Seminar 4 - Sudden Death Flashcards
A medical certificate of cause of death is a statutory requirement - true or false
True
It should provide the required information to the best of the medical practitioner’s knowledge
What can cause central apnoeas in SUDEP
Seizures can cause direct propagation of the electrical discharge to the respiratory centre
This leads to a central apnoea which lasts 10-63 second
O2 sats will drop
Can lead to cardiac arrest which can cause secondary cardiopulmonary arrest
What can cause airway obstruction in SUDEP
In the prone position they may suffer asphyxiation secondary to an obstructive cause
If the URT is obstructed it will affect ventilation and increases chances of aspiration
In unsupervised patients you may get laryngeal spasm and stridor before death
List the main indications for autopsy
Unexpected death of children and infants
Unexpected death when person was in good health
Death known or suspected to be caused by a disease that threatens public health
Death of a person not under a doctors care
Almost all sudden deaths are investigated
What are the major autopsy incisions
Standard midline
Y-shaped - most common
Subclavicular
What causes enzyme defects as seen in single gene disorders
Mutations may result in the synthesis of an enzyme with limited activity or a reduced amount of normal enzyme resulting in a metabolic block
Describe the central dogma of molecular biology
First step involves DNA being transcribed by RNA polymerase to produce a strip of mRNA - transcription
Then mRNA is translated to produce a polypeptide - translation
The polypeptide is then modified to form a functional protein.
List the common types of gene mutations
Point mutations
Larger deletions and insertions
Chromosome mutations
Structural alterations/copy number variations
Alterations in non-coding RNA, mutations within non-coding sequences
What is one of the best indicators of physical abuse in an infant
Broken frenulum
This may also occur due to force-feeding with a bottle
Describe the autopsy findings in the heart in a SUDEP case
May have non-fatal pathologic findings
Myocytic hypertrophy
Mild institial fibrosis of the conductive system
How do you differentiate between AM and PM clots
PM blood clot is quite elastic in erythrocyte-poor (“chicken fat”) portions and smoothly gelatinous in erythrocyte-rich portions
They leave behind glistening endocardial surfaces when pulled away.
AM clot is more friable.
How can you differentiate SIDS from asphyxiation
Often very little to differentiate between them
Often no autopsy findings
How do channelopathies cause sudden cardiac death
Via arrhythmia
Most likely have no structural changes
What is the generalised cause of epilepsy
A sudden imbalance occurs between excitatory and inhibitory forces within the network of cortical neurons in favor of a sudden net excitation
Sudden burst of el
What is the Rest of UK equivalent to the Lord Advocate
The coroner
What is the definition of sudden unexpected death in infancy/childhood
All cases in which there is death if a child which would not have been expected 24 hours previously, and for which there is no pre-existing medical condition or cause of death
List the potential respiratory findings in an autopsy of a suspected SIDS case
Epiglottitis Laryngotracheobronchitis Bronchiolitis Pneumonia/bronchopneumonia Pulmonary hypertension Bronchopulmonary dysplasia (chronic interstitial lung disease) Impaction of a foreign body
What causes hypertrophic cardiomyopathy
Most commonly a genetic cause with autosomal dominant mutations in genes for sarcomeric proteins
Define unexpected death
When death is not the result of a known illness and may be due to unnatural causes
May occur in a previously healthy individual or when a doctor feels the existing medical conditions were not enough to cause death
Describe the normal conduction system of the heart
SA node containing cells with spontaneous pacemaker potential sets it of and impulses travel through gap junctions to AV node
AV node delays transmission to ventricles so that the atria can fully contract
From AV node travel through bundle of HIS
From Bundle of HIS travel into left and right bundle branches then on to the purkinje networks to supply the ventricles
What is the definition of sudden cardiac death
Death that occurs due to cardiac causes that is unexpected and occurs within 1-24hrs of symptom onset
What are the microscopic signs of chronic asthma
Airway remodelling with fibrosis, muscular hypertrophy in bronchial walls, mucus gland hyperplasia
Describe the myocyte hypertrophy seen in hypertrophic cardiomyopathy
Transverse diameter of myocytes is >40Um
Most commonly seen in the subendocardial region
List some of the infectious causes of myocarditis
Viral – coxsackie, HIV, echo, CMV, influenza
Chlamydia psittaci
Rickettsial – rickettsia typhi, typhus fever
Bacterial – diphtheria, neisseria meningococcus, borriella
Protozoal – toxoplasmosis, chagus
Helminth - trichinosis
Genetic defects resulting in alterations of non enzyme proteins often have widespread secondary effects - true or false
True
Seen in thalassemia, haemoglobinopathies and osteogenesis imperfecta
Which drugs can cause sudden cardiac death
Cocaine Amphetamine Ecstasy Marijuana Antidepressants/antipsychotics
Most patients with epilepsy have impaired autonomic regulation of the heart - true or false
True
What effect can enzyme defects have on the body as seen in single gene disorders
Can lead to the accumulation of substrate (and sometimes intermediates)
Can cause a metabolic block and a decreased amount of end product
Can lead to failure inactivate a tissue damaging substrate
Who is given the Certificate of Registration of Death
Next of Kin are given a copy
Also is given to the funeral director to initiate arrangements for a burial or cremation
What can cause restrictive cardiomyopathy
Can be idiopathic
Can be due to disorders that effect the myocardium:
Amyloidosis
Sarcoidosis
Radiation induced fibrosis
Metastatic tumours
Accumulation of metabolites form issues with metabolism
List common multigenic disorders
Psoriasis/ Psoriatic Arthritis Parkinson’s Alzheimer’s Asthma Spina bifida
List the microscopic features of restrictive cardiomyopathy
Unremarkable myocardium
Patchy or diffuse interstitial fibrosis that can be minimal or extensive
What can cause neurogenic oedema in SUDEP
A massive alpha-adrenergic response leads to generalized vasoconstriction
This causes pulmonary hypertension and then neurogenic pulmonary edema
Describe the X-linked recessive pattern of inheritance of single gene disorders
Result from presence of mutation on the X sex chromosome
Almost all are recessive so males are far more commonly affected
What are the risk factors for SIDS
Age – Most cases of SIDS occur in infants <6 months in age
Sex – Males are slightly more at risk
Sleeping position – Side/ prone positions pose more risk
Bed sharing – Increases risk of SUDI, either through SIDS or accidental asphyxiation
Maternal tobacco smoking
Premature birth/ Low birth weight/ Multiple births (twins, triplets etc.)
What are the health and safety concerns in a sudden cardiac death autopsy
No additional infection risk
Additional risk from pacemakers or ICD
May be an extra sharps risk
Describe the autopsy findings in the liver in a SUDEP case
Increase in weight & venous congestion
How might the cortex be affected in epilepsy
Left insular cortical damage
Which disease can be caused by accumulation of substrate
Lysosomal storage diseases
List different types of PCR
Sanger sequencing Single base primer extension - highly specific Restriction fragment length analysis Amplication length analysis Real time PCR Next Generation Sequencing
What are the responsibilities of the Lord Advocate
Responsible for investigating any death which needs further explanation
They are also head of the systems for the investigation and prosecution of crime and investigation of deathsand principal legal adviser to the Scottish Government
What causes the impaired autonomic regulation of the heart in SUDEP
Repetitive exposure to catecholamines can cause myocardial and cardiac conduction system fibrosis
Catecholamines can surge during seizures
This increases risk of arrhythmia
When might the PF take no further action
If the doctor has completed the death certificate to the best of their knowledge and the PF is satisfied from the history and circumstances that the death was natural and needs no investigation
What can microscopy be used for at autopsy
Find patterns of changes that signify disease
Estimating the age of a lesion - e.g. MI
To confirm diagnosis of workplace related disease such as asbestosis or silicosis
What is involved in the external examination during an autopsy
Check for heart devices prior to autopsy and examine them first
Carefully examine the outside of the body and document findings - injuries (old and new), rashes, needle marks and signs of medical intervention (surgical scars)
Also look for signs of disease (clubbing) and general wellbeing (hygiene, dehydration etc.)
