Progress to AML Associated with previous chemotherapy irradiation or toxic exposure
MDS classes
Refractory cytopenia with unilineage dysplasia Refractory cytopenia with multilineage dysplasia Refractory anaemia with ringed sideroblasts Refractory anaemia with excess blasts MDS with 5q- Childhood MDS
MDS diagnosis
PBS CBC -> pancytopenia BMA -> hypercellularity Cytogenetic -> monosomy 5 or 7, deletion of long arm of 5 or 7 5q- 7q-
MDS management
1) risk stratification 2) supportive, transfusion for most - erythropoietin for anaemia - iron chelation for chronic transfusion 3) allogeneic HSCT in younger patients for RAMD RAEB 4) lenalidomide for 5q- syndrome 5) demethylating agents (eg azacytidine decitabine)
MDS prognosis
Incurable except in young patients after HSCT May transform to AML, especially in RAEB
MPN features
Clonal disease of pluripotent HSC 1) increased circulating cells of all haematopoietic lineages 2) hypercellularity in BM 3) absence of muelodysplastic features Pre-leukemia
MPN common subtypes
CML -> myeloid Polycythaemia Vera -> erythroid Primary myelofibrosis -> fibrous tissue Essential thrombocythaemia -> megakaryocytic
MPN genetic mutations
CML -> BCR-ABL1 PV -> JAK2 MF -> 50% JAK2; 40% CALR ET -> 50% JAK2; 40% CALR CALR = calreticulin gene
PV features
MPN *) pruritus 1) high Hb -> facial plethora 2) leucocytosis thrombocytosis 3) splenomegaly 4) suppressed serum erythropoietin diagnosis by exclusion JAK2 mutation
PV treatment
Venesection -> replace venesected blood with normal saline Cytoreduction with hydroxyurea Avoid secondary leukemia inducing agents eg alkylating agents or radioactive phosphorus Thrombosis prophylaxis eg aspirin
Primary myelofibrosis features
- Hepatosplenomegaly; Extramedullary hematopoiesis, which is non functional Leuco-erythroblastic picture with tear drop RBC JAK2, CALR mutation Diffuse fibrosis of BM -> megakaryocytic proliferation Terminally present with hepatic fibrosus -> variceal bleeding and portal hypertension CELLULAR PHASE (prefibrotic) -anaemia -leucocytosis -thrombocytosis FIBROTIC PHASE -pancytopenia
Primary myelofibrosis management
1) supportive 2) early splenectomy helps to decrease blood transfusion requirement 3) alligeneic HSCT in younger patient 4) JAK2 inhibitor for high risk 5) Cytoreduction with hydroxyurea 6) avoid secondary leukemia inducing agents eg alkylating agents or radioactive phosphorus
ET features
Sustained thrombocytosis (must exclude chronic inflammatory disorder, infection, neoplasm) JAK2 CALR mutation
ET treatment
Treatment not required in young patient Prophylactic anti thrombotic agents eg aspirin esp in elderly Cytoreduction with hydroxyurea Anagrelide to reduce platelet count Avoid leukarmogenic agents eg alkylating agents or radioactive phosphorus
MDS/MPN feature
Increased circulating cells Hypercellularity of BM Myelodysplastic features of blood cells
MDS/MPN classification
Chronic myelomonocytic leukemia (CMML) atypical chronic myeloid leukemia (aCML)
CMML features
Elderly Monocytic lineage proliferation High monocyte count No Philadelphia chromosome
Cortical lesion of S1
Contralateral loss of discriminative touch and position sense; thermoception and nociception relatively unaffected
Lesion of association somatosensory cortex
Tactile agnosia - inability to recognise object despite sensation Constructional apraxia - deficit in ability to relate extra personal space Neglect syndrome (contralateral) Spatial orientation difficulty eg map reading, driving
MDS/MPN management
Supportive in elderly patients Allogeneic HSCT in children Tyrosine kinase inhibitor for some CMML
Thalamic pain syndrome
Lesions in the Ventral Posterior nuclei of thalamus (VPM, VPL) Analgesia followed by paraesthesia and hyperalgesia or even severe spontaneous pain; associated with exaggerated affective response
Lesion of M1
Interferes with motor proficiency and manual dexterity Independent control of fingers may be lost (corticospinal tract)
Lesion of PMA
Paresis or weakness of axial and proximal muscles (medial descending system) Interfere with choreography of complex movement (complex movement possible but slow execution) Severely affects visually guided movement
Lesion of SMA
Interferes with goal-directed behaviours that require planning and execution of complex motor sequence e.g. circumventing a transparent screen deficit in bimanual coordination
Unilateral UMN lesion of corticobulbar tract
No symptoms for CN III IV V VI upper face (VII) IX X XI Contralateral symptoms for lower face VII (e.g. lower face paralysis, sagging mouth corner obicularis oris) and XII (tongue deviate to contralateral side of lesion)
Unilateral LMN lesion of corticobulbar tract
Ipsilateral LMN symptoms for cranial nuclei III-XIII except VIII
Unilateral supranuclear facial paralysis
UMN lesion of corticobulbar tract Contralateral lower face paralysis (sagging mouth corner - orbicularis oris)
Unilateral peripheral facial paralysis
LMN lesion of corticobulbar tract Ipsilateral upper and lower face paralysis (incomplete closure of eyelid - obicularis oculi; sagging mouth corner - orbicularis oris)
Lentico-striate artery occlusion
Leads to capsular infarction/ haemorrhage -> internal capsule function affected UMN paralysis of contralateral limbs and lower face
Causes of UMN lesion
Lentico-striate artery occlusion -> capsular infarction MCA infarction Pontine infarction Corona radiata tumour etc.
UMN vs LMN lesions
CNS vs CNS/PNS Involve cortex, corticospinal or corticobulbar tract vs alpha motor neuron, motor fibres of cranial or spinal nerves Distribute to groups of muscles vs segmental muscles Spastic paralysis (antigravity muscle, clasp-knife rigidity) vs flaccid paralysis Hyperreflexia vs hyporeflexia Mild disuse atrophy of muscle vs pronounced atrophy Babinski’s sign vs no Babinski’s sign
Lesion above red nucleus (midbrain)
Decorticate posturing: Rubrospinal cord intact, therefore UL flexion (elbow and wrist flexed) - wrist flexed - leg extended - plantar flexion
Lesion between red nucleus and vestibular nucleus
Decerebrate posturing/rigidity Unopposed pontine reticular nucleus and vestibular nuclrus -> extensor activities –> UL extension (extension of elbow, pronation) - wrist flexed - leg extended - plantar flexion
Visual field defect in optic nerve lesion
Monocular amaurosis (ipsilateral) e.g. in optic neuritis
Visual field defect in optic chiasma lesion
Bitemporal hemianopia e.g. pituitary macroadenoma
Visual field defect in optic tract lesion
Homonymous hemianopia (contralateral side of visual field busted in both eyes) e.g. craniopharyngioma
Visual field defect in optic radiation lesion
Temporal: homonymous upper quadrantic hemianopia Parietal: homonymous lower quadrantic hemianopia
Visual field defect in visual cortex lesion
Dense homonymous hemianopia with macular sparing
Prefrontal cortex lesion
- primitive reflex(grasp, snout, suck, rooting) - high distractibility - lack of foresight/insight - inability to switch tasks - lack of ambition/ responsibility - lack of social propriety and self-monitoring
Limbic lesion
- Amnesia - Flat emotion/ affect - Akinetic mutism
Types of aphasia
Expressive (Broca’s) non-fluent Receptive (Wernicke’s) fluent Global
Mental retardation defintion
2 SDs less than mean intelligence; never had a normal IQ
Dementia definition
loss of previously acquired intelligence
Causes of dementia
1) Primary neurodegenerative dementia - alzheimer’s - Lewy bodies 2) Vascular dementia - infarct ——–uncommon— 3) Infective dementia - e.g. syphilis, AIDS, CJD 4) Intracranial pathology - tumour - hydrocephalus - subdural hematoma 5) Chronic alcoholism etc.
Vascular dementia
History of stroke Abrupt decline Focal neurological signs Management: Stroke prevention
Spinal cord injury repair strategy
1) Neuronal and glial cell death (1º & 2º) - reduce cell death with methylprednisolone - block death receptor activation to reduce 2º injury - Stem cell transplant to replace neurons 2) Axontomy and intrinsic changes of injured neurons - Enhance regeneration by modifying intrinsic environment e.g. increase cAMP, inhibit PKC 3) Demyelination - Oligodendrocyte or Schwann cell transplant 4) Glial Scars 5) Inhibit molecules 6) Poor blood supply - reduce glial scar and inhibit molecules by enzymes, antibodies
Ectopic Thyroid Tissue
may be found anywhere along the path of descent of the thyroid gland. It is commonly found in the base of the tongue or with the lateral cervical lymph nodes.
Thyroglossal duct cyst
found anywhere along the path of descent of the thyroid gland, but always in the midline of the neck Sometimes connected to the outside by a canal, a thyroglossal fistula
Ectopic parathyroid tissue
persist along the path of migration (may be as low as aortic arch) Can be visualised by Parathyroid scintigraphy dual phase planar imaging
Parathyroid scintigraphy dual phase planar imaging
Patients are injected with tracer (Tc99m, Technetium -99m) and imaged at 5 min and images repeated at 2h. This radiotracer is taken up by the thyroid gland, but cleared from the thyroid with a half-life of 30 min. It is usually retained by abnormal parathyroid tissue
Recurrent laryngeal nerve injury
(normally supplies all laryngeal muscles except cricothyroid; especially important as it innervates superior cricoarytenoid muscle, the only abductor of vocal cords) Unilateral: Hoarseness, dysphagia, partial (abductor) paralysis of the vocal cord Bilateral: Bilateral (abductor) paralysis of vocal cord, airway obstruction, which may leads to death
Pituitary adenoma classification
1) By size: Macroadenoma 1cm+; microadenoma 1cm - 2) - Functional (hormone overproduction with clinical manifestation) or - silent (hormone overproduction without clinical manifestation) or - hormone negative
Pituitary adenoma histology
Monotonous pinkish secretory cells - uniform polygonal cells in sheets/cord Rare mitosis, little pleomorphism Increased vascularity
GH hypersecretion causes
PRIMARY: 1) pituitary adenoma (acidophil cell tumour) SECONDARY: 1) Hypothalamic tumour releasing GHRH 2) Ectopic GH or GHRH from lung cancer or pancreatic cancer
GH hypersecretion pathology
Gigantism in children; Acromegaly in adults Symptoms: 1) outgrowth of all organs, bones, joints and soft tissues (excessive height in gigantism; skeletal overgrowth with large nose feet hands on acromegaly) 2) hyperglycaemia (osmotic diuresis?)
