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