Take pictures of external surfaces
Children or high risk corpses may get radiographs
Describe the autopsy findings in the brain in a SUDEP case
The standard epilepsy findings (other card)
Cerebral oedema - majority of cases
Brain lesion - e.g. tumours, contusions, scars, atrophy
In surgical epilepsy you may see hippocampal sclerosis or cortical malformations
How does PCR work
It uses specifically designed primer sites to identify a strip of DNA and then used DNA polymerases to amplify the sequence making further analysis a lot easier. This is a mainstay of diagnostics for decades and is used widely.
What are the microscopic features of silicosis
Bundles of interlacing pink collagen, minimal inflammatory reaction
Describe the underlying pathophysiology of status epilepticus
Catecholamine amine surge which leads to systemic response = tachycardia, cardiac arrhythmias, hyperglycemia
There is an elevation of systemic arterial pressure but as the SE continues the BP drops again (often to below baseline)
The vigorous muscle activity and central sympathetic drive can cause hyperthermia which has poor neurological outcomes
Get acidosis which resolves with the end of seizure - anticonvulsant effect
The exact aetiology of SIDS is unknown - true or false
True
If a specific mechanism of death is identified it becomes explained SIDS rather than a true case of SIDS
What is the WHO definition of the underlying CoD
The disease or injury, which initiated the train of morbid events leading directly to death
Or the circumstances of the accident or violence which produced the fatal injury
When would the PF instruct a PM
When no medical practitioner can certify CoD or in rare cases than PF doesn’t accept the certificate
Can be full PM or external exam (view and grant PM)
What is found in part E of the medical certificate of cause of death
Additional information:
- Has a PM been done
- Was a doctor attending the deceased
- Has the death been reported to the PF
- Can extra info be provided for statistical purposes
- Is it a maternal death
What can cause epilepsy
Injury to the brain
Low oxygen during birth
Head injuries that occur during birth or from accidents during youth or adulthood
Brain tumors
Genetic conditions that lead to brain injury
Infections e.g. meningitis or encephalitis
Stroke or any other brain damage
Abnormal level of substances e.g. sodium or blood sugar
Developmental disorders e.g. autism and neurofibromatosis
Injury before birth
What is a point mutation
A single base is inserted, deleted or substituted with another base. This base change can alter the triplet code thus affecting the protein produced
The effect can vary - can be silent or alter the amino acid
How is real time PCR used
Can detect and quantify particular DNA sequences during the exponential phase of PCR
Used to analyse cancer cells and infectious loads e.g. HIV, EBV
How does dilated cardiomyopathy present
Sudden cardiac death or progressive heart failure
Describe the penetrance in rare mendelian disorders
High penetrance with a low environmental contribution
Mutation at a single locus causes disease
What is the definition of a sudden unexpected death in epilepsy
Sudden, unexpected, nontraumatic, non-drowning death in an individual with epilepsy
May be witnessed or unwitnessed
However, if witnessed the seizure stops before death, may even regain consciousness
The PM doesn’t reveal an anatomic or toxicologic cause for the death
What is the classic triad seen abusive head trauma (shaken baby syndrome)
Encephalopathy,
Subdural haematoma
Retinal haemorrhages
How might the hippocampus be affected in epilepsy
Sclerosis, malrotation, loss of neuronal density
Describe the myocyte disarray seen in hypertrophic cardiomyopathy
Tends to be regional and effects non hypertrophied regions as well as hypertrophied
Structurally disorganised
Hypertrophied myocytes align perpendicularly and obliquely around collagen either like a pinwheel or a herringbone
Nuclei are strange, enlarged, pleomorphic and hyperchromatic
Poor architecture of myofibrils in myocytes
Usually effects >20% myocardium
Describe how the lungs are examined on autopsy
Vasculature opened and examined for clots, airways are opened, section the tissue
How does hypertrophic cardiomyopathy progress
The hypertrophy causes reduced filling and CO which leads to LHF
Can lead to mural thrombi from atrial dilatation and AF = stroke
Abnormal heart structure and ischemia from abnormal intramural arteries and hypertrophy = V tach and Vfib causing SCD
What is meant by penetrance
The proportion of individuals carrying a particular variant of agenethat also express an associated trait (thephenotype)
If you have the mutation how likely is it that you have the disease
What are the 3 main classes of cardiomyopathy
Dilated (most common)
Hypertrophic
Restrictive (least common)
How do you test for single gene disorders
Genetic testing is available for many disorders
Physical examination is also very important
Particularly if no family history
Who has responsibility of the body after the death is reported to the procurator fiscal
The Procurator fiscal
They are responsible for the body until a death certificate is written and given to next of kin
What is the definition of ‘unascertained’ in terms of death of an infant
A legal term used by those involved in death investigation, where the medical cause of death has not been determined to the appropriate legal standard
Describe the biochemical tests performed at a sudden death autopsy
Can perform biochemical tests such as sodium or potassium levels but the results are hard to interpret due to post-mortem changes - not really a standard reference value
Vitreous fluid is the best sample to take as relatively protected
Outline the general approach to autopsy in cases of sudden death
Approach autopsy as if any cause of death is possible
Review the past medical history and the circumstances of death prior to autopsy
A complete autopsy is then performed, including internal and external examinations and potentially toxicology/microbiology
Samples should be taken at autopsy for potential future lab tests
How do you test for chromosome abnormalities
Traditionally karyotyping was sued to analyse larger scale chromosome abnormalities but newer methods such as noninvasive prenatal testing are more common nowadays
Non-invasive test involves examining samples of the baby’s DNA from the mother’s blood
List the macroscopic features of hypertrophic cardiomyopathy
Heavy hearts
Massive left ventricular hypertrophy without cavity dilatation
Occasionally right heart effected
Septal hypertrophy
Anterior mitral leaflet is thickened and there is an endocardial plaque in the ventricular outflow tract if obstructed
Subaortic mitral impact lesions if ventricular outflow obstruction
Banana shaped left ventricular cavity
Replacement fibrosis forms white punctae on the ventricular, and more commonly septal, walls
Occasionally will see dilatation laterally
What are the main groups of causes of myocarditis
Infections
Immune mediated
Unknown
List some of the endocrine causes of sudden death
Diabetic ketoacidosis, pituitary dysfunction, thyroid disorders etc.
Which single gene disorder is caused by a membrane defect
FH or familial hypercholesterolaemia
There is reduced synthesis of LDL receptors/impaired function. LDL can’t cross the membrane which results in excess cholesterol
Describe how the heart is examined on autopsy
Assess myocardial thickness, weight, coronary arteries and valve condition.
