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89
CASE 32: SEIZURE IN A NEONATE
A 5-day-old neonate, born via normal delivery, is seen by his mother to have a “seizure”
when she is feeding him. She says that he became limp and his arms flexed before being
released. The episode ended within a minute without any medical intervention. Routine
prenatal scanning had identified cardiac features consistent with tetralogy of Fallot.
Examination
The neonate is cyanotic, with a soft ejection systolic murmur. The physician notes dys-
morphic facies, including microcephaly, low-set ears with abnormal folding and increased
distance between the medial epicanthi of the eyes. The eyes are downward slanting.
INVESTIGATIONS
FBC Normal
U+E Normal
Alkaline phosphatase 80
Corrected calcium 1.25
Phosphate 1.81
Parathyroid hormone 0.35
QUESTIONS
1.
What are some of the causes of a neonatal seizure?
2. Suggest a unifying diagnosis in light of the neonate’s medical history, clinical
findings and investigation results.
3. Describe the pathology underlying the diagnosis, and explain how it may pro-
duce tetralogy of Fallot and this biochemical abnormality.
DOI: 10.1201/9781003242697-33
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ANSWERS
Neonatal seizures may be caused by several conditions, the most common of which are
hypoxic-ischaemia encephalopathy, intracranial haemorrhage, central nervous system (CNS)
infections and metabolic disorders. Seizures may also be benign, typically occurring in the
first week of life. Here, blood tests show low calcium, high phosphate and low parathyroid
hormone levels, which are suggestive of hypoparathyroidism, and this is the most likely cause
of the seizure in this case.
Approximately 40% of serum calcium exists in the active ionised form. However, the major-
ity of calcium is bound to proteins such as albumin. Thus the most common cause of hypocal-
caemia is hypoalbuminemia, usually caused by reduced synthesis resulting from liver failure
or increased protein losses as a result of nephrotic syndrome. Other causes of hypocalcae-
mia include autoimmune or congenital hypoparathyroidism, vitamin D deficiency and loop
diuretics (not thiazide diuretics, which can cause hypercalcaemia).
Tetralogy of Fallot is a reasonably common congenital cardiac anomaly, characterised by (1)
significant ventricular septal defect, (2) pulmonic stenosis, (3) over-riding aorta with respect to
the septal defect and (4) subsequent right ventricular hypertrophy. The association of tetral-
ogy of Fallot with neonatal seizures (due to hypoparathyroidism) as well as dysmorphic facies
is very suggestive of a congenital cause.
The most likely cause for this combination of problems is DiGeorge syndrome. DiGeorge
syndrome is caused by a deletion in chromosome 22q11 (aecting the gene TBX1). This
results in defects in neural crest cell migration and their derived tissues, notably the third and
fourth branchial pouch. Embryologically, the third branchial pouch is responsible for the
development of the inferior parathyroid glands and the thymus, whereas the fourth branchial
pouch develops into the superior parathyroid glands. Neural crest migration is also critical
for the development of the heart, ascending aorta and pulmonary trunk.
Clinically, erroneous development of the parathyroid glands results in hypocalcaemia, which
can present as neonatal seizures, tetany, proximal muscle weakness or mental state changes.
Hypoplasia of the thymus gland results in T-cell deficiency and recurrent viral or fungal
infections. Congenital cardiac anomalies such as tetralogy of Fallot are caused by problems
with neural crest cell migration. Of note, DiGeorge syndrome is the second most common
cause of congenital cardiac abnormalities after Down’s syndrome. Other signs include learn-
ing diculties and dysmorphic facies, as described in the case.
DiGeorge syndrome is usually the result of de novo mutations, with 100% penetrance and
variable expression. It may also be inherited in an autosomal dominant fashion.
KEY POINTS
•
Neonatal seizures are commonly a result of ischaemia, haemorrhage, and meta-
bolic disturbances, or they may be benign.
•
Aberrant development of the third and fourth branchial pouches causes DiGeorge
syndrome (deletion in chromosome 22q11).
•
This is associated with T-cell deficiency (thymic aplasia) and hypocalcaemia (failure
of parathyroid development). It is also the second most common cause of con-
genital heart defects.