GH deficiency causes
PRIMARY: 1) idiopathic in childhood 2) Pituitary tumours e.g. Silent or hormone negative pituitary adenoma; carniopharyngioma
GH deficiency pathology
Pituitary dwarfism in children Symptoms: 1) delayed physical maturation 2) short stature 3) reduced skeleton and muscular mass - affected walking jumping and standing 4) sparse hair growth and frontal recession
GH secretion tests
1) Blood test for GH or IGF-1 - difficult as t1/2 is short 2a) Functional test - stimulation test - insulin tolerance test - arginine infusion test 2b) functional test - suppression test - glucose tolerance test
GH deficiency functional test
Arginine infusion test and insulin resistance test Arginine and insulin normally reduces plasma glucose, thus increasing GH secretion -> if GH not increased, GH hyposecretion
GH over secretion functional test
Suppression test (glucose tolerance test) Increased glucose normally lead to reduction of GH secretion If GH level not decreased, then GH hypersecretion
Hyper prolactinemia causes
PRIMARY: 1) prolactinoma (a pituitary adenoma) SECONDARY: 1) pregnancy 2) psychiatric medications
Hyper-prolactinemia symptoms
Men: loss of libido, impotency, low sperm count, gynaecomastia Women: menstrual disturbances (amenorrhea), galactorrhea, loss of libido, infertility
ACTH hypersecretion causes and pathology
Cause: pituitary adenoma Pathology: Cushing’s disease (secondary hypercortisolaemia) - ACTH and Cortisol increased - symptoms: Cushing’s syndrome
Cushing’s disease definition
Hypercortisolaemia (Cushing’s syndrome) caused by increased ACTH production due to pituitary adenoma
ACTH hyposecretion causes and pathology
Causes: inefficient pituitary production; or use of exogenous steroids Pathology: secondary hypocortisolism (secondary adrenal insufficiency) - reduced ACTH and cortisol - Nausea, vomiting - fatigue, weakness, hypotension - hyperpigmentation and hyperkalemia NOT SEEN
TSH hypersecretion causes and pathology
Cause: pituitary adenoma Pathology: secondary hyperthyroidism - increase TSH and TH
TSH hyposecretion pathology
Secondary hypothyroidism - decrease TSH and decrease TH
LH and FSH hyposecretion
Hypogonadotropic hypogonadism female: - breast atrophy - vaginal dryness - reduced libido Male: - reduced libido - impotency
Panhypopituitarism
Where all pituitary hormones are insufficient GH, Prolactin, FLAT
Causes of hypopituitarism (especially Panhypopituitarism)
1) post surgery or radiation 2) trauma 3) infection/ inflammation 4) pituitary tumour (silent/ hormone negative) 5) Sheehan syndrome
Sheehan’s syndrome
Aka postpartum hypopituitarism - caused by ischaemia necrosis of pituitary gland due to blood loss during or after childbirth
ADH deficiency due to hypopituitarism
- Neurogenic diabetes insipidus (polyuria, polydipsia) - hypernatremia
Diabetes insipidus classes
1) Neurogenic DI (decreased ADH release due to hypopituitarism) 2) nephrogenic DI (inability of kidney to respond to ADH) 3) Dipsogenic (defect in hypothalamic thirst mechanism) 4) Gestational (placenta produce vasopressinase that cleaves ADH)
Pancreatic islet cell tumours classifications
A. FUNCTIONAL: 1) insulinoma (beta cells) 2) gastrinoma (G cells) 3) glucagonoma (alpha cells) 4) VIP-oma (VIP cells) B. NON-FUNCTIONAL
Insulinoma pathology
Hypoglycaemia Triad: 1) recurrent hypoglycaemic attack 2) CNS symptoms (confusion, loss of consciousness) 3) Attack promptly relieved by glucose administration
Gastrinoma pathology
Excess gastrin over stimulated H+ production by gastric parietal cells: Severe peptic ulcer - Zollinger-Ellison Syndrome
Glucagonoma pathology
Secondary diabetes with hyperglycaemia
VIP-oma pathology
Increased digestive motility -> watery diarrhoea
Pancreatic islet cell tumour histology
In ribbons and anastomosing trabeculae Richly vascularised Round nuclei with fine chromatin Eosinophilic cytoplasm
Adrenal insufficiency types
PRIMARY (both aldosterone and cortisol deficient) 1) acute primary (Waterhouse-friderichsen syndrome) 2) chronic primary (addison’s disease) SECONDARY (only cortisol deficient) 1) reduced ACTH secretion due to hypopituitarism
Waterhouse-Friderichsen Syndrome
Acute primary adrenal insufficiency Due to overwhelming bacterial infection -> hypotension and shock -> DIC -> adrenocortical insuffiency -> massive adrenal haemorrhage - reduce cortisol and aldosterone
Causes of Addison’s disease
Autoimmune adrenalitia, amyloidosis TB, infections Metastasis
How to distinguish primary and secondary hypoadrenalism
Primary vs secondary Reduction in cortisol and aldosterone vs reduction in cortisol ACTH increase vs ACTH decrease Hyperpigmentation vs none Hyperkalemia vs none
Addison’s disease pathology
- reduce cortisol and aldosterone - Nausea, vomiting - fatigue, weakness, hypotension (due to hyponatremic volume contraction) - hyperpigmentation - hyperkalemia
Hyperpigmentation in primary adrenal insufficiency
Reduced cortisol leads to negative feedback increase in pituitary ACTH secretion, which will lead to concomitant MSH secretion as ACTH is the precursor
Hyperadrenalism presentation
1) Primary hyperaldosteronism (Conn’s syndrome) 2) primary hypercortisolaemia (Adrenal Cushing’s syndrome) 3) Primary androgen hypersecretion (Androgenital syndrome or virilism)
Hyperadrenalism causes
Congenital Adrenal Hyperplasia Cortical adenoma
Hyperaldosteronism causes
PRIMARY (hyperadrenalism) 1) adrenal hyperplasia 2) cortical adenoma —- SECONDARY (renal perception of low intravascular volume -> overreaction of renin-angiotensin system) 1) renal artery stenosis 2) CHF 3) chronic renal failure 4) cirrhosis
Primary hyperaldosteronism features
Conn’s: HypoK, HyperNa, alkalosis, ↑ plasma & urinary aldosterone - muscle weakness (due to hypokalemia) - tetany (metabolic alkalosis, hypokalemia) - hypertension (hypernatremia) - decrease plasma renin
Primary vs secondary hyperaldosteronism
Low plasma renin VS High plasma renin
Cushing’s syndrome causes
1) iatrogenic/ exogenous glucocorticoid 2) Cushing’s disease (secondary to pituitary ACTH hypersecretion from adenoma) 3) ectopic ACTH (from SCLC or pancreatic cancer) 4) Adrenal adenoma, carcinoma or hyperplasia (PRIMARY) 5) hypothalamic CRH hypersecretion
Cushing’s syndrome presentation
1) CVS - hypertension (hypernatremia, water retention) - left ventricular hypertrophy - capillary weakness 2) GI - peptic ulcer 3) U - sodium and water retention - hypokalemia - hypercalciuria -> ureteric calculus - polyuria sometimes 4) G - increased androgen with clitoral hypertrophy, virilism, hirsutism, and amenorrhea 5) MSS - muscle weakness (hypokalemia) - osteoporosis - decrease bone mass -> fractured - thin limbs 6) Skin - truncal obesity - buffalo hump - moon face - abdominal striae 7) CNS - irritability 8) Immune - poor wound healing - immunosuppresion 9) endocrine - hyperglycemia - diabetic
Pheochromocytoma presentation
Adult adrenal medullary tumour - pressure (hypertension) - pain (headache) - perspiration - palpitation, tachycardia - pallor - tremor, sense of apprehension Complication: –> MI due to vasoconstriction Increase urine catecholamine and vanillylmandelic acid
Pheochromocytoma 10% rule
10% extra-adrenal 10% bilateral 10% malignant 10% without hypertension
Adrenal Neuroblastoma
Adrenal medullary neoplasm of children less than age of 3 Often metastasise Soft and lobulated (small blue round cells)
Retropharyngeal space infection underlying causes and pathogen
(Oral flora): Odontitis Pharynx perforation Quinsy (Staph aureus): Cervical vertebral osteomyelitis
Retropharyngeal space infection features
Fever Dysphagia Neck stiffness Sore throat
Retropharyngeal space infection complications
Spread of infection -> mediastinitis
Retropharyngeal space infection investigation
Neck XR: prevertebral soft tissue swelling CT to check involvement extent Blood and pus culture
Retropharyngeal space infection management
Airway protection Antibiotic Surgical drainage
Acute epiglottitis vs croup
Epi vs croup 2-4 yo VS 3 m - 3yo Toxic and unwell VS well looking Abrupt onset VS viral prodrome High fever VS moderate Fever More sever stridor vs less Minimal cough VS barking cough Dysphonia vs hoaseness Drooling and Dysphagia vs intact swallow
Non infective URT obstruction
Foreign body aspirations Tumour Goitre Bilateral vocal cord palsy
Nasal cavity pathologies
V: juvenile angiofibroma I: nasal polyps N: Nasal papilloma, squamous carcinoma, malignant melanoma, adenocarcinoma D: / I: TB, leprosy, Scleroma, aspergillosis, candidiasis C: cleft palate, choanal atresia or stenosis A: Wegener’s granulomatosis, lethal midline granuloma T: wood dust associated adenocarcinoma E: allergic nasal polyps
Oral cavity and tongue pathologies
V I: aphthous ulcer N: squamous cell carcinoma D I C A: lichen planus T: ulcer E
Salivary gland pathologies
V I: sialadenitis N: pleomorphic adenoma, warthin’s tumour, mucoepidermoid carcinoma, adenoid cyst, lymphoepithelioma-like- carcinoma D I: viral mumps C A: Sjögren’s syndrome T E
Larynx pathologies
V I: vocal polyps (singer’s nodule) N: squamous papilloma, carcinoma in situ, invasive squamous cell carcinoma D I: viral (influenza, adenovirus, chicken pox) Acute laryngitis, acute epiglottitis, croup, TB C: laryngeal web A: laryngeal edema T E
Aphthous ulcer
May be due to HSV infection
Oral cavity squamous cell carcinoma (risk)
Commonest oral cavity neoplasm Risks: - smoking!! - alcohol abuse - HSV HPV infection - sunlight - poor dentition
Sialadenitis complication
Mucocele - obstruction of minor salivary gland
Salivary gland neoplasm
1) pleomorphic adenoma 2) Warthin’s tumour —MALIGNANT 3) mucoepidermoid carcinoma 4) adenoid cyst 5) lymphoepithelioma like carcinoma
Sjögren’s syndrome
Autoimmune destruction of salivary glands; Lymphocyte, fibrous tissue in glands -> dry mouth -> tooth decay -> dry eye
Pleomorphic adenoma
Most commonly in parotid gland (ensure facial nerve preservation in excision!) Pleomorphic histology 1) Epithelium forming small ducts and myoepithelial cells 2) Myxoid (shiny surface) or chondroid stroma
Warthin’s tumour
Mostly in parotid gland, bilaterally Aka cystadenoma lymphomatosum papilliferum
Mucoepidermoid carcinoma