How often can SIDS be explained on autopsy
One study found causes in 37% of cases
Determined by a range of tests such as histology, macroscopic findings, microbiology and clinical history (listed in order of how common)
The remaining 63% were unexplained
How can anti-epileptic drugs lead to SUDEP
Modification of ANS functions
Withdrawal from medications can increase a patient’s vulnerability to cardiac arrhythmia
Seizure threshold might diminish causing a rebound effect & increase in seizure frequency
Who is responsible for investigating sudden/unexplained deaths in the UK
The procurator fiscal
when a doctor cannot confirm CoD
Describe the arrhythmias seen in Brugada syndrome
They are monomorphic VT and VF
Occur around sleep/rest
Exacerbated by fever
How does giant cell myocarditis appear
Widespread cellular infiltrate with multinucleated giant cells, lymphocytes, eosinophils, plasma cells, macrophages
Myocyte damage can be focal or extensive
Which respiratory events can cause a SUDEP
Airway obstruction
Central apnoeas
Neurogenic oedema
What is the Rokitansky method of autopsy
In situ dissection of individual organs
Rarely used in modern autopsy
May be required due to consent restrictions or severe time limitations.
Give an example of a disease caused by gene amplification
It is important in the pathogenesis of breast cancers
What is the difference between primary and secondary cardiomyopathy
Primary = only the heart is affected Secondary = the heart is affected as a result of systemic disease
Describe how the GI tract is examined on autopsy
Examine stomach contents (e.g. check for undigested tablets etc.)
Look for obvious haemorrhage, examine internal surfaces and section each organ
Describe the effect of membrane defects seen in single gene disorders
Impaired receptor function
Failure / reduced function to transport substance across membrane
Caused by a mutation in one of the proteins involved
How is a medical certificate of cause of death processed
Following death an “informer” is provided with the MCCD
This allows the family to register the death and make funeral/estate arrangement
The informer must take this to the registry office within 8 days of verification of death (21 days if stillbirth) to register the death
After registering the death, and before being able to proceed with burial or cremation, the next of kin are given a certified copy of the register entry, called the “Certificate of Registration of Death”
What is the role of the autopsy in a case of sudden cardiac death
To ascertain if death was cardiac disease related or not
The work out the nature of the cardiac disease if it is there
To determine whether the cardiac disease found is linked to systemic conditions
To determine if the cardiac disease has been inherited
To think about if known about if that cardiac disease could have been treated
To determine if the cardiac disease is related to substance abuse
Describe the autopsy procedure in a suspected SIDS case
Full autopsy with particular attention paid to any evidence of injury (consider photography)
Body measurements, and weights of major organs
List the major macroscopic features of the cardiovascular system that should be noted on autopsy
Weight Configuration Coronary arteries Valves Myocardium (incl. left & right ventricular wall thickness) Aorta and vena cava
Natural causes alone is not enough on the MCCD to get the death registered - true or false
True
Doctors should state to their best knowledge and belief what disease caused their patient to die
May require a PM and PF involvement if cause uncertain
What are considered unnatural causes of death
Suspicious deaths, i.e. where homicide cannot be ruled out.
Drugs related deaths – including ADRs
Accidental deaths – including those from falls.
Deaths resulting from an accident at a workplace
Deaths of children from overlaying or suffocation
Deaths where the circumstances indicate the possibility of suicide.
How can epilepsy itself cause death
Status epilepticus Trauma sustained during seizure Drowning as a result of seizure Airway obstruction during a seizure Aspiration during a seizure Death due to epilepsy treatment (e.g. anticonvulsant drug interaction, overdose or surgical treatments) Epilepsy related suicide SUDEP
Describe the septal hypertrophy seen in hypertrophic cardiomyopathy
Usually more severe subaortically but can be uniform
List the major macroscopic features of the neck that should be noted on autopsy
General appearance Thyroid gland Lymph nodes Airway Blood vessels
How can chromosomal disorders be categorized
Abnormalities in chromosome structure
OR
Abnormalities in the number of chromosomes
What is the general pathologist definition of sudden death
Broader term
A death which occurred before a diagnosis of a potentially fatal disease was made
How might the thalamus be affected in epilepsy
A reduction of grey matter volume in the posterior thalamus
What causes channelopathies
Caused by genetic mutations that involve the ion channels of the heart
They either affect the structure of the channel or accessory proteins needed for channel function
Where in the UK can you get a view and grant post-mortem
Only in Scotland
How does amplicon length analysis work
Compares DNA sequence length of normal individuals with individual that has a mutation affecting DNA length e.g. deletions or expansions
What are the criteria for possible SUDEP
As per definite SUDEP but a competing cause of death is identified at postmortem examination
What are the criteria for definite SUDEP
Sudden, unexpected, witnessed or unwitnessed;
Exclude traumatic causes and drowning (death in “benign” circumstances)
Clinical diagnosis of epilepsy
Status epilepticus cases excluded (seizure ≥ 30 min or serial seizures without recovery between)
No cause of death identified on autopsy
What is found in part D of the medical certificate of cause of death
Potential hazards from the body
DH1 - does the deceased pose a risk to public health
DH2 - is there a pacemaker or other potentially explosive device in the body
DH3 - Is there radioactive matierial or other hazardous implant in the body
Define status epilepticus
More than 30 minutes of continuous seizure activity; or
2 or more sequential seizures without full recovery of consciousness between seizures
What is the effect of a mutation arising in a germ cell
Mutations that affect germ cells are transmitted to the offspring and can give rise to inherited diseases
If you find disease on autopsy, can you put that down as cause of death
NO
It does not mean they died of that disease
e.g. finding atherosclerosis in an 80 year old doesn’t mean they died from this, look for other signs as this is common in their age
List the major macroscopic features of the respiratory system that should be noted on autopsy
Lung weights
General appearance
Tracheobronchial tree
Parenchyma appearance, with details of diffuse or focal lesions
Describe the microbiology tests performed at a sudden death autopsy
Take samples from blood, CSF, effusions (pleural or pericardial), grossly infected tissue
May be checked for bacteria, fungal, viral and blood cultures
However, bacteria naturally spread after death and so cultures may produce different results in death than in life
SUDEP accounts for what proportion of deaths in those with epilepsy
8-17%
What autopsy findings would you expect to see in the brain of someone with epilepsy
Neuronal loss, gliosis, microgliosis and inflammation, blood–brain barrier breakdown, vascular changes, and axonal re-organization
Might be found in cortex, thalamus, and cerebellum can be observed post-mortem
Not specific to SUDEP
What is found in part B of the medical certificate of cause of death
Details of the certifying doctor
GMC number, address etc.
Sign to agree it has been filled to the best of their knowledge
Give an example of an autosomal dominant disease
Huntington’s
Describe the autosomal recessive pattern of inheritance of single gene disorders
Disease only occurs in the homozygous state - require 2 copies of the mutant allele
One healthy copy of gene masks mutation so won’t have disease effect but will be a carrier
What caused Brugada syndrome
An autosomal dominant mutation leading to loss of channel function
Can be SCN5A effecting Na channel
CACNB2b affecting Ca channel
or SCN1b affecting Na
What are copy number changes
Originally thought we had 2 copies of each gene but in fact large sections of DNA can vary in copy number
This can lead to dose imbalances
Can get gene amplification - more copies
Expanding trinucleotide repeats - amplification of a sequence of three nucleotides
List the major sudden death syndromes
Sudden cardiac death
Sudden unexpected death syndrome (SUDS)
Sudden unexplained death in children (SUDC)
Sudden infant death syndrome (SIDS)
Sudden unexplained nocturnal death syndrome (SUNDS)
Sudden unexpected death in epilepsy (SUDEP)
What is involved in the internal examination during an autopsy
On opening the body, look for obvious haemorrhage, effusions and potentially ‘air’ from pneumothoraxes.