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HISTOPATHOLOGY
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93
CASE 33: A YOUNG WOMAN WITH ANKLE
SWELLING AND SHORTNESS OF BREATH
A 25-year-old woman of Indian origin presents to the emergency department with progres-
sive shortness of breath and ankle oedema over the previous 3 months. There is a history of
fever with joint pains during her childhood, which was spent in India. She moved to the UK
at age 18. There is no family history of note.
Examination
General examination confirms bilateral, pitting pedal oedema and mild clubbing of the fin-
gers but no cyanosis. Cardiac examination reveals a rumbling mid-diastolic murmur heard
best at the apex and a decrescendo early diastolic murmur heard best in end expiration at the
left sternal edge. There are fine basal crepitations at both lung bases.
INVESTIGATIONS
ECG shows features consistent with left atrial enlargement. A chest radiograph
shows mild cardiomegaly, and an echocardiogram is booked.
QUESTIONS
1.
What is the relevance of fever and joint pains in childhood?
2. Why is there a delay in the appearance of the cardiac symptoms?
3. What complications may arise from this condition?
DOI: 10.1201/9781003242697-35
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ANSWERS
A history of fever and joint pains in childhood suggests rheumatic fever following group A
(beta-haemolytic) streptococcal infection. The immune response to the bacterial antigens
cross-reacts with cardiac valvular and connective tissue elements in the joints and other sites.
It must be emphasised that cardiac valvular pathology is due to a type II (immune mediated)
hypersensitivity reaction and not direct bacterial infection. The characteristic presentation
includes migratory polyarthritis of large joints, carditis, subcutaneous nodules, erythema
marginatum of the skin and Sydenham’s chorea. Blood investigations typically show a raised
ESR or the presence of anti-streptolysin O (ASO) antibody.
The most common valve to be involved is the mitral valve, followed by the aortic valve. The
murmurs found in this patient reflect this, being indicative of mitral stenosis (mid-diastolic
murmur) and aortic regurgitation (early diastolic murmur). The mitral valve is most fre-
quently aected, as it is the valve across which the greatest pressure dierence arises. The
continued immunologic damage and fibrosis may progress over years to cause deformity of
the valves. This is the reason for the late manifestation of symptoms of valvular heart disease,
although features of myocarditis may be present in the acute phase of rheumatic fever. Initial
valve damage results in mitral prolapse and with time the valvular damage takes the form of
thickening of the leaflets and fusion of commissures and of chordae tendinae.
Inflammation of all three layers of the heart is termed pancarditis. If this is caused by rheu-
matic heart disease, pathognomonic Ascho bodies may form in all three layers of the heart,
but predominantly the myocardium. Ascho bodies are granulomas with giant cells (mainly
macrophages), which can develop into Anitschkow’s cells, which represent activated enlarged
macrophages.
The signs and symptoms of valvular disease depend on the valves involved and the severity of
involvement. Cardiac failure may develop, accompanied by cardiac hypertrophy and dilata-
tion. In a tight mitral stenosis, the left atrium becomes dilated and a mural thrombus may
form. Arrhythmias such as atrial fibrillation (which may arise as a result of left atrial enlarge-
ment) may lead to thromboembolic complications. Damaged cardiac valves are also suscep-
tible to infective endocarditis, which can worsen the valvular insuciency and also result in
infective emboli to the brain, kidneys, spleen (left-sided lesions) and lungs (right-sided lesions).
KEY POINTS
•
Rheumatic heart disease results from a type II immune-mediated hypersensitivity
reaction to group A beta-haemolytic streptococci.
•
It most commonly affects the mitral valve, causing prolapse in early stages of the
disease and stenosis later on.
•
Pathognomonic lesions that affect all three layers of the heart in rheumatic heart
disease include Aschoff bodies and Anitschkow’s cells, which represent granulo-
mas with giant cells (macrophages).
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95
CASE 34: CHEST PAIN AND SUDDEN DEATH
A 70-year-old man is working in his garden when he suddenly experiences crushing central
chest pain, starts sweating profusely and feels short of breath. An ambulance is called, but he
collapses in the interim and becomes unresponsive. Cardiopulmonary resuscitation is com-
menced by the paramedics and continued until they reach hospital, where no output can be
restored and the patient is declared dead. The coroner requests that a post-mortem examina-
tion be carried out.