Malignant salivary gland tumour Combination of glandular and squamous epithelium
Adenoid cystic carcinoma
Common in submandibular and sublingual glands Locally invasive Mixture of glandular cells and myoepithelial cells
Lymphoepithelioma-like- carcinoma
Salivary gland tumour Common in Chinese Resembles NPC and associated with EBV Metastasise to lungs and lymph nodes
Vocal polyp
Chronic laryngitis due to mechanical injury to vocal folds eg voice misuse - squamous metaplasia - localised stromal edema - degeneration
Laryngeal edema
Autoimmune or traumatic eg when patient is allergic to bee sting or medication Massive swelling of larynx -> obstruct inlet -> death due to respiratory distress
Laryngeal squamous papilloma subtypes
JUVENILE - multiple - wide area - high recurrence ADULT - single - from vocal cord exclusively - rare recurrence
Laryngeal carcinoma in situ
Occurs on true vocal cords
Laryngeal invasive squamous cell carcinoma subtypes
- history of chronic laryngitis - heavy smoking - hoarseness, pain - dysphagia - haemoptysis Supraglottic - metastatic to lymph nodes, lungs Glottic - commonest, beat prognosis - confined to larynx Subglottic - rare, worst prognosis - metastatic to lymph nodes, lungs
Laryngeal web
Thin and translucent membrane between vocal folds near anterior commisure (congenital)
NPC epidemiology
Common in southern Chinese Male more common than female Middle aged
NPC aetiology
1) Genetics - combination of HLA A2 and BW 46 (not found in western populations) 2) Diet - dimethylnitrosamines in salted fish and phorbol ester in plant and oil are mutagenic compounds 3) EBV - IgA component of Viral Capsid Antigen for EBV found in patient serology; may due to proliferators effect on epithelial cells
NPC location (and metastases)
Fossa of Rosenmuller of nasopharynx - clinically obscure area therefore will be clinically silent until widespread metastases occur Local spread to parapharyngeal space -> base of skull -> cranium via foramina Distal spread -> usually by lymphatics to H&N lymph nodes - may be hemat spread to organs
NPC clinical presentation
1) deafness and tinnitus - blockage of Eustachian tube 2) Bleeding - postnasal drip bleeding 3) headache and facial pains - trigeminal nerve compression - test for corneal reflex - temporal headache 4) neck nodes - upper jugular group at posterior triangle apex - contralateral most common; sometimes bilateral
NPC histology subtypes
Squamous cell carcinoma (-> squamous cells) Nonkeratinising carcinoma (-> transitional cells) Undifferentiated carcinoma
Most common histological subtype of NPC
Undifferentiated carcinoma (95%)
Undifferentiated carcinoma (NPC) character
Sheets of polygonal cells or spindle cells Prominent lymphoid infiltrate (only reactive)
NPC treatment and complication
Radiotherapy (best for undifferentiated carcinoma, SCC least) with adjuvant chemotherapy Routine follow up - High recurrence in first 2 year and after 10 years Use of plasma EBV tests to determine relapse COMPLICATION: - sarcomas after radiotherapy
Common extranodal lymphoma
1) GI lymphoma 2) malignant nasal lymphoma
Malignant nasal lymphoma
- second most frequent extranodal lymphoma in Chinese - T cell lymphoma mostly - associated with EBV - polymorphic reticulosis - early biopsy may be mistaken for benign lesion
Epithelial nasal neoplasms
BENIGN 1) squamous papilloma 2) transitional papilloma MALIGNANT 1) squamous cell carcinoma 2) malignant melanoma 3) Adenocarcinoma (from mucosal glands; associated with wood dust)
Juvenile angiofibroma
Young boys nasal vascular lesion; develop around puberty and regress afterwards 1) nasal obstruction 2) epistaxis - due to malformation of nasal erectile tissue
Nasal polyps
Covered by respiratory epithelium with goblet cell hyperplasia Inflammation, allergy cystic fibrosis
Scleroma
Chronic bacterial infection (in form of granulomatous disease) beginning in the nose and extend progressively to nasopharynx, orophaynx and larynx
Wegener’s granulomatosis
Autoimmune nasal pathology - necrotising giant cell granulomas (histiocytes, multinucleated giant cells) - will spread to trachea and lungs - death in a year from renal failure due to: 1) renal arteritis 2) necrotising glomerulitis
Lethal midline granulomas
Non inflammatory destructive lesion of URT - Wegener’s granulomatosis - conventional malignant lymphoma - polymorphic reticulosis
Polymorphic reticulosis
TYPICAL OF NASAL MALIGNANT LYMPHOMA Small number of lymphoma cell presented intermixed with reactive cells (plasma, immuneblast, histiocytes, neutrophil, eosinophil), forming a polymorphic mixture
Cerebral edema comparison
Vasogenic vs cytotoxic vs hydrocephalic 1) due to increased capillary permeability and filtration pressure VS disturbed cellular osmoregulation from metabolic derangement VS increased CSF accumulation 2) white matter VS Gray and White matter VS periventricular white 3) Edema formed by plasma filtrate with plasma protein VS intercellular Na and water VS CSF 4) ECF increased vs Decreased vs increased
Stroke definition
A clinical term for rapid onset of focal cerebral dysfunction of presumed vascular origin, of more than 24 hours with structural brain damage
transient ischaemic attack definition
A fully reversible neurological deficit, lasting less than 24 hours with no structural brain damage
Stroke subtype epidemiology
HK: Ischaemic stroke (70%) common than haemorrhagic stroke (30%) Western: Ischaemic stroke (85%) vs haemorrhagic stroke (15%)
Brain infarction causes
1) atherosclerosis or lipohyalinosis causing occlusion 2) Emboli 3) Hypotension eg boundary zone infarct 4) vasculitis eg TB/ HI meningitis 5) vascular complication of raised ICP 6) vasospasm in subarachnoid haemorrhage 7) venous occlusion
Morphology change in cerebral infarct
Pale vs haemorrhagic PALE - swollen and softened - cracking and liquefaction in 5 days - resorption with replacement by fluid filled cavity in weeks Ischaemic necrosis in 6 hours Macrophage in 6-12h In a week heavy macrophage infiltration with astrocytic proliferation
Common source of atherosclerotic artery
Intracranial artery or extracranial artery like vertebral artery or **internal carotid artery at carotid bifurcation
Vascular occlusion site epidemiology
Caucasian: more extracranial African, Asian: more intracranial
Common source of emboli leading to stroke
Atheroma plaque in carotid bifurcation Mural thrombi in the heart (chronic rheumatic heart disease)
Small vessel disease
Lipohyalinosis of deep penetrating arteries leading to thalamus, basal ganglia and pons - hyalinization - fibrinoid degeneration - lipid deposition - foamy macrophage accumulation Severe in hypertension Lead to lacunar infarct
Lacunar infarct
Small infarct that lie deep in cerebral cortex or brainstem, usually due to small vessel disease or lipohyalinosis Significant neurological deficit
Cerebral infarct caused by vasculitis
Endarteritis obliterans in TB meningitis or haemophilia influenzae meningitis
Boundary zone infarct most common site
Border between ACA and MCA
Boundary zone infarct
Cause: diffuse intracranial atherosclerosis with drop in systemic blood pressure or congestive heart failure -> zone between 2 arterial beds becomes maximally deficient in blood supply and progressively ischaemia and necrosis May not have clear neurological signs
Intracranial haemorrhage pathological types
1) Intracerebral 2) subarachnoid 3) Epidural and subdural
Intracerebral haemorrhage common causes
1) blood vessel abnormality - hypertension with small vessel disease and microaneurysm - saccular aneurysm - angioma - congophilic angiopathy - arteritis 2) blood disorder - thrombocytopenia - coagulopathy - anti-coagulants 3) brain tissue abnormality - infarct, tumour 4) traumatic 5) drugs, alcohol 6) idiopathic
Congophilic angiopathy
Amyloid deposition in pial and intracortical arterioles Incidence increase with age Cause lobar Intracerebral haemorrhage
Thrombocytopenia intracranial haemorrhage site
Multifocal, lobar
Angioma subtypes
Congenital malformation of vessels 1) arteriovenous malformation AVM (most aggressive) 2) venous angioma (most common) 3) capillary angioma 4) cavernous angioma
Angioma clinical effect
Rupture with massive haemorrhage Mass effect Steal (adjacent tissue deprived of blood supply), leading to epilepsy and neurological deficit
Subarachnoid haemorrhage causes
1) rupture of saccular aneurysm (65%) 2) rupture of AVM (5%) 3) idiopathic (20%)
Location of berry aneurysm
Arterial bifurcations, 90% in anterior circulation: 1) middle cerebral artery’s first main branch in Sylvian fissure 2) anterior communicating artery’s origin from anterior cerebral artery 3) internal carotid artery’s terminal bifurcation and origin of posterior communicating artery
Berry aneurysm prevalence
All ages post puberty
Berry aneurysm co existing condition
Adult polycyclic kidneys Aorta coarctation
Berry aneurysm size
Rupture: 5mm to 10mm Mass effect: > 3cm
Berry aneurysm rupture
1) Spontaneous closure 2) rebleeding 3) cerebral ischaemia and infarction due to vasospasm of artery harbouring ruptured aneurysm 4) expanding haematoma 5) progressive hydrocephalus due to subarachnoid space occlusion by haematoma 6) epilepsy
Reason for high morbidity and mortality of CNS infection
1) neurons don’t regenerate - permanent neurological dysfunction 2) little space in cranium -> mass effect prominent 3) meninges damage will lead to hydrocephalus
Clinical signs of CNS infection
1) meningeal irritation 2) encephalopathic signs (seizures or altered consciousness) 3) raised ICP presentation 4) Focal neurological sign -> paralysis, anaesthesia, endocrine, focal epilepsy 5) primary or metastatic foci of infection: skin rashes, pneumonia, endocarditis l, sinusitis 6) systemic signs: Fever, leucocytosis
Acute pyogenic meningitis pathology
1) pus is subarachnoid space, may infiltrate ventricles and choroid plexus, posterior spinal cord 2) petechia haemorrhages and focal infarction 3) small abscess in white matter 4) subarachnoid space filled with neutrophils then lymphocytes, plasma cells and macrophage
Acute pyogenic meningitis complications