Then use a systematic approach for examination of tissues and organs.
Each organ is examined individually - assessing overall structure, signs of disease and malignancy, associated vessels
Each organ is also weighed.
Examine in situ before removing.
List some of the outcomes of myocarditis
Can be asymptomatic
Can completely recover from it
Can also cause heart failure, dilated cardiomyopathy and SCD
What is meant by deaths in legal custody
It can include deaths in prisons, police offices and during transportation to/from prisons/police stations or even in hospital or on custodial leave.
List the Treiman classifications of status epilepticus
Generalized convulsive SE (obvious)
Subtle SE
Nonconvulsive SE (Absence SE & complex partial SE)
Simple partial SE
Describe common abnormalities in the number of chromosomes
Can be monosomy or trisomy
e.g. down’s syndrome is trisomy 21
What is long QT syndrome
A channelopathy which causes arrhythmia and SCD due to excessive prolongation of cardiac repolarisation
How does Chagus disease myocarditis appear
Parasitization of scattered myofibres by trypanosomes
Inflammatory infiltrate of neutrophils, lymphocytes, macrophages and eosinophils
List the causes of sudden cardiac death that come under the myocardial disease class
Myocarditis Cardiomyopathy LVH Obesity cardiomyopathy Idiopathic myocardial fibrosis Amyloid Storage disease, Connective tissue disease
Which samples should be taken for biochemistry in a suspected SIDS case
Urine (metabolic investigations/ toxicology)
Vitreous fluid (dehydration)
Bile (carnitines)
Blood (inborn error of metabolism
What is information from the medical certificate of cause of death used for
Used to measure the relative contributions of different diseases to mortality
Also used extensively in research into health effects of exposure to a wide range of risk factors such as environment, work, medical and surgical care, and other sources
List the FDA/Burroughs-Wellcome criteria for SUDEP
The patient has epilepsy, which is defined as recurrent, unprovokedseizures
The patient died unexpectedly while in a reasonable state of health
The death occurred suddenly (ie, within minutes)
The death occurred during normal and benign circumstances
An obvious medical cause of death could not be determined at autopsy
The death was not the direct result of a seizure orStatus epilepticus
Which samples should be taken for virology in a suspected SIDS case
Nasopharyngeal swabs/ aspirate, lung, CSF, faeces (if indicated)
What are the 3 main classes of seizure type
Focal onset
Generalised onset
Unknown onset
Which samples should be taken for bacteriology in a suspected SIDS case
Blood, CSF, respiratory tract, spleen, infective lesions
What is included in part II of Part C of the MCCD
Any diseases, injuries, conditions, or events that you believe to have contributed to the death, but were not part of the direct sequence
E.g. DM may cause someone to die sooner of another condition than they would’ve without DM but something like OA is unlikely to contribute to cancer
What are the microscopic signs of a lung abscess
Suppurative necrosis of lung parenchyma and cavitation
How should you fill in part C of the MCCD if there are more than 4 conditions in the fatal sequence
If needed, you can write more than 1 condition on a line, indicating clearly that one is due to the next.
List the different classes of sudden cardiac death
CAD and IHD Valve disease Myocardial disease Congenital heart disease Cardiac Tumours Structural abnormalities Drug toxicity No morphological changes Pregnancy
How do most chromosome abnormalities occur
Most are an accident in the egg or sperm - abnormality will be present in every cell
Some happen after conception - not all cells will have it
They can be inherited from a parent or occur de novo
List some of the respiratory causes of sudden death
Asthma, airway obstruction, tumours, pneumothorax, asphyxia etc.
List the potential liver findings in an autopsy of a suspected SIDS case
Hepatitis Fatty liver (metabolic disorder, Reye’s syndrome)
List some of the hepatobiliary causes of sudden death
Tumours or cirrhosis (associated complications like varices)
How are epigenetic techniques used
It involves the study of heritable chemical modification of DNA that does not alter the protein coding sequence itself
e.g. DNA methylation
DNA can be treated to detect these modifications which are essential for function
List the major macroscopic features of the body cavities that should be noted on autopsy
Organ arrangement
Presence / absence of fluids and adhesions
General appearance of viscera (degree of decomposition, colour, malodour)
Adipose layer of anterior abdominal body wall
What is the job of the Scottish Fatalities Investigation Unit (SFIO)
They a specialist unit responsible for investigating all sudden, suspicious, accidental and unexplained deaths in Scotland
What are the microscopic features of Niemann Pick disease
Accumulation of lipids in hepatocytes which gives a foamy vacuolated appearance
Can cause death within 3 years of life
Give an example of a disease caused by expanding trinucleotide repeats
Fragile X
Why does the left ventricular cavity become banana shaped in hypertrophic cardiomyopathy
Due to hypertrophy of the septum
It bulges and changes the shape of the cavity
What is the definition of ‘unexplained’ in terms of death of an infant
Term used in cases with no clear cause of death, and no indication of unnatural death, but where the circumstances do not fit the criteria for SIDS
What must you differentiate myocarditis from
Secondary inflammation in the myocardium caused by diseases such as IHD
List the macroscopic features of restrictive cardiomyopathy
Non-specific changes
Potentially enlarged ventricles with non-dilated cavities
Atria may be dilated bilaterally
What is restrictive cardiomyopathy
A form of cardiomyopathy which has decreased compliance of the ventricles
This impairs the hearts diastolic function but the systolic function remains normal
What can cause status epilepticus
Change in medication in known epileptic patients
Children: An infection with a fever
Adults: Stroke, imbalance of substances in blood
What is FISH and how does it work
Fluorescence in situ hybridization
Locates specific DNA sequences on chromosomes using fluorescent molecules attached to specific probes
These probes bind to the corresponding regions on the chromosomes
Should toxicology be carried out in a suspected SIDS case
May be considered after discussion with coroner
What are the clinical features of hypertrophic cardiomyopathy
Asymptomatic with first presentation being SCD
Exertional dyspnoea
Syncopal attacks (usually on exercise) and palpitations
Ischemic chest pain
Ejection systolic murmur
Features of LHF
How does hypersentivity myocarditis appear
Perivascular infiltrate of lymphocytes, macrophages and eosinophils
What are the major objectives of an autopsy
To establish final diagnoses and determine cause of death
List the macroscopic features of dilated cardiomyopathy
Enlarged but flabby heart
2-3x normal weight
Mural thrombi possibly due to reduced contraction
May have coronary obstruction or valve disease (causative)
Mitral and tricuspid regurgitation possibly
List some of the immune mediated causes of myocarditis
Post viral Rheumatic fever SLE Drug hypersensitivity (-methyldopa, sulphonamides Transplant rejection Immune checkpoint inhibitors
What is the effect of the myocyte disarray seen in hypertrophic cardiomyopathy
Contributes to the arrhythmia
List the microscopic features of myocarditis
In acute mycocarditis you see interstitial inflammatory infiltrate with degenerating or apoptosing myocytes
They have diffuse mononuclear lymphocytic infiltrates
Inflammatory lesions will resolve complete or leave progressive fibrosis
Describe common abnormalities in chromosome structure
Structural abnormalities include deletions, duplications, translocations where portions of chromosomes are altered such as Robertsonian translocation
May be more or less than two copies of a gene
Often doesn’t have effects
List the potential brain findings in an autopsy of a suspected SIDS case
Meningitis/encephalitis
Arteriovenous malformation +/- intracerebral bleeding
Cranial/cerebral trauma (skull fractures, subdural haemorrhage, diffuse axonal injury)