Examination
External examination of the body is unremarkable. The heart is of mildly increased weight
compared to the normal expected weight (up to 0.5% of body weight). The heart valves are
normal, and there is concentric thickening of the left ventricle. The coronary arteries show
marked eccentric thickening and calcification of their walls, resulting in such narrowing that
only a pinpoint lumen can be seen at one site in the right-sided coronary artery.
QUESTIONS
1.
How is sudden cardiac death defined, and what are the main causes?
2. What is the most likely cause of death in this patient?
3. What are the aetiology and pathogenesis of the likely cause of death?
4. If the patient had been successfully resuscitated, what complications might have
occurred?
DOI: 10.1201/9781003242697-36
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ANSWERS
Sudden cardiac death is defined as unexpected death from a cardiac cause early after the onset
of symptoms, usually within 1 hour. The most common causes of sudden cardiac death include
ischaemic heart disease and myocardial infarction or, especially in younger patients, dilated or
hypertrophic cardiomyopathy. Other causes include aortic valve stenosis, mitral valve prolapse,
myocarditis, pulmonary hypertension, congenital structural abnormalities or, when all of these
conditions and other non-cardiac causes of sudden death have been excluded, hereditary or
acquired abnormalities of the conduction system. Irrespective of the underlying cause of sudden
cardiac death, the common mechanism of death is a lethal arrhythmia triggered by irritability of
the myocardium even if the abnormality or injury is distant from the conduction system. These
conditions often do not cause symptoms, and sudden death may be the first presentation.
The cause of death in this patient is ischaemic heart disease. This term encompasses related presen-
tations of myocardial ischaemia and includes myocardial infarction, where the degree and dura-
tion of interruption of blood supply are sucient to cause death of the heart muscle, or angina, a
lesser form where the heart muscle does not become infarcted. Since myocardial ischaemia of up to
30 minutes may be reversible, features of an acute infarct would not necessarily be seen at autopsy.
Ischaemic heart disease is the most common cause of death in industrialised countries. The
dominant cause of ischaemic heart disease is reduced perfusion of coronary arteries rela-
tive to myocardial requirement, and in over 90% of cases reduced perfusion is the result
of atherosclerosis of the coronary arteries with progressive narrowing of the aected coro-
nary artery. Such atherosclerotic plaques, which commonly show calcification, may rupture
(‘acute plaque change’) and result in overlying thrombosis, which may completely interrupt
perfusion, or progressive stenosis of the coronary artery may lead to critical narrowing (usu-
ally defined as a pinpoint residual lumen or narrowing of more than 75%).
Myocardial infarction, also known as a ‘heart attack’, implies death of heart muscle from
ischaemia. Whether ischaemia of the heart muscle results in infarction depends on the loca-
tion and severity of the coronary artery narrowing, the rate at which it develops, the extent of
collateral blood supply and the metabolic needs of the heart muscle (this explains why angina
or infarction often occurs following exertion).
Great progress has been made in the timely diagnosis and treatment of myocardial infarction,
and as a result the overall mortality of myocardial infarction has sharply declined over the last
50 years. In general, patients with previous infarcts, diabetes mellitus or higher age are less
likely to survive an infarct, whereas those who do commonly develop one or more complica-
tions, some of which may be life threatening in themselves. These include heart failure (which
may be early or late), arrhythmias, rupture of the heart muscle with collection of blood in the
pericardial sac (cardiac tamponade), pericarditis, extension of the infarct, mural thrombosis
and embolism (e.g., a stroke) or valvular dysfunction due to papillary muscle rupture.
KEY POINTS
•
Sudden cardiac death is defined as death occurring within 1 hour of the onset of
cardiac symptoms.
•
The most common cause of sudden cardiac death in the middle aged and elderly
is ischaemic heart disease.
•
Patients who survive a myocardial infarct may suffer from complications such as
heart failure, arrhythmia and cardiac tamponade, which may all cause death some
time after the infarct.