1) Organization of inflammatory exudate -> fibrosis, thickening of meninges and obliteration of subarachnoid space 2) hydrocephalus 3) cranial nerve palsy due to entrapment by fibrosis - CN 2 and 6 7 8 4) septic thrombosis of cerebral vessels may lead to cerebral infarction 5) if parenchyma involved by infection or infarction, then epilepsy, mental retardation and focal neurological sign
Acute pyogenic meningitis pathogensis
1) asymptomatic colonisation of nasopharyngeal mucosa (usu via fimbriae) 2) bacteria pass mucosal barrier and enter blood stream via phagocytic vacuole 3) bacterial capsule evade phagocytosis and complement pathway 4) sustained high grade bacteraemia 5) bacteria attach to laminin receptor on brain microvascular endothelium 6) meningeal invasion -> breakdown of epithelial tight junction or cross BBB by endocytosis 7) uncontrolled replication of bacteria in subarachnoid space (defenceless due to low complement, antibody and WBC) 8) bacterial release endotoxins and components that activate endothelial and macrophage Toll like receptor -> release of pro inflammatory cytokines 9) inflammation of subarachnoid space, increased permeability of BBB and endothelium
Acute pyogenic meningitis pathogen in age 0-8wks
E coli (K1) Streptococcus agalactiae Listeria monocytogenes (unpasteurised milk) Enterobacteriaceae eg salmonella
Acute pyogenic meningitis pathogen in 3mon to 18 yo
HIB Neisseria meningitidis Streptococcus pneumoniae
Acute pyogenic meningitis pathogen in 18yo to 50yo
Neisseria meningitidis Streptococcus pneumoniae
Acute pyogenic meningitis pathogen in 50yo+
Neisseria meningitidis Streptococcus pneumoniae Aerobic gram neg (Klebsiella, Escherichia, salmonella)
Acute pyogenic meningitis pathogen in immunocompromised
Neisseria meningitidis Streptococcus pneumoniae Aerobic gram neg (Klebsiella, Escherichia, salmonella) Listeria monocytogenes Pseudomonas aeruginosa
Acute pyogenic meningitis pathogen in pig contact
Streptococcus suis
Acute pyogenic meningitis pathogen in fresh water contamination
Nagleria fowleri Other amoeba
Acute pyogenic meningitis pathogen in ingestion of raw mollusk
Angiostrongylus cantonensis (eosinophilia meningitis)
Acute pyogenic meningitis pathogen in head trauma, post neurosurgery or intrathecal injection
Staphylococcus aureus Staphylococcus epidermidis Aerobic gram neg (Klebsiella, Escherichia, salmonella) Aspergillus
Acute pyogenic meningitis pathogen post shunting
Staphylococcus aureus Staphylococcus epidermidis Aerobic gram neg (Klebsiella, Escherichia, salmonella) Proprionibacterium acne
Management of Acute pyogenic meningitis
1) LP for CSF gram smear and culture and antigen detection, after exclusion of SOL by CT/MRI 2) empirical IV high dose antibiotic that crosses BBB eg penicillin G, ceftriaxone 3) adjunctive dexamethasone before/with first dose of antibiotics to decrease inflammatory complications in HIB or strep pneumoniae 4) elevation of head by 30 degrees and anticonvulsant for ICP symptoms relief 5) chemoprophylaxis with rifampicin before HIB or Neisseria meningitidis contact 6) active immunisation eg HIB vaccination, meningococcus/ pneumococcal vaccination
Subacute or chronic meningitis common pathogen
1) mycobacterium tuberculosis 2) cryptococcus neoformans 3) Treponema pallidum (syphilis) 4) Lyme’s disease - ticks 5) nocardia 6) candida,
TB meningitis pathology
1) granulomatous inflammation - granuloma - central caseous necrosis bordered by epithelioid histiocytes - Langhan’s giant cells with fibrosis in periphery 2) thick gelatinous exudate around granuloma
TB meningitis complications
0) chronic inflammation causes intimal proliferation and luminal narrowing of cerebral arteries (endarteritis obliteran) -> superficial infarct 1) Organization of inflammatory exudate -> fibrosis, thickening of meninges and obliteration of subarachnoid space 2) hydrocephalus 3) cranial nerve palsy due to entrapment by fibrosis - CN 2 and 6 7 8 4) septic thrombosis of cerebral vessels may lead to cerebral infarction 5) if parenchyma involved by infection or infarction, then epilepsy, mental retardation and focal neurological sign
TB meningitis Lab results
1) CSF lymphocytosis and monocytosis 2) CSF high protein low sugar 3) CSF and sputum LJ medium culture positive 4) CSF ZN stain positive 5) CSF TB PCR positive 6) CXR may reveal concomitant pulmonary TB
TB meningitis treatment
PIER Pyrazinamise Isoniazid Ethambutol Rifampicin Steroid for reducing inflammatory complication
Cryptococcal meningitis presentation and lab
Underlying immunodeficiency - malignant lymphoma, AIDS, post transplant - positive CSF Indian ink - CSF high protein low glucose - serum or CSF cryptococcal antigen - positive fungal culture
Fungal meningitis pathology
Thickened opalescent meninges Contains mucoid exudate Small cysts Granuloma
Cryptococcus treatment
Fluconazole Amphotericin B
Brain abscess pathogenesis
A spread from contiguous suppurating focus, hematogenous spread from distant focus, direct inoculation for trauma 1) bacteria crosses BBB and enter brain parenchyma 2) acute inflammation -> early cerebritis, late cerebritis 3) early capsule formation with tissue necrosis and collagen fiber encapsulation 4) late capsule formation
Brain abscess pathogen and site in immunocompromised
Multiple sites Toxoplasma gondii Aspergillosis Mucomycosis Nocardia
Brain abscess pathogen and site in otitis media
Temporal or cerebellar Streptococcus viridans Bacteroides Peptostreptococcus
Brain abscess pathogen and site in sphenoidal abscess
Frontal, temporal Streptococcus viridans Peptostreptococcus Bacteroides
Brain abscess pathogen and site in dental root
Frontal Streptococcus viridans Peptostreptococcus Bacteroides
Brain abscess pathogen and site in congenital heart disease or pulmonary suppurations
Multiple sites Viridans strep Peptostreptococcus Bacteroides Enterobacteriaceae
Brain abscess pathogen and site in endocarditis
Multiple sites Staphylococcus aureus Streps
Brain abscess pathogen and site in trauma
Related to wound Staphylococcus aureus Streps
Intracerebral abscess pathology
1) acute inflammation with pus, tissue necrosis and neutrophilia (cerebritis) 2) capsule formation and collagen fibre encapsulation 3) gliosis 4) may cause cerebral herniation 5) epilepsy
Intracerebral abscess management
1) contrast CT or MRI shows focal lesion with hypodense centre with perilesional ring 2) surgical aspiration yield pus for gram smear, aerobic culture 3) empirical high dose IV antibiotic that crosses BBB
Meningeal irritation clinical sign
Neck stiffness Headache Photophobia Kernig’s sign (when hip and knee bent at 90 degree in supine patient, extension of knee is painful) Brudzinski’s sign (forced flexion of neck of supine patient will lead to flexion of hips)
CSF finding in bacterial, virus and TB/fungal infection
Turbid vs clear or sl turbid vs clear or sl turbid Cell count >500 VS <500 Neutrophil vs lymphcyte vs lymphcyte Low glucose vs normal vs low High protein vs high vs high
Pathogensis of viral CNS infection
1) direct invasion of CNS -cytoplasmic effect of virus replication in CNS 2) post infection syndrome - cross reacting immunological response to myelin -> dysmyelination of CNS
Post infective encephalitis pathology and viral encephalitis pathology
Follow vaccination measles VZ, influenza - wide spread perivascular demyelination, with lymphocytic cuffing - astrocytic proliferation and perivascular gliosis at later stage —– Same + neurophagia by microglia
CNS infection virus detection
1) cell line culture from CSF (good isolation rate in meningitis, poor in encephalitis esp post infection; enterovirus subtypes are often inculturable) 2) cell culture from other sites Eg throat swab (mumps, enterovirus) Stool (enterovirus) 3) serology - paired titre with raising - IgM antibody for EBV JE CMV - intrathecal antibody detection - enterovirus seri types got no common antigen 4) brain biopsy 5) PCR RT-PCR of CSF
Common viral meningitis pathogen
1) enterovirus (echovirus, coxsackie A, B, EV71) 2) HSV 2 (recurrent genital herpes) —– 3) mumps 4) LCM 5) HIV
Common viral encephalitis pathogen
1) HSV 1 2) Enterovirus (echovirus, EV71) 3) VZV —— 4) Japanese encephalitis 5) Febrile exanthems (measles, rubella) 6) rabies
Viral myelitis pathogen
Enterovirus (polio, EV71) HSV 2 VZV Mumps Exanthems JE EBV CMV
Enterovirus virology
Picornavirus RNA, single strand Non encapsulated Summer seasonality
HSV meningitis
HSV type 2 (usu recurrent genital lesion) Self limiting (may not require acyclovir) Winter seasonality
HSV encephalitis
HSV 1 (in neonate is type 2) Entry to CNS via - blood; - or spread along olfactory nerve from nasopharynx -> frontal lobe - reactivation from trigeminal ganglion -> pia mater Often affects temporal lobe or orbital surface of frontal lobe
Why is serology or isolation of HSV from throat swab of little use in CNS infection
May be reactivation of latent virus unconnected with CNS Approximately 1% of population have HSV isolated from mouth
Treatment of HSV encephalitis
Treatment with acyclovir upon clinical suspicion -> mortality is 70% if untreated
Japanese encephalitis virology
- arbovirus - common is South China or SE Asia but not HK (check travel history) - mostly asymptomatic - water birds and pigs as reservoir, mosquito as vector; no human to human infection - vaccine
VZV CNS infection
Especially prominent in immunocompromised (reactivation in AIDS) - latent infection in dorsal root ganglion - skin lesion may precede (shingles) - skin lesion may absent (zoster sine herpete)
Rabies virology
Rhabdovirus Zoonosis -> animal reservoir dogs and other mammals Animal saliva infectious when introduced on mucosal surface Human human transmission not known Replicates in striated muscles, enter nerve endings via acetylcholine receptor -> carried via axon to brain/ spinal cord -> replication in brain -> travels to salivary gland, skin, muscles via peripheral nerves Incubation in face bite is shorter due to shorter travel distance
Rabid encephalitis diagnosis
Viral antigen via immunofluorescence Negri bodies
Clinical presentation of rabies
Prodrome: itching at bite wound Furious rabies: hydrophobia, aerophobia, meningo-encephalitis Paralytic rabies: paralysis of bitten limb and spread