Evidence of current or past episodes of hypoxia/ischaemia
List some of the cardiovascular causes of sudden death
Most common cause
IHD, MI, cardiomyopathies, arrhythmias, congenital abnormalities
What are the benefits of post-mortem genetic testing
Can help to identify the cause of death
Confirm a suspected diagnosis
Provide closure for relatives and assess their risk of having the disease/gene mutations
Which type of arrhythmia can be caused by long QT syndrome
Can lead to torsades de pointes (monomorphic ventricular tachycardia)
List the potential GI findings in an autopsy of a suspected SIDS case
Enterocolitis with dehydration
Intestinal obstruction
Intestinal perforation with peritonitis
Ruptured viscus with intraperitoneal haemorrhage
Who should perform the autopsy in a suspected SIDS case
A paediatric pathologist
If there is suspicion of neglect or abuse, a joint post mortem should be carried out with a paediatric pathologist and a forensic pathologist
Describe the ventricular hypertrophy seen in hypertrophic cardiomyopathy
Significant in the left ventricle
May have right heart affected
Usually asymmetrical with septum more affected than free wall
Give an example of a disease caused by a point mutation
Substitution - sickle cell anaemia
Insertion - thalassemia
Deletion - CF
How does the Royal College of pathologists define infancy
<24 months
Chromosomal disorders are common - true or false
False
They are rare
Describe complex multigenic disorders
Very common occurrence
Caused be a combination of many different polymorphisms and environmental factors
Complex interactions between these factors
Polymorphisms are not always specific to one disease so hard to estimate risk
What are the main roles of an autopsy in sudden death
Identify the cause of death
Identify hereditary diseases so that surviving family can get treatment/tested
Providing closure to the family which can help with grieving
Public health - identifying public health risks and disease trends
This includes notifiable diseases so that close contacts can respond appropriately
What is the role of autopsy in a patient with epilepsy
To establish whether epilepsy has caused or contributed to death (e.g. through status epilepticus or trauma)
To identify or confirm the cause of the epilepsy if present (e.g. neuropathological lesion)
To provide accurate data for the inquiries and audits into the incidence of and remedial factors around epilepsy-associated deaths
To exclude causes of death that might mimic SUDEP, e.g. sudden cardiac death
To exclude death from drugs or poisoning
Describe the penetrance in multifactorial disease
A genetic change is just another risk factor
Penetrance for any one mutation is very low
List the causes of sudden cardiac death that come under the cardiac tumour class
Usually a myxoma
Could be a sarcoma or a metastasis
List some of the GI causes of sudden death
Perforated peptic ulcer, pancreatitis, volvulus/strangulated herniation, vascular issues etc.
How many categories of SUDEP are there
5 Definite Definite plus Probable Possible Sudden death with symptomatic epilepsy
Which histological samples should be taken in a suspected SIDS case
Cardioresp – Lung (4 lobes), heart (free ventricular walls, interventricular septum)
GI – Duodenum w/ head of pancreas, liver (L & R lobes), spleen, mesentery w/ lymph nodes
MSK – Muscle (diaphragm and pec major/ psoas), costo-chondral junction of 6th rib
CNS – Brain (4-6 blocks including all major structures)
Epiglottis, larynx, trachea, kidneys and adrenal glands, thymus
Blocks should be taken of any lesions (including fractured ribs)
What is the effect of a mutation arising in a somatic cell
They do not cause hereditary disease but are important in the pathogenesis of cancers and other acquired diseases.
Describe the toxicology tests performed at a sudden death autopsy
Take aortic and femoral blood sample, vitreous fluid from the eye, urine, samples from the brain and liver
May also keep bile or gastric contents but non-routine
List the microscopic features of dilated cardiomyopathy
Non-specific changes
Interstitial and endocardial fibrosis
Subendocardial scars
Most myocytes have hypertrophy and enlarged nuclei
What determines the extent of histology sampling in a PM
It is decided per case by pathologist
Can be confined to the suspect organ or include other organ systems significant to the CoD
Must be done within the confines of consent
Which diseases are seen as a risk to public health on a death certificate
Air borne communicable diseases (e.g. pulmonary TB)
Blood borne disease (e.g HepC)
Exposed to radioactive material or a toxin or poison to which others might be exposed
List the major macroscopic features of the liver and biliary system that should be noted on autopsy
Weight
Colour
Consistency
GB and contents
Which disease can be caused by a failure to inactivate a tissue damaging substrate
a1-antitrypsin deficiency which leads to emphysema
Individuals cannot inactivate the neutrophil elastase in their lungs which destroys the elastin
What is contained in a Certificate of Registration of Death
Exact information given by the certifying doctor on CoD
May also provide the family with important info about conditions that may affect them
Give an example of an X-linked recessive disease
Haemophilia A
Duchenne’s Muscular Dystrophy
How can genetics predispose you to SUDEP
Increasing evidence of certain channelopathies involving the brain and heart increasing risk of SUDEP
They affect phenotypic expressions of cardiac arrhythmias, epilepsy, SUDEP
What causes Long QT Syndrome
Usually autosomal dominant mutations
Mutations either cause decrease in K outward flow or increase in Na inward flow
This leads to prolonged repolarisation
List the causes of sudden cardiac death that come under the CAD/IHD class
Atheroma Coronary artery anomaly, Kawasaki disease Vasculitis Myocardial bridging Coronary dissection Aortitis and atherosclerosis Emboli in coronaries Fibromuscular dysplasia of coronaries Regional coronary spasm
When might the PF request a police report
Where the CoD hasn’t been determined or PF wants more information
Does not mean it is a criminal case!
Just that they anticipate a PM
What macroscopic features may be seen on external examination
Inspection and palpation from head to toe, incl. clothing. Catheters, tube or lines - should be recorded an removed
Significant and identifiable features such as tattoos and scars - consider photographing for documentation
Stigmata of disease, occupation, social habits and injuries.
Signs of trauma
Which population group typically presents with hypertrophic cardiomyopathy
Classically a disease of the young male
Common cause of sudden death in young athletes
List some of the CNS causes of sudden death
Cerebral infarct, brain haemorrhage, seizure, tumour etc.
What are the 3 main types of gene disorders
Single gene
Chromosomal disorders
Complex multigenic disorders
What disease intervals should be recorded in part C of the MCCD
The approx. interval between the onset of each disease, injury, condition or event and death
What is the most common inheritance pattern for a channelopathy
Autosomal dominant
List the ethical issues surrounding genetic testing
Consent to being screened – needs to be informed before consent, clear up misbeliefs
Stigma – barrier to uptake / based of misbeliefs
Counselling may be required – psychological support, help with next steps (disclosing to family, etc), counselling about reproductive options for couples
Confidentiality / disclosure to family members – when is it okay to break confidentiality?
Potential use of genetic information by employers – how will a genetic test affect your life/ financial situation
List the potential cardiovascular findings in an autopsy of a suspected SIDS case
Congenital heart disease Myocarditis Cardiomyopathy Subendocardial fibroelastosis Trauma (aortic rupture, cardiac tamponade) Coronary arteritis (Kawasaki disease) Total anomalous pulmonary venous drainage Idiopathic arterial calcinosis Cardiac tumours
What macroscopic features should be noted on internal examination
The appearance of organs and overlying structures (e.g. omentum)
Organs – location, condition, size and surface appearance
Presence/absence of appendix
Glands – presence/lack there of, condition (e.g. hypertrophic).