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97
CASE 35: AN ELDERLY MAN WITH SEVERE
BACKPAIN
A 77-year-old man phones ‘999’ after experiencing severe backache. The paramedics arrive
to find him in severe pain, cold and clammy. While at his house, they note that he smokes and
also elicit a history of hypertension. He is tachycardic and hypotensive en route to hospital,
and intravenous fluids are started.
Examination
At the emergency department, his observations are HR 120, BP 90/60, RR 26, O
2
92% on
room air. The physician is uncertain about the presence of an expansile mass in the abdo-
men, but examination is hampered by an obese body habitus. Before further imaging or
treatment could be commenced, the patient has a cardiac arrest. Cardiopulmonary resusci-
tation is commenced but proves unsuccessful.
In view of the sudden, unexplained death, the case is referred to the coroner and an autopsy
is performed. This shows extensive haematoma in the retroperitoneum.
QUESTIONS
1.
What is the diagnosis?
2. What are the risk factors for this condition?
3. Where else can this condition be seen?
DOI: 10.1201/9781003242697-37
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ANSWERS
The autopsy demonstrates massive haemorrhage into the retroperitoneum from a ruptured
abdominal aortic aneurysm (AA A). The definition of an aneurysm is an abnormal focal
permanent dilatation of all the layers of a blood vessel. An AA A is defined when the aortic
diameter, as measured below the level of the renal arteries, is one and a half times normal.
Women have smaller aortas, but for convenience, more than 3 cm qualifies as aneurysmal.
The main risk factors for aneurysm formation are male gender, smoking, hypertension,
Caucasian/European descent and atherosclerosis. Although atherosclerosis is a risk factor and
both diseases share common predisposing factors, there are also dierences. Atherosclerosis
is primarily a disease of the intima, the innermost layer of the vessel wall, whereas in aneu-
rysms, there is degeneration of the media, the middle layer. The mechanisms are not fully
understood, but inflammation, oxidative stress and inappropriate enzyme activation result in
degradation of tissue matrix, collagen, and elastin. The weakened wall progressively dilates,
and with increasing diameter, the tension in the wall increases, as does the risk of rupture.
The annual risk of rupture equals and begins to outstrip the risk of dying from surgery when
the aneurysm exceeds 5.5 cm. This is the size above which surgical repair is recommended,
comorbidities permitting. A UK national screening programme will eventually (by way of
abdominal ultrasound) target all men over the age of 65.
Clinical examination for an expansile, as opposed to a merely pulsatile, mass is helpful, but
not always reliable. Ultrasound and computed tomography are the preferred imaging modali-
ties. In some AAAs, incipient rupture may be heralded by a ‘sentinel’ leak that is contained by
haematoma—this can be misdiagnosed as back strain or ureteric colic. Catastrophic rupture,
as in this case, presents with hypovolaemic shock and carries a dismal prognosis. The aorta is
retroperitoneal, so the pain may be felt in the back, flank and groins as well as the abdomen.
Aneurysmal change can occur in any vessel, including the iliac, femoral, and popliteal arter-
ies, albeit more rarely. More proximally, thoracic aortic aneurysms share a similar patho-
genesis, but in the ascending aorta, a dierent form of degeneration known as cystic medial
necrosis is also described. Late-stage syphilis and inherited collagen defects such as Marfan’s
syndrome are associated with thoracic aneurysms.
Aneurysms of a dierent pathogenesis can occur in the cerebral circulation, sometimes called
berry aneurysms due to their appearance, which, if they rupture, cause subarachnoid haem-
orrhage. Coronary artery aneurysms occur in Kawasaki’s disease, a form of autoimmune
vasculitis. The term aneurysm is also used to refer to the thinning and dilatation of the heart
wall following myocardial infarction.
The term ‘false aneurysm’ is used to refer to contained collections of blood immediately out-
side a vessel but where there is still a direct communication through a defect in the vessel wall.
This usually occurs following trauma, commonly iatrogenic trauma caused during arterial
puncture required for percutaneous transarterial interventional procedures.
KEY POINTS
•
An aneurysm is an abnormal focal permanent dilatation of all the layers of a blood
vessel.
•
Some of the risk factors for aneurysm formation are male gender, smoking, hyper-
tension and atherosclerosis.
•
Rupture of a previously unsuspected aortic aneurysm is a life-threatening condition.
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