Management and prevention of rabies
1) wound toilet; clean with soap and water with good debridment 2) assess rabies risk by observing animal and area —— Prevention: 1) control/ vaccination of dogs 2) passive immunisation - human rabies globulin - infiltrate wound and inject IM 3) active immunisation - 6 doses of killed vaccine
Prion nature
Relatively resistant to heat, UV, ionising radiation, formalin Protease resistant protein Isoform of normal cell prion-related protein PrPc Accumulation leads to disease
Spongiform encephalopathy nature
Accumulation of PrPsc in brain Loss of neuron -> spongiform vacuolation Lack of inflammatory or immune response Long incubation time -> rapidly progressive dementia -> loss of memory -> intellect loss -> personality change -> clumsiness
Example of spongiform encephalopathy
Human: 1) Kuru (cannibalism) 2) Creutzfeldt-Jakob disease - classical sporadic - familial - new variant CJD (BSE in human) Sheep: Scrapie Cattle: Bovine SE (BSE)
iatrogenic CJD
Implantation of contaminated graft (dura mater, cornea) Human GH Human pituitary gonadotropin Contaminated surgical equipment
How to minimise CJD risk in surgery
Inform relevant department Use disposable equipments in contact with CSF blood or tissues Avoid aerosol generating procedures in high risk tissues eg high speed drill Special sterilisation (chlorine, NaOH, enzymatic detergents, autoclave)
H&N Treatment’s side effecs
FORM AND FUNCTION 1) Form - H&N not covered - treatment will affect external appearance - psychosocial well being 2) Function
Virchow’s node
Left supraclavicular node adenopathy; indicates infraclavicular lesion or infra diaphragmatic lesion from thoracic duct eg pelvic cancer or gastric cancer
Radical neck dissection
Removal of neck lymphatic that harbours cancer metastasis - Level I to V nodes - sternocleidomastoid muscle - internal jugular vein - Accessary nerve - Cervical plexus
Modified radical neck dissection
Removal of level I-V neck lymphatics - cervical plexus With preservation of one or more: - sternocleidomastoid muscle - internal jugular vein - accessory nerve
Selective neck dissection
Removal of areas of lymphatics with highest chance of occult nodal metastasis, for those with no clinical evidence of nodal metastases but high chance of occult nodal metastases - supraomohyoid neck dissection (I, II, III for oral tongue cancer) - central compartment dissection (bilateral VI) for thyroid cancer
Laryngectomy (physiological effects)
Complete removal of larynx - loss of speech - loss filter function of the nose - loss of humidification - ineffective cough
Tetanus toxin biochemical effect
Cleaves synaptobrevin (V-SNARE)
Botulinum toxin biochemical effects
B, D, F, G cleaves synaptobrevin (V-SNARE) C cleaves syntaxin (T-SNARE) A, E cleaves SNAP-25 (T-SNARE)
Alpha-latrotoxin
Venom of female black widow spider Causes CA independent discharge of synaptic vesicles - Binds neurexin, bypass Ca dependent requirement for triggering vesicle fusion - Blinds CL1 and activate intracellular signal transduction cascade for Ca independent action
Presynaptic congenital myasthenic syndrome
Decreased production or release of Ach Syndromes: - episodic apnea - weakness of eye muscles (diplopia) - weakness of throat and mouth muscles (dysphagia, cannot chew)
Congenital mysasthenia graves with episodic apnea (CMG-EA)
Autosomal recessive (usually missense) - loss of function of choline acetyltransferase - defective ACH resynthesis and packaging Treatment: - Acetylcholine esterase inhibitors
Lambert-Eaton myasthenic syndrome (LEMS)
- Serum IgG against presynaptic voltage-gated calcium channels - P>Q>N - Reduced presynaptic voltage based calcium influx and calcium-dependent quantal exocytosis of Ach
Porphyrias
- Enzyme dificiency in heme synthesis - autosomal dominant - intermediates of heme excreted in urine (uro, copro) or faeces (copro, proto)
what is the most prevalent porphyria
Acute intermittent porphyria
Acute intermittent porphyria
- most prevalent porphyria affecting liver - lack of porphobilinogen deaminase - accumulation of ALA and porphobilinogen I Symptoms: - sever abdominal pain - neurological dysfunction
Congenital erythropoietic porphyria
- prematurely destroys RBC - insufficient co-enzymes - excess uroporphyrinogen I produced - accumulation of uroporphyrin I, coproporphyrin I Symptoms: - port wine urine - red fluorescent teeth under UV - light sensitivity of skin
Causes of cutaneous symptoms in porphyria
porphyrins under sunlight will produce Oxygen free radicals (those from less water soluble ones will attack organelle targets) -> inflammation
Iron-overloading etiology
1) Over absorption - thalassemia, alcoholic cirrhosis 2) Defect in iron absorption - hereditary hemochromatosis
Plasma transferrin and ferritin in pathology
High plasma iron: increased ferritin, decreased transferrin Low plasma iron: increased transferrin, decreased ferritin
Chronic Iron toxicity biochemistry
The Fenton reaction is catalysed by ferric and ferrous irons: O2-*(superoxide) + H2O2 => O2 + OH- + OH* Which produces highly reactive hydroxyl radicals that damage polysaccharides, proteins, lipids, DNA
Free radical damage caused by iron toxicity
Caused by hydroxyl radicals 1) Lipid peroxidation - lysosome, mitochondria, and microsome damage 2) Fibrosis - stimulate collagen synthesis (stimulate prolyl hydroxylase) - Fibrosis and lipid peroxidation tgt => liver cirrhosis 3) Ascorbic acid depletion - iron overload => excretion of oxalic acid - scurvy - reduce iron for erythropoiesis - osteoporosis
Hereditary hemochromatosis pathology
- Iron mainly stored as hemosiderin - large amount of iron in spleen, BM, liver, thyroid, pancreas, heart - accumulation takes many years -> symptoms not present until middle aged - increased ferritin, decreased transferrin, increased transferrin saturation Symptoms: - skin pigmentation - Hepatomegaly and cirrhosis - diabetes - hypogonadism (reduce libido) - arthritis, osteoporosis - diabetes - Heart failure
Hereditary hemochromatosis genetics
2 possible HFE gene mutations on chromosome 6: 1) C282Y (cysteine to tyrosine) - mutant HFE protein does not bind Beta2-microglobulin, preventing its transport to cell surface - decreased affinity of transferrin receptor for transferrin => iron accumulation 2) H63D (histidine to aspartic acid) - prevent HFE protein from interacting with cell surface proteins that detect iron concentration => failed iron absorption regulation, thus accumulation
Hereditary hemochrombtosis Management
1) Phlebotomy until all excess of iron is removed (monitor Hb level to prevent anaemia) 2) Stop phlebotomy when ferritin level normalised 3) continuous monitoring of ferritin level and periodic phlebotomy to prevent iron reaccumulation 4) Iron chelators (Removal of iron before irreversible pathologies improve prognosis)
G6PD deficiency genetics
- Defect in G6PD gene (Xq28) - X-linked - Heterogenous (No single mutation, large insertion or deletion) - Never complete absence of G6PD - Most common enzymopathy
G6PD deficiency offending agents
Food: fava bean Drugs: primaquine, pamaquine (malaria), sulfamethoxazole, chloramphenicol, trimethoprim, aspirin, Vitamin K Chinese herbal medicine (especially breast feed!) Others: Mothballs
Mechanism of oxidative damage in G6PD deficiency
With offending agent: 1) Cells have lowered reduced glutathione dur to lack of G6PD 2) Offending agent generates peroxides 3) Glutathione peroxidase cannot reduce peroxides due to absence of reduced glutathione 4) Oxidative attacks lead to homeless Without offending agent: 1) Cells have lowered reduced glutathione due to lack of G6PD 2) sulfhydryl groups of Hb cannot maintain in reduced form without G6PD 3) Hb crosslink to form Heinz body 4) RBC membrane more prone to oxidative stress -> haemolysis
Motor Neuron Disease aetiology
1) Infective (poliomyelitis, HIV) 2) Toxic 3) Immunological (multifocal motor neuropathy) 4) Degenerative (sporadic e.g. ALS; or genetic e.g. familial ALS)
Amylotrophic Lateral Sclerosis symptoms
Both UMN and LMN damage: UMN: - spastic paralysis - fasciculation (twitching) - clonus (shaking) LMN: - profound muscle atrophy - muscle weakness
Spinal onset ALS presentation
- more common (75%) - progressive weight loss - 6 months of progressive weakness of hand grip - loss of ambulation within 1 year - death from respiratory failure after 40 months - fasciculation of muscle in affected limbs - cramps and spasms
Bulbar onset ALS presentation
- less common (25%); usu elderly women - profound progressive weight loss - 9 months of progressive dysphonia and dysphagia - ambulation maintained to death - death from respiratory failure after 12 months - inappropriate laughing or crying - apnoea when lying flat
DDx for spinal onset ALS
- Spinal muscular atrophy - spondylotic myelopathy - conductive block neuropathy
DDx for bulbar onset ALS
- Myasthenia Gravis - progressive supranuclear palsy
ALS cytopathology
**Deposition of neurofilament - Bunina bodies in motor neurone - “skeins” in anterior horn cells (rare glial inclusions) - Hyaline bodies in anterior horn cells - Dystrophic neurites in anterior horn **AXONAL SWELLING **increased anterograde and decreased retrograde axonal transport **decreased mitochondrial transport
Genetic deposition of ALS
1) SOD1 dismutase mutation (AD) 2) Dynactin gene point mutation (AD)
SOD1 in familial ALS
-> impaired dismutase activity; Gain of toxic function 1) Aberrant redox chemistry; change in conformation of SOD1 dismutase that allow channel to accept larger molecules 2) Protein instability and SOD1 aggregation
Neurodegenerative disease by common
1st Alzheimer’s disease 2nd Parkinson’s disease
Parkinson’s disease epidemiology
1) Increase with age 2) men more common than women
Cardinal features of parkinsonism
6 1) Resting tremor (pill-rolling) 2) Bradykinesia/ Akinesia 3) Cogwheel rigidity 4) Flexed posture of neck, trunk, limb 5) Loss of postural reflexes 6) Freezing phenomenon
Lewy bodies
- Intracellular eosinophilic masses made up of alpha-synuclein - pathologic landmark of PD, but not specific
Parkinson’s pathology