Nerves – chance of impingement or damage and Identification of CNs.
Vessels and ducts – patency, obstructions Bone structure- abnormalities, fractures
Muscles, connective tissues, dura.
PM vs. AM clots
Structural abnormalities – congenital, acquired.
Secretions – pericardial, pleural, abdominal fluid (colour, volume).
Which causes of sudden cardiac death may occur in pregnancy
IHD
Congenital Hd
Cardiomyopathy
Coronary dissection
What is found in part C of the medical certificate of cause of death
Cause of death
I - conditions directly leading to death
II - other significant conditions contributing to death but not related to the direct cause
Where appropriate, in parts I or II, you should give info about clinical interventions, procedures or drugs that may have led to adverse events
What is considered a maternal death on the medical certificate of cause of death
M1 - death during pregnancy or within 42 days of the pregnancy ending
M2 - Death between 43 days and 12 months after the end of a pregnancy
These should be ticked if appropriate regardless of cause of death
List the features of a generalised onset seizure
Will have impaired awareness
Motor symptoms can be tonic clonic
Non motor include absences
What are the microscopic signs of pulmonary oedema on PM
Accumulations of pink, granular, protein-rich material, typically with alveolar capillary engorgement
Which conditions do not require the interval to be recorded on the MCCD
Old age
Genetic and congenital conditions that have been present since birth
What is the definition of Sudden Infant Death Syndrome (SIDS)
The sudden and unexpected death of an infant <12 months, where the onset of the lethal episode appears to occur during normal sleep, which remains unexplained after a thorough investigation (including a complete post-mortem and review of the clinical history)
List some signs of infant asphyxiation at autopsy
Petechial haemorrhages on the visceral pleura, thymus and epicardium present in 70% of SIDS cases
Often no autopsy findings
List some of the miscellaneous causes of sudden death
Drug overdose, poisoning, electrocution, drowning
List some of the GU causes of sudden death
Pyelonephritis, rupture of an ectopic, amniotic embolism, kidney failure
Describe the 3 main patterns of prolonged QT
1 – broad based T waves, syncope and SCD during exercise, KCNQ1 mutation
2- notched or low amp T waves, syncope and SCD in strong emotions and sudden auditory stimuli, KCNH2 mutation
3 – late peaked T waves, tendency for bradycardia, flat ST segments, syncope and SCD occurs during sleep, SCN5A mutation
What are the main indications for autopsy
Unnatural cause of death (accidents, suspicious, drugs etc.)
Deaths in legal custody
Deaths in whole/partly due to natural causes but occur in the following:
CoD can’t be identified by doctors
Due to neglect or fault
Death of children
Deaths from notifiable/industrial diseases
Deaths under medical or dental care
Deaths while subject to compulsory treatment under the mental health legislation
Any death not falling into any of these categories where the circumstances surrounding the death may cause public anxiety.
When might there be further examination on autopsy (aside from the major internal organs)
Some extra procedures for certain causes - e.g. Examination of leg veins after finding a PE
What is myocarditis
Myocardial injury either due to infectious or inflammatory processes
Very wide ranging disease - can go from asymptomatic to sudden cardiac death
Which disease can be caused by
metabolic block and a decreased amount of end product
Albinism
End product of the enzyme affected is required for the production of melanin
When might molecular testing (PCR) be used in PM
CSF PCR may be preferred for meningitis, encephalitis or CNS involvement by enteroviruses, HSV, EBV, CMV, VZV, toxoplasma gondii
Plasma PCR used for HIV, HCV
PCR used on resp samples for TB, pertussis, legionella etc.
Which samples should be taken and frozen as sections in a suspected SIDS case
Heart, liver, kidney or muscle stained with Oil Red O for fat
List the potential pancreatic findings in an autopsy of a suspected SIDS case
Pancreatitis (viral, drug induced)
How might the brainstem be affected in epilepsy
Medullary volume loss and disorganization
List the potential MSK findings in an autopsy of a suspected SIDS case
Infections/inflammation
Fractures/dislocations
Skin and soft tissue injury
List the potential renal findings in an autopsy of a suspected SIDS case
Pyelonephritis
Evidence of ischaemia
Who should report the death to the PF
The doctor with the greatest understanding and knowledge of the death should
They must understand why they are reporting and be able to answer any Qs about the circumstances of the death which the PF may ask
What is found in part A of the medical certificate of cause of death
Details of the deceased
Name, DOB, time and place of death etc.
What are the main objectives of a forensic PM
Positive identification Determining CoD Mode of dying and timing (where possible) Internal and external injuries Abnormalities and diseases To take samples for analysis.
Which terms should not be used as the sole cause of death on the MCCD
Old age or frailty - only a few cases apply
Organ failure - need to specify the causative condition/disease
Natural causes - not specific enough
List potential signs of non accidental injury that may be seen on autopsy
Malnutrition
Broken frenulum
Poisoning
Drowning
Scalding
Trauma (aortic rupture, cardiac tamponade)
Impaction of a foreign body
Ruptured viscus with intraperitoneal haemorrhage
Cranial/cerebral trauma (skull fractures, subdural haemorrhage, diffuse axonal injury)
Fractures/dislocations
Skin and soft tissue injury
What is included in Part Ib, c and d in Part C of the MCCD
The sequence of events or conditions that led to death, ending with the initiating factor of the fatal sequence.
What is dilated cardiomyopathy
It’s a progressive dilatation of the heart
Usually has concomitant hypertrophy that causes issues with contractile function
What condition is also known as cot death
Sudden Infant Death Syndrome (SIDS)
What is the benefit of next generation sequencing
It can sequence an entire human genome within a single day
Very sensitive and specific
The future
What causes a single gene disorder
A single gene mutation
Has a large effect
If an individual has the mutation they will exhibit the disease
Despite being caused by one gene, several mutations can lead to the same disease with varying degrees of severity and phenotype
Evaluation of autonomic cardiac reflexes in patients with epilepsy can tell you what
It indicates dysfunction of sympathetic component and parasympathetic division
If there is hypofunction they are at a high risk of SUDEP
Presents as decreased baseline heart rate which increases the vulnerability of cardioregulatory centres & ventricular automaticity which raises risk of arrhythmia
What actions can the PF take when a death is reported to them
Accept the death certificate offered and take no further action Consent to a hospital PM (non-PF) Request a police report Instruct a PM Release the body
What are the cardiomyopathies
A group of diseases of the myocardium with multiple causes that cause mechanical and or electrical issues and usually includes hypertrophy or dilatation. They can cause cardiovascular death or morbidity
What are the effects of restrictive cardiomyopathy
Leads to heart failure as there is reduced compliance in the ventricles
The heart cannot fill properly which leads to a reduction in CO
What are the characteristics of epilepsy
Recurrent seizures (partial or generalized)
Vary in frequency
Paroxysmal manifestation of the electrical properties of the cerebral cortex
Sometimes with loss of consciousness and control of bowel or bladder function
How many sudden death cases can be linked to genetics
A major proportion are caused by inherited cardiac disease
In 50% of sudden cardiac deaths in the under 35’s there were no warning signs/symptoms and often no autopsy findings
15% of sudden infant death cases have been shown to have an underlying genetic cause
How might the amygdala be affected in epilepsy
Neuronal loss or sclerosis, especially left lateral nucleus
List the macroscopic features of myocarditis
Normal or dilated
Hypertrophy possibly present depending on duration
Advanced stages have flabby ventricular myocardium that can be mottled by pale foci or minute haemorrhages
Mural thrombi may be present
A majority of epilepsy patients have a clear underlying cause for their condition - true or false
False
Only a minority find a cause
When can old age or fragility be given as the sole cause of death
Only when all of the following conditions are met:
Patient is 80+
You have personally or your clinical team have cared for the deceased over a long (years, or many months).
You have observed a gradual decline in your patient’s general health and functioning.
You are not aware of any identifiable disease or injury that contributed to the death.
You are certain that there is no other reason that the death should be reported to the PF.
What is the most common cause of sudden cardiac death in young athletes
Hypertrophic cardiomyopathy
How does status epilepticus cause death
Most often related to underlying brain injury
Affects mechanical aspects of breathing + causes pulmonary edema
Cerebral metabolic demand increases greatly
Abnormal neuronal discharges lead to neuronal loss after focal or generalized SE
The neurons are unable to cope with the prolonged calcium/excitatory neurotransmitter exposure and they begin to die
This inhibits respiratory drive
SE associate with brain-injuring illnesses like stroke and encephaltiis
What is the incidence of SIDS in the UK
According to the Lullaby Trust, there were 230 unexplained infant deaths in the UK in 2018
This is the equivalent to 0.31 deaths/ 1,000 live births
Describe the cytogenic and chromosome analysis tests performed at a sudden death autopsy
Can take blood, marrow, fascia lata (for fibroblast analysis) or solid tumours
List the valvular disease caused of sudden cardiac death
Aortic stenosis Mitral prolapse Rheumatic heart disease, Infective endocarditis Tricuspid and pulmonary disease
Describe sudden cardiac death
Loss of heart function within seconds/minutes of symptom onset
Up until 1 hour
How can RNA analysis be used
Can in principle stand in for DNA in a wide range of diagnostic applications
Also very useful in detection and quantification of RNA viruses e.g. HIV
On the MCCD what is selected as the underlying cause of death
The initiating condition, on the lowest line of part I, will usually be selected as the underlying cause of death
The condition that started the sequence of events that lead ot death
What age group is affected by dilated cardiomyopathy
Occurs at any age but most common between 20-50
The impaired autonomic regulation of the heart in SUDEP most commonly causes which type of arrhythmia
Bradyarrhythmia’s
How might the cerebellum be affected in epilepsy
Macroscopic atrophy or selective Purkinje cell loss
When does the PF usually release a body
The body is released after the PM is complete and the death certificate issues
PF also surrender legal responsibility when the death certificate has been issued
What are the 3 main autopsy techniques which modern PM are derived from
Virchow - removal of organs individually
Ghon - removal of organs in functional/regional groups
Letuille - removing the organs as one group (faster)
Give an example of a complex multigenic disorder and it’s causes
Psoriasis/ Psoriatic Arthritis
Caused by a combination of gene mutations and environmental factors
Genes – CARD14, HLA-B, HLA-DRB1 & IL23R
Environment – UV exposure, smoking, diet, alcohol intake and stress
Give an example of an autosomal dominant disease
Huntington’s
What is included in Part Ia in Part C of the MCCD
The immediate, direct cause of death
How soon should a death be reported to the PF
All notifiable deaths should be reported ASAP, before any steps towards issuing a death certificate are taken
In urgent cases such as suspicious death the report can be made out-of-hours to the police
How does Sanger sequencing work
Chain terminating dideoxynucleotides are introduced during DNA replication which terminate the target strand are different lengths
These strands are separated by electrophoresis and then analysed
Most widely used method for the detection of SNVs
List the causes of myocarditis which come under the ‘unknown’ category of causes
Sarcoidosis
Giant cell myocarditis
What causes Long QT Syndrome
Usually autosomal dominant mutations
Mutations either cause decrease in K outward flow or increase in Na inward flow
This leads to prolonged repolarization
What clinical information is required in a suspected SIDS case
Precise circumstances of death along with detailed clinical history of pregnancy, delivery, and post-natal health
Event scene investigation report from police
GP records (including ‘Red Book’)
Details of resuscitation attempts and A&E investigations, as well as external examination report from consultant paediatrician
Reference to child protection register
Full skeletal survey by mandatory
What are the potential cardiac causes of death in SUDEP
Fatal arrhythmias occur during ictal attack and interictally
There is electrical activity to the amygdala which is connected to the cardioregulatory centres in the medulla via the central nuclei - this can trigger an arrhythmia
Right temporal lobe seizure often lead to tachycardia, cardiac arrhythmia and T-wave flattening - get reduced brain perfusion
Describe sudden unexplained death in children (SUDC)
Sudden death in a child over 1 year old
No cause identified on autopsy
List the main microscopic features of hypertrophic cardiomyopathy
Myocyte hypertrophy
Myocyte dissaray - disordered structure
Intimal thickening and smooth muscle hyperplasia in the intramural arteries
Perivascular and medial collagen increases in the intramural coronaries
Intimal arteries have fibrosis
A witness to a SUDEP case may see what
Seizures stopped before death
Many can regain consciousness
Most victims had difficulty breathing before death
Attempts at cardiopulmonary resuscitation were unsuccessful
List causes of unnatural death in infants
Non-accidental injury
Abusive head trauma - shaken baby syndrome
Asphyxiation
Give an example of a single gene disorder
Lysosomal storage diseases such as Gaucher’s disease and Niemann-Pick disease
What makes an explanation of injury/circumstance inconsistent
Explanations change with time or questioning
Explanations inconsistent with infant’s stage of development
Explanation in relation to time or circumstances of death not supported
How are samples taken and processed for histology in PM
Small tissue sample cut out
Tissues placed in large volume of formo-saline and allowed to fix for several days before processing.
Haematoxylin and eosin (H&E) stain is typical but alternative can be used depending on case, e.g. Congo Red in amyloidosis
How do you treat single gene disorders
Some can be treated for their symptoms
If caught early enough (e.g. on newborn screening) then some treatments can help slow progression or onset
However, for many there is no treatment available
What is a view and grant post-mortem
The pathologist examines the deceased’s body, considers the medical history and the circumstances of death, and is able to grant a death certificate certifying the CoD without the need for a full post-mortem
Which samples should be taken for genetics in a suspected SIDS case
Only taken if indicated
Skin/ pericardial sample for fibroblasts
Mitochondrial studies on frozen muscle
Which document is often incorrectly called the death certificate
Certificate of Registration of Death
Can the next of kin’s decision to not do a full PM be overridden
Yes
If PF decides that a full PM is necessary for an effective investigation into the deceased’s death
Describe the autosomal dominant pattern of inheritance of single gene disorders
High penetrance, individual only has to have one mutant copy of gene for it to exhibit in phenotype (heterozygous)
Two copies of mutant gene can make symptoms more severe
Who is the procurator fiscal
A qualified lawyer who is employed by the Crown Office & Procurator Fiscal Service (COPFS) who act on the instructions of the Lord Advocate
Describe sudden unexplained death in epilepsy (SUDEP)
Sudden, unexpected, and nontraumatic death of persons with epilepsy in whom the postmortem examination fails to reveal a structural or toxicologic cause of death
Can occur with or without seizure (but excludes Status Epilepticus)
Environmental factors or other gene mutations can impact single gene disorders - true or false
True
The same single gene mutation can result in slightly different phenotypes due to this impact
Give an example of an autosomal recessive disease
Phenylketonuria (PKU)
Describe how the brain is examined on autopsy
Examine structure, look for haemorrhage, section and take samples
There are 3 Scottish Fatalities Investigation Units, which areas do they each cover
North (Dundee, Aberdeen, Inverness offices)
East (Edinburgh office)
West (Glasgow office).