1) Dopamine depletion in SN and nigrostriatal pathway to caudate and putamen -> increased inhibition of thalamus and reduced excitatory input to motor cortex 2) Depigmentation (loss of neuromelanin) in SNpc and LC (neuromelanin is derived from oxidised dopamine) 3) Presence of Lewy bodies, and increased glial cells in SNpc and LC 4) Loss of monoaminergic neurons in SNpc and LC leading to decreased monoamine level at site and nerve terminals
Parkinson’s disease genetic mutation
PARK1 -> alpha-synuclein mutation (AD) PARK2 -> parkin (ubiquitin ligase) mutation (AR)
PARK1 mutation
Parkinson’s disease alpha-synuclein mutation (AD) Alpha-synuclein aggregate to large fibrillar forms, and form Lewy body with ubiquitin Alpha-synuclein and Abeta peptides, also form calcium channels at plasma surface -> calcium overload -> mitochondrial dysfunction -> cell death
PARK2 mutation
Parkinson’s disease Parkin (E3 ubiquitin ligase) mutation (AR) Inactivation -> accumulation of parkin substrate in neutrons -> selective toxicity to DA neurons
Classification of AD
1) Age on onset - early: 65yo 2) Family history - familial - sporadic
AD Risk factors
1) Age (increase) 2) Down’s syndrome 3) severe head injury 4) Family history of dementia (esp early onset)
Pathological hallmark of AD
1) Amyloid plague -> amyloid proteins and other associated proteins 2) Neurofibrillary tangles -> abnormal microtubules associated with protein tau 3) Macroscopically wide spread cortical atrophy (deepening of sulcus)
Diagnostic criteria of AD
1) Deficits in 2 or more areas of cognition 2) MMSE score <24, with neuropsychological test evaluation 3) progressive worsening of cognitive function
Cognitive deficits in AD
1) Memory - impaired anterograde episodic memory - delayed recall of stories - Sparring working memory - Poor word list learning (12 words memorise after 3 readings) 2) Attention and execution - poor concentration - selective attention - problem with complex tasks - Wisconsin card sorting test (ability to display flexibility in changing schedules) 3) Language and knowledge - impaired semantics - word definition poor - word finding poor - later phonological and syntactic deficits 4) Visuospatial and perceptual abilities - impaired drawing esp 3D - Conceptual apraxia
neuropsychological features of AD
- Apathy - Anxiety - agitation and destructive behaviour later - Depression - Delusions in late stage - Theft of items or paranoia - phantom lodger
Early onset AD common genetic mutation
50% of early onset AD APP gene PSEN1 gene PSEN2 gene (ApoE4 allele increases AD risk and reduce onset age) (MAPT gene in tau hypothesis)
AD pathogenesis hypotheses
1) Amyloid hypothesis - amyloid precursor protein (APP gene) is broken down by secretases - a non-soluble fragment of APP, Aβ-42, accumulates and deposit outside cell - Aβ-42 helps other protein fragments (e.g. apoE) to gather into plagues - plagues cause neuronal death - PSEN1 and PSEN2 gene -> gamma secretase subunits 2) Tau hypothesis (less favourable) - microtubule associated protein tau (MAPT gene) is associated with microtubule responsible for axonal transport - accumulation of phosphate on tau causes “Paired Helical Filaments) and form neurofibrillary tangles - impaired axonal transport cause neuronal death
Apolipoprotein E and AD
Risk factor for AD - for transport of plasma lipids within tissues - mechanism is associated with Aβ clearance and neuronal repair ApoE2 allele - protective for AD, risk for cardiovascular disease ApoE3 allele - normal ApoE4 allele - risk allele for AD (increase risk and earlier onset age)
Pathologic Haemoglobin tetramers in thalassemias
HbH (β4) - 3 gene deletion α thal Hb Bart (γ4) - 4 gene deletion α thal HbF (α2γ2) - β thal major Inviable tetramer (α4) - precipitate immediately - β thal major
α thalassemia genetic haplotypes
(- -) α-thal-1 (i.e. α0-thal) means both α-globin genes deleted in the chromosome (α -) α-thal-2 (i.e. α+-thal) means only one α-globin gene deleted in the chromosome
α thalassemia genotypes and phenotypes
(αα/αα) = normal (αα/α-) = silent carrier (clinically and haematologically silent) (αα/- -) cis OR (α-/α-) trans = α thalassemia trait or α thalassemia minor -> considered carrier (α-/- -) = HbH disease (- -/- -) = Hydrops fetalis: could not survive and die shortly after birth due to lethal haemolytic anaemia from Hb Bart precipitation
α thalassemia descriptive classifications
α thalassemia major: sever and transfusion dependent α thalassemia intermediate: between major and minor α thalassemia minor (asymptomatic carrier state, trait) silent carrier: clinically and haematologically silent
α thalassemia molecular epidmiology
cis 2-gene deletion more common in Asians. Most common single gene disorder in the world
De novo mutation leading to α-thal
Unequal crossover of chromosome 16 during meiosis 1) Two homologous sister chromatids of chromosome 16 align side by side and form chiasma 2) if misaligned, then the DNA crossover recombination may remove α-globin gene (gene deletion) from one of the chromosome
β thalassemia genetic haplotypes
β0: mutation that produce little or no β chain β+: mutation that produce detectable β chain level β++: mild β chain production defect
β thalassemia descriptive classes
β thalassemia major (Cooley’s anemia) - severe anaemia - require lifelong regular transfusion starting in infancy - severe iron overload - splenomegaly and bone disease common β thalassemia intermedia - mild to moderate anaemia, may be asymptomatic - relatively independent from transfusion - variable iron overload - splenomegaly and bone deformity common β thalassemia minor (trait) - mild or no anaemia - microcytosis - no splenomegaly no bone deformities
Genetic basis of phenotypical diversity of β thal
Primary modifier - β-globin gene genotype (greater production of β globin -> better condition) Secondary modifier - α-globin gene genotype (less production of α globin -> alleviate imbalance and reduce α4 precipitation -> better condition) - α-hemoglobin stabilizing protein (AHSP) -> stabilise α-harmohlobin to reduce α4 precipitation -> better condition - γ gene (more γ chain -> functional HbF formation -> better condition) - BCL11A SNP (low BCL11A -> higher HbF formation -> better condition)
β thal pathogenesis
Excess α globin chain which leads to: - inclusion bodies - ineffective erythropoiesis - anaemia which then cause: > Jaundice, gallstone, iron overload, bone deformity
AHSP and β thal
α-hemoglobin stabilizing protein (AHSP) -> stabilise α-harmohlobin to reduce α4 precipitation -> better condition
BCL11A SNP and β thal
BCL11A SNP (AA) -> low BCL11A -> higher HbF formation -> better condition BCL11A SNP (GG) -> high BCL11A -> lower HbF formation -> worse condition
β thal genetic mutation (specific and general)
Codon 41/42 (frameshift) Intron 2-654 (single nucleotide change that create new splice site that cause extra exon) General ——- 1) splicing mutation (SNP that activate cryptic splice sites, or create new splice site thus extra exon, or destroy normal splice site thus exon skip) 2) Missense 3) Frameshift by insertion/deletion 4) Nonsense mutation -> premature terminated mRNA undergo nonsense-mediated decay
X linked agammaglobulinaemia
Failure of B cell signal transduction (lack of Bruton’s tyrosine kinase) - Bruton’s syndrome - recurrent infection - no humeral response - few or no mature B cells
Genes predisposition to DM type 1
1) mutated MHC gene on chromosome 6 leading to faulty positive and negative selection of T cells -> active autoreactive T cells in periphery that kills B cells 2) Proinsulin gene class I VNTR leads to under expression of thymic insulin -> faulty selection of T cells and Treg cells; class III VNTR is protective as it promotes thymic insulin expression 3) PTPN22 (specific phosphatase) 4) AIRE (autoimmune regulator for thymic epithelial cell self-antigen expression)
DM type 1 aetiology
- Immune-related (T cell autoimmune) - genetically predisposed - may need virus or environmental hit (diet, trauma) - loss of beta cell mass - presence of insulitis
DMT1 virus mediated beta cell death
Viral Infected beta cells -> beta cell’s MHC class I display viral antigen -> activation of Tc cells for killing -> APC’s MHC II display viral antigen -> activate Th2 cell -> B cell activation to make beta cell auto antibody for killing
DMT1 environmental stimuli mediated beta cell death
Damaged B cell release B cell autoantigen that is taken up by APC, processed and presented via MHC II -> Th1 cell activation -> release cytokines, and activate Tc cell -> killing
Development and spreading of otitis media
- Spread posteriorly to mastoid antrum - damage structures deep to the walls of tympanic cavity (e.g. internal carotid artery, IJV) - and then spread to middle or posterior cranial fossa by bone resorption, and then extend to brain!
Rhinitis definition and spread
Inflammation of nasal mucosa Spread to: 1) Anterior cranial fossa 2) Middle ear via auditory tube 3) Paranasal sinus 4) Lacrimal apparatus and conjunctiva
Nasal septal deviation
Caused by birth injury, congenital malformation or postnatal trauma -> severe may obstruct breathing and need surgery
Nose fracture
If extends above, may affect roof and cribriform plate of ethmoid bone May tear meninges => CSF rhinorrhea
Most likely infected paranasal sinus
Maxillary sinus, because the drainage site (hiatus semilunaris) of the maxillary sinus is located superior to the sinus floor Thus secretions more likely to be retained and easily infected
Orbital floor fracture with herniation symptoms
Visual symptoms: Vertical diplopia Sensory symptoms: Cheek hypothesia
Pharyngeal diverticulum (most likely site?)
Herniation of pharyngeal mucosa, at the region between thyropharyngeus and cricopharyngeus, the only region without constrictor overlapping
Recurrent palatine tonsil infection
Shows an enlarged jugulodigastric lymph nodes -> if chronic then perform tonsillectomy
Tonsillectomy
Used for chronic tonsillitis - safe if the fibrous capsule is respected - large vein between tonsil and soft palate may cause bleeding during operation - CN IX (lateral wall accompanies tonsillar artery) and internal carotid artery (lateral to tonsils) may be damaged (!!)
Hyperparathyroidism causes
1) Primary (PTH secretion without known stimuli): - parathyroid Adenoma (80%) - parathyroid Hyperplasia (15%) - parathyroid Carcinoma (5%) - MEN I, IIa 2) Secondary (chronic ↓ Ca2+ stimulates PTH secretion): - chronic renal disease (decreased phosphate excretion, which results in hyperphosphataemia. The elevated serum phosphate levels depress ionized calcium levels) - Vitamin D deficiency - Calcium deficiency in diet - Malabsorption 3) Tertiary (develops after secondary hyperparathyroidism; The glands become autonomous and do not respond to the level of calcium in blood)
Hyperparathyroidism diagnosis
fasting then blood test for plasma Ca2+ & PTH level. PTH high Ca high -> primary PTH high Ca low/normal -> secondary
Primary Hyperparathyroidism clinical manifestation
1) Hypercalcaemia: Metastatic calcification in multiple sites e.g. stomach, lungs, myocardium, cardiac valves, blood vessels, skin, etc 2) Hypercalciuria - Urinary stones and associated infection 3) Gastrointestinal disturbances - pancreatitis, gallstones, constipation 4) hyperpolarization -> depression of CNS/PNS, muscular weakness, cardiac arrhythmias 5) Bone disease: - Osteopenia (Prominent osteoclasts erode bone matrix and resorption) - Osteitis fibrosa cystica - Fracture - Brown tumors of hyperparathyroidism (Aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris occasionally form masses that may be mistaken for neoplasm)
Secondary hyperparathyroidism clinical manifestation
Low and normal calcium level, therefore: 1) Bone disease: - Osteopenia (Prominent osteoclasts erode bone matrix and resorption) - Osteitis fibrosa cystica - Fracture - Brown tumors of hyperparathyroidism (Aggregates of osteoclasts, reactive giant cells, and hemorrhagic debris occasionally form masses that may be mistaken for neoplasm)
Hypercalcemia causes
1) Primary Hyperparathyroidism - parathyroid Adenoma (80%) - parathyroid Hyperplasia (15%) - parathyroid Carcinoma (5%) - MEN I, IIa 2) malignancy (releases PTH-related protein) - PTHrP is an essential tissue factor - It can bind to PTH receptors and acts like PTH - produced in excess by some malignant tumors e.g. squamous cell carcinoma of lung and breast cancers
Hypoparathyroidism causes
A. Surgical removal, or iatrogenic (damage to blood supply during thyroidectomy) B. Congenital absence, as in DiGeorge syndrome. C. Autoimmune parathyroiditis, ends up in primary (idiopathic) atrophy.
Hypoparathyroidism clinical manifestation
- hypocalcaemia - enhanced neuromuscularexcitability (tetany)
Genetic changes in Parathyroid Adenoma
- Somatic mutation of MEN1 2. Relocation of cyclin D1 to near the PTH gene, leading to transcriptional activation Each of the above is found in about 20% of all sporadic parathyroid adenomas.
Parathyroid hyperplasia pathology
The weights of the glands are increased. The hyperplastic gland shows decreased stromal fat
Parathyroid adenoma pathology
- Fat content virtually absent in adenoma - The presence of capsule or compressed gland strongly favors adenoma
Parathyroid gland pathological examinations
1) Sestamibi scan (parathyroid scintigraphy dual phase planar imaging) using Tc99m 2) Intra-operative (frozen section) diagnosis -> Determine if the tissue is of parathyroid origin -> look at stromal fat content, capsule, and compressed gland to Determine the nature of the lesion (Definite diagnosis depends on the examination of at least 2 glands, preferably all 4 glands) 3) Radioguided Parathyroidectomy - hyperactive parathyroid tumor is made radioactive before surgery so probe can detect
Pseudohypoparathyroidism
resistance to parathyroid hormone (PTH insensitivity in the target organs): - hypocalcaemia - elevated PTH levels - parathyroid gland hyperplasia - Type Ia, associated developmental bone defects (Albright hereditary osteodystrophy) Chromsome 20 GNAS1 mutation
Adrenal gland Neoplasms
Cortical - cortical adenoma (adult) - cortical carcinoma (children, adult) Medullary - Pheochromocytoma (adult) - Neuroblastoma (children)
Adrenal cortical neoplasm histology
1) Arranged in packets 2) vascularized background 3) Central regular nuclei & pale to clear cytoplasm 4) Monotonous cells
Pheochromocytoma histology
Grossly - Pale gray or brown - Cystic change - Haemorrhage Histo: - Finely granular basophilic or amphophilic cytoplasm (dirty blue) - Zellballen, trabecular or solid pattern - Polygonal or spindle cells in rich vascular network
Thyroid neoplastic or hyperplastic diseases
1) Thyroid hyperplasia - Diffuse nontoxic (simple) goiter - Multinodular goitre 2) Thyroid adenoma (more than 90% of neoplasm) - Follicular adenoma 3) Thyroid carcinoma - Papillary carcinoma (>85%) - Follicular carcinoma - Medullary carcinoma - Anaplastic carcinoma
Diffuse nontoxic (simple) goiter pathology
Involves entire thyroid gland Two stages i) Hyperplastic stage (enlarged follicles filled with colloid) ii) Colloid involution -> long standing ones may convert to multi nodular goitre
Simple goitre causes
Thyroid hyperplastic - Endemic due to compensatory increase in TSH (e.g. Poor nutrition, lack of iodine in diet)
Multinodular goitre pathology and symptoms
long-standing simple goiter convert into multi nodular goiter Symptoms: - Toxic or non-toxic - Most patients are euthyroid or with subclinical hyperthyroidism
Multinodular goitre histology
Thyroid hyperplastic : Nodular hyperplasia with variably sized colloid-filled follicles
Thyroid Follicular adenoma histology
- forms fibrous capsule (benign) - Hurtle cell change
Major histological subtypes of thyroid carcinoma
1) Papillary carcinoma (>85%) 2) Follicular carcinoma (5% - 15%) 3) Anaplastic carcinoma 4) Medullary carcinoma
Thyroid Papillary carcinoma pathology (prognosis, risk and symptoms)
EXCELLENT PROGNOSIS; 25-50 yo Risk factor: ionizing radiation exposure Symptoms: - asymptomatic thyroid nodules - mass in cervical lymph nodes - hoarseness, dysphagia, cough, dyspnoea
Thyroid Papillary carcinoma histology
- Orphan annie eye Nuclear inclusions - Nuclear grooves - Papillary structure - Psammoma bodies - multinucleated giant cells - over-lapping ground-glass nucleus
Thyroid Follicular carcinoma epidemiology
40-60 yo; Female: male= 3:1
Thyroid Follicular carcinoma histology
SAME AS FOLLICULAR ADENOMA - encapsulated - Hurtle cell change - Malignancy defined by **Vascular invasion and **capsular invasion
Thyroid Follicular carcinoma spread
Prone to haematogenous metastasis (bone, liver, lungs)
Thyroid Anaplastic carcinoma patho and histo
65 yo, Mortality rate approaching 100% Preceding or concurrent well-differentiated thyroid carcinoma Histologically: markedly pleormorphic cells/spindle cells/squamoid cells
Thyroid Medullary carcinoma
Derived from parafollicular C cells -> secrete calcitonin 70% sporadic and remaining as MEN syndrome (MEN 2a and 2b)
Management of thyroid carcinoma
1) Surgical (thyroidectomy) 2) Hormone replacement 3) Radiotherapy for ablation 4) Serum thyroglobulin level for monitoring relapse
Hypothyroidism causes
PRIMARY: 1) due to thyroid gland insufficiency: - congenital absence of thyroid tissue - autoimmune destruction of thyroid tissue (e.g. Hashimoto’s thyroiditis, Fibrous atrophy of thyroid) - surgical removal of thyroid tissue - radio ablation of thyroid by radioactive iodine - tumour (Thyroid Follicular adenoma) 2) due to Impaired thyroid hormone synthesis: - iodine deficiency - Goitrogens (cabbage) - congenital enzymatic defects - drug mediated inhibition SECONDARY: - Insufficient secretion of TRH or TSH (e.g. hypothalamic tumour or pituitary non-functional macroadenoma, Sheehan’s, etc.)
Primary or secondary hypothyroidism difference
Primary: Low free T4 and elevated TSH (feedback), may present with goitre Secondary: Low TSH leading to low free T4, no goitre
Symptoms of hypothyroidism
1) Cretinism in Infant: delayed/incomplete physical and mental development -> IRREVERSIBLE mental retardation and dwarfism 2) Youth: impaired physical growth 3) Adult onset: ** myxedema - decreased basal metabolic rate, cold intolerance, lack of energy and tiredness (decrease Na/K ATPase) - Anorexic, weight gain - bradycardia, decrease in cardiac output - slowing of mental function and motor activity (decreased catecholaimine response and Na/K ATPase) - goiter (in primary due to TSH increase) - dry skin (reduced sebaceous gland activity) - constipation (⇩GI tract motility & secretion) - menorrhagia, amenorrhea
Myxedema
Characteristic of hypothyroidism -> due to deposition of glycosaminoglycan Mechanism: accumulation of mucopolysaccharides, hyaluronic acid and chondroitin sulphate (highly hydrophilic molecules) that retain fluid in the subcutaneous area - Facial puffiness and periorbital swelling - Peri-orbital haemorrhage is due to increased fragility of swollen dermal tissues
How does hypothyroidism induce goiter?