When might the PF consent to a hospital PM
Where a reportable death occurs in hospital and is due to natural causes but the doctors want a PM to make CoD more accurate
Relatives need to consent
List the features of a seizure of unknown onset
Motor symptoms can be tonic clonic
Non motor include absences
What is the most common final mechanism of death in SIDS
A failure of autonomic cardiorespiratory control which is associated with inefficient or inadequate autoresuscitation
e.g. a prone infant rebreathes exhaled gases but is unable to turn/lift head which leads to progressive asphyxia and loss of consciousness Ineffectual hypoxic gasping leads to prolonged apnoea and death
What is the medical certificate of cause of death
A permanent legal record of the fact of death and enables family to register the death, make arrangements for disposal of body and settle the deceased’s estate
What are the main mechanisms of death in SUDEP
Respiratory events (terminal events) Cardiac arrhythmia during an ictal event Impaired autonomic regulation of the heart Antiepileptic drugs Genetics
List the main ancillary tests performed at a sudden death autopsy
Toxicology
Microbiology
Cytogenic and chromosome analysis
Biochemical tests
What is the WHO definition of sudden death
Death occurring within 24 hours of symptom onset
Sudden cardiac death and SIDS are different - this is within 1 hour
How can polymorphisms be analysed
SNPs and repeat length polymorphisms can be analysed using linkage analysis
If you don’t disclose the presence of a public health risk on the death certificate what can happen
Can be regarded as a criminal offence
What caused Brugada syndrome
An autosomal dominant mutation leading to loss of channel function
Can be SCN5A effecting Na channel
CACNB2b affecting Ca channel
or SCN1b affecting Na
No morphological changes
What is a channelopathy
a primary electrical issue in the heart with no structural changes that predisposes to arrhythmia and SCD
What type of sample is needed for genetic testing
Fresh samples
What are the microscopic signs of acute severe asthma on PM
Acute airway oedema
Thick, cellular mucus plugs blocking small bronchi and bronchioles
Mucus contains eosinophils, Charcot-Leiden crystals, and sloughed epithelial cells
Which groups can benefit from an autopsy
Healthcare professionals & organisations - allows them to correlate finding and evaluate accuracy of diagnosis and outcome of treatments and interventions
The family of the deceased - helps to grieve and can identify genetic/contagious diseases
Public health - contributions to detection of contagious diseases, identification of environmental hazards and vital statistics
Medical education and research
Law enforcement
What are the clinical features of Brugada syndrome
Can be asymptomatic Syncope Thrashing during the night Arrhythmias - occur around rest/sleep and are exacerbated by fever Sudden cardiac death
Describe sudden unexplained nocturnal death syndrome (SUNDS)
Sudden death during sleep
Commonly seen in young healthy men, particularly of south-east Asian decent
Describe sudden infant death syndrome (SIDS)
The sudden death of an infant under 1 year old that cannot be explained
Describe the effect of larger deletions and insertions
These can involve several base pairs and have two possible effects :
1) If it is in a multiple of 3 then reading frame remains intact and protein produced will be the same +/- one amino acid.
2) If not a multiple of three then a frameshift will occur which can be far more devastating
Which samples are taken for toxicology in PM
Blood, urine, vitreous humour, stomach contents, tissue samples, CSF, bile and hair samples.
Toxicology form should include brief history with details of suspected toxic substances and state if the subject was known to suffer from any infective conditions, e.g. hepatitis or HIV.
List the potential ‘general’ findings in an autopsy of a suspected SIDS case
Malnutrition
Sepsis +/- DIC
Poisoning
Drowning
Scalding
Hyperthermia (cystic fibrosis, congenital adrenal hyperplasia)
Inborn errors of metabolism (e.g. fatty acid oxidation defects)
What is the definition of a mutation
A mutation is a permanent change in the DNA
What are the microscopic features of Gaucher’s disease
Gaucher cells
They are like plump macrophages
Have the appearance in the cytoplasm of crumpled tissue paper due to the accumulation of the enzyme
What causes dilated cardiomyopathy
50% caused by familial autosomal dominant mutation effecting the cytoskeleton
Others include - alcohol, peripartum, viral myocarditis, haemochromatosis, chronic anaemia, anthracycline toxicity, sarcoidosis
If no cause identified its classed as idiopathic
List the features of a focal onset seizure
Can either be aware or have impaired awareness
Symptoms vary from focal to bilateral tonic-clonic
List factors suggesting suspicious death in a child
Previous or ongoing safeguarding concerns
Previous sibling deaths, including previous sibling SUDI
Delay in seeking help and history of poor engagement with healthcare e.g. missing health visitor appointments
Inconsistent explanations of injuries/ circumstances of death
Unexplained injury
Hx of domestic abuse
Evidence of past or present drug or alcohol abuse
Evidence of parental mental health problems
Neglect – Condition of infant and environment on home visits
Previous convictions of parents/ carers, particularly involving violence
How can drug reaction uncover a genetic disorder
Some enzyme deficiencies or defects are only revealed upon exposure to a particular drug.
e.g. G6PD deficiency does not cause harmful effects until exposed to the antimalarial drug primaquine as patients experience a severe haemolytic anaemia
List the major macroscopic features of the CNS that should be noted on autopsy
Weight Configuration Meninges Visually evident abnormalities (haemorrhage, herniations, infection, etc.) Blood vessels Internal abnormalities Ventricles Pituitary gland Scalp and skull
List some of the reticuloendothelial/hematopoietic of sudden death
Splenic rupture or sickle cell anaemia
What are the indications for post-mortem genetic testing
Suspected SIDS (cot death)
Cardiomyopathy
Thoracic aneurysm
Known genetic diagnosis/ family history
Findings on autopsy suggestive of genetic condition (e.g. fatty liver)
Symptoms/circumstances before death suggestive of genetic condition (unexplained seizure)
What is the role of the autopsy in a suspected SIDS case
To establish whether the death is attributable to a natural disease process
To consider the possibility of accidental death, asphyxia/ airway obstruction, and/or non-accidental injury
To document the presence/ absence of pathological processes and to contribute to the multidisciplinary clinicopathological evaluation of death
How does dilated cardiomyopathy lead to death
Progresses to heart failure due to poor contractile function
Death is either through the HF itself or through arrhythmogenic sudden cardiac death
Describe sudden unexpected death syndrome (SUDS)
Sudden death in an otherwise healthy individual
No cause identified on autopsy
Explain the triple risk hypothesis of SIDS
A popular model used to explain SIDS as a multifactorial phenomenon
1st risk - An intrinsically vulnerable infant e.g. low birth weight, prematurity, genetic factors
2 - A critical development period for homeostatic control e.g. cardiorespiratory regulatory mechanisms
3 - Exposure to an exogenous stressor e.g. over-heating, sleep environment, cigarette smoke
Describe hypertrophic cardiomyopathy
Involves mainly left ventricular hypertrophy without dilatation in the cavity
This impairs diastolic filling and potentially has a ventricular outflow tract obstruction
Systolic function tends to be normal
Which structural abnormalities can lead to sudden cardiac death
Lack of AV node His bundle damage, Inflammation AV note cystic tumour Wolf-Parkinson White
What are the criteria for probable SUDEP
As per definite SUDEP but elements of the autopsy are incomplete (e.g. no tox screen)