In primary hypothyroidism, thyroid hormone production decreases this results in increased TSH release (less negative feedback) TSH acts on thyroid, stimulating follicular cell proliferation and increasing colloid production (hypertrophy)
Hashimoto’s thyroiditis clinical picture
Middle-aged women - Diffusely enlarged thyroid -> Progressive thyroid enlargement - (early phase of hyperthyroidism) -> euthyroid -> hypothyroid COMPLICATIONS: - Tracheal compression, especially when thyroid is retrosternal - Malignant lymphoma (diffuse large B cell lymphoma)
Hashimoto’s thyroiditis - Pathogenesis
Cell mediated autoimmune reaction against the thyroid cells - parenchymal destruction Thyroid enlargement is a result of lymphoid infiltration and TSH-stimulated proliferation TSH is elevated due to ineffective production of thyroid hormones (Hurthle cell change) in thyroiditis
Hashimoto’s thyroiditis - test
1) Thyroid function tests (TSH, T3, T4) 2) Antithyroid antibodies assay i) anti-thyroglobulin ii) anti-thyroid (microsomal) peroxidase antibodies
Antithyroid antibodies test
antibodies usually measured clinically as a confirmatory test for autoimmune thyroiditis (Grave’s, Hashimoto’s, and fibrous atrophy of thyroid) i) anti-thyroglobulin ii) anti-thyroid (microsomal) peroxidase antibodies
Hashimoto’s thyroiditis - Treatment
- Observe and wait (early period) - Replacement thyroid hormone - Surgery, to relieve pressure effects (especially for retrosternal goiter), or for cosmetic reasons
Hurthle cells
Enlarged thyroid follicular cells - eosinophilic, full of mitochondria, but with ineffective hormone production - e.g. in Hashimoto’s thyroiditis, and Thyroid Follicular adenoma
Lymphocytic thyroiditis
Variant of Hashimoto’s thyroiditis
Fibrous atrophy of thyroid pathology
autoimmune thryoiditis AKA idiopathic myxedema: - progressive shrinking of the thyroid gland - loss of epithelium and follicles; oxyphilic and squamous metaplasia of follicular cells - dense infiltration by sensitized lymphocytes and plasma cells - Chronic inflammation - final replacement of the gland by keloid tissue-like fibrous tissue (when 90% gland destroyed -> hypothyroidism) - increased TSH, but with no hyperplastic effect - inability to respond to TSH suggests that blocking antibodies exist in this disease which compete with TSH for its receptors
Fibrous atrophy of thyroid pathogenesis
Antibodies directed against thyroglobulin and microsomal antibodies, detectable years before the onset of hormonal failure, and cell-mediated immune mechanisms contribute to the pathogenesis
Non-autoimmune thyroiditis
1) Granulomatous thyroiditis - TB, fungal infections - subacute granulomatous (De Quervain’s) thyroiditis 2) Drug induced thyroiditis 3) Radiation thyroiditis
De Quervain’s thyroiditis
aka subacute granulomatous thyroiditis Follows a viral URT infection Pain and tenderness, enlarged thyroid Self limiting
Riedel’s thyroiditis
Invasive fibrous thyroiditis -> IDIOPATHIC - May be mistaken clinically for malignancy because: Hard and adherent to surrounding soft tissues; and Fibrosis may compress the trachea or esophagus - May remain stable over many years, or it may progress slowly and produce hypothyroidism - May be associated with multifocal fibrosis (IgG4-related disease) - May overlap with autoimmune thyroiditis
Autoimmune thyroid disorders
- Graves’ disease (diffuse toxic goiter, autoimmune hyperthyroidism) 2. Hashimoto’s thyroiditis 3. Fibrous atrophy of thyroid (idiopathic myxoedema)
Thyrotoxicosis causes
1) Grave’s disease 2) Toxic Adenoma 3) Toxic Multinodular Goiter 4) TSH-Secreting Pituitary Adenoma
Hyperthyroidism symptoms
- exophthalmos - increase in basal metabolic rate, heat intolerance, sweating, warm and moist skin - Tachycardia - weight loss, very hungry - tremour - diarrhoea - nervousness
Graves’ disease cause and clinical picture
an autoimmune disorder characterized by a variable combination of hyperthyroidism, goitre, ophthalmopathy (exophthlamos) and dermopathy (**Pretibial myxoedema), DIFFUSE INVOLVEMENT OF thyroid - production of autoantibodies that bind to and activate the TSH receptor, promoting TH secretion and growth of the thyroid gland Autoantibodies: - thyrotropin receptor antibodies (TRA), - thyroid stimulating immunoglobins (TSI), and - thyroid growth stimulating immunoglobins
Grave’s disease risk factors
smoking, high dietary iodine intake, stress and infections.
exophthalmos pathogenesis
Eye lid retraction and protrusion of eye balls (in Grave’s Disease) - T cells and autoantibodies reactive to the extraocular eye muscles and retro-orbital tissues => inflammation and swelling (tissue deposit) of the extraocular muscles and orbital fat, eyelid retraction, periorbitaledema =>swelling of soft tissues within the confines of the orbits precipitated by fibroblast growth and inflammatory cell infiltration.
Exophthalmos complication
- Keratoconjunctivitis => blindness - Compression of optic nerve => blindness
Dermopathy in Grave’s
Pretibial myxedema: - Localized non-pitting edema of skin - Hyaluronic acid accumulates in dermis and subcutis
half-life of TSH?
1-2 hours
Genetic factors of Grave’s
HLA-DR3 HLA-B8 (25% concordance in identical twins)
Grave’s disease recurrence test
Positive thyrotropin receptor antibody at end of treatment predicts disease recurrence
Toxic Adenoma
solitary, autonomously functioning thyroid neoplasm (uncontrolled growth of abnormal tissue or tumor) that synthesizes and secretes excessive amounts of TH -> hyperthyroidism
Toxic Multinodular Goiter
- composed of multiple autonomously functioning thyroid nodules that synthesize and secrete excessive TH (Like Grave’s, but NODULAR FOCI) - common in old people -> hyperthyroidism; goiter with multiple palpable thyroid nodules
Thyrotoxicosis suscipion clinical tests
1) TSH immunoassay (all primary are TSH suppressed; increased in secondary from TSH secreting pituitary adenoma) 2) Thyroid function test (test serum T3 T4) to check underlying cause: 3) screening for autoantibodies 4) radioactive iodine uptake assay 5) thyroid ultrasonography
Genetic defect in MENs
MEN1: MEN1 encoding MENIN MEN2a, 2b: RET gene
MEN characteristics
A group of genetically inherited diseases resulting in proliferative lesions (hyperplasia, adenomas, and carcinomas) of multiple endocrine organs - Younger age of onset - Multiple organs - Agressive and recur
MEN pathology
MEN1: - pituitary tumour, frequently prolactinoma - parathyroid hyperplasia/adenoma - pancreas endocrine tumour MEN2a: - Parathyroid hyperplasia - Pheochromocytoma - Medullary thyroid carcinoma MEN2b: - Pheochromocytoma - Medullary thyroid carcinoma - Neuromas or ganglioneuromas of the skin, oral mucosa, eyes, respiratory tract, and gastrointestinal tract
Wermer Syndrome
aka MEN1
MEN2 management
Prophylactic thyroidectomy is generally recommended
Depression classes
Minor depression disorder - less severe symptoms - short duration Major depression disorder - severe symptoms that interfere with function - more than 2 weeks Dysthymic disorder - less severe symptoms - more than 2 years
Depression causes
Monoamine hypothesis - caused by dysfunction or deficiency of monoamine neurotransmitters (decreased synaptic availability) Neurotrophic hypothesis - caused by dropped Brain Derived Neurotrophic Factor BDNF, leading to impaired growth of neurons -> loss of hippocampal volume
Problems with depression cause hypothesis
Monoamine - monoamine level improve immediately with drug, but depression not immediately cured - removal of monoamine precursor does not cause depression Neurotrophic - BDNF knock out mice does not experience depression
psychosis symptoms
1) Hallucination (5 senses perception without stimulation) 2) Delusion (believe in untrue things) 3) Confused and disturbed thoughts (rapid random constant speech, with abrupt stop and change in direction) 4) A lack of insight and self-awareness
Causes of psychosis
1) Psychological problems - Schizophrenia - Bipolar disorder - severe depression or stress - lack of sleep 2) Medical condition - Stroke - Hyponatremia - CNS tumour - neurosyphilis - HIV encephalitis 3) alcohol or drugs - cocaine, ketamine, LSD
Psychosis pathogenesis
Dopamine hypothesis - Excess dopamine interrupts the mesolimbic and mesocortical pathways responsible for memory, social behaviour, emotion, self awareness
Grave’s Disease Gross and Histology
Gorss 1) Diffuse parenchymal goitre 2) Beefy red colour of thyroid gland Histo 1) Hyperplastic follicle (from cuboidal turned to low columnar or squamous) with papillary infolding 2) Scanty colloid content; patchy lymphocytoc infiltration 3) Increased vascularity
Feedback and feed forward of cerebellum
FEEDBACK: correct ongoing movement when deviate from intended movement FEEDFORWARD: modify central programs so that subsequent movement fulfil goal with few errors
Lingual nerve injury
Operation on molar teeth or mandible eg sublingual glands -> loss of general sensation to anterior 2/3 tongue -> loss of secretomotor and special taste to anterior 2/3 tongue IF distal to joining of chorda tympani
Pterion fracture
Anterior branch of middle meningeal artery, may produce haematoma and cause death due to raises ICP
Mechanism of brain trauma damage
Primary damage: sudden acceleration or deceleration, focal impact Secondary: alteration of cerebral blood flow and ICP
Traumatic head injury radiology considerations
1) plain skull X-Ray -> USELESS low diagnostic value since can only visualise skull fractures ——– Not all patient need neuroimaging, so only perform following if proper identification 2) conventional CT + more available than MRI + relatively cheaper than MRI + short time + great for bone and acute subarachnoid and parenchymal hemorrhage - still costly - image quality problems due to metal objects - miss small amt of blood - CT comes late after intracranial damage - radiation 3) MRI + greater sensitivity in chronic settings eg after surgery + better than CT for detecting axonal damage, subtle changes + better for brainstem, basal ganglia and thalamus - more costly and inaccessible
Criteria that need imaging after head trauma
Based on New Orleans Criteria or Camadian Head CT rules: *) low Glasgow Coma Scale 1) vomiting and headache (not for children) 2) amnesia esp longer and severe 3) ethanol or drug intoxication 4) Age greater than 60 or 65 5) maybe Coagulopathy/ anticoagulant use 6) sign of basal skull fracture
New Orleans criteria
Glasgow coma score of 15/15 CT After TBI: 1) headache 2) vomit 3) age greater than 60 4) drug or alcohol intoxication 5) persistent anterograde amnesia 6) visible trauma above clavicle 7) seizure
Canadian Head CT Rule
1) GCS <15 2) 65 yo 3) vomit X 2 4) signs of basal skull fracture 5) suspected open or depressed skull fracture 6) amnesia 7) dangerous impact mechanism eg fall from more than 5 stairs, ejected from motor vehicles, struck by vehicle
Glasgow coma scale categories
Eye opening Verbal ability Motor ability
Basal skull fracture signs
- Racoon eyes - Battle’s sign - Hemotympanum - CSF otorrhea or rhinorrhea
Bell’s palsy
- incomplete eye closure (obicularis oculi) -> exposure keratitis and ectropion - incomplete mouth closure (obicularis oris), sagging mouth corner, dribbling saliva - alteration of anterior 2/3 tongue taste (chorda tympani) - hyperacusis (stapedius)
Trigeminal neuralgia
Intensive pain in facial area due to vascular compression upon trigeminal nerve root -> suicidal disease
