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Mystery Series. “ Moratorium on Mayhem Lest There be a Requiem”. Sir Arthur Conan Doyle. Karl T. Weber, MD. Rami Khouzam as…Sherlock Holmes Louisa Balazs as…Forensic advisor. Disclaimer.

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moratorium on mayhem lest there be a requiem

“Moratorium on Mayhem Lest There be a Requiem”

Sir Arthur Conan Doyle

Karl T. Weber, MD

slide3
Rami Khouzam as…Sherlock Holmes

LouisaBalazs as…Forensic advisor

disclaimer
Disclaimer
  • The use of the Webster’s, Oxford, Portuguese, Latin dictionaries have been used, in order to understand some of the tough words the writer chose to use
  • as well as some Medical Textbooks, and Websites...
slide5
Moratorium:Suspension, freeze, halt, pause, cessation, standstill
  • Mayhem:Chaos, disorder, confusion, turmoil, anarchy
  • Lest There be:in case, for fear that
  • Requiem:Funeral song, hymn,

lament, mournful chant

slide6

“Moratorium on Mayhem Lest There be a Requiem”

  • Cessation of chaos for fear of hearing a funeral song !!!
cpc moratorium on mayhem lest there be a requiem

Bridging the Gap. Where Clinical and Basic Sciences Meet

CPC: Moratorium on Mayhem Lest There be a Requiem

Louisa Balazs, MD, PhD

Associate Professor of Pathology

Rami N. Khouzam, MD

Fellow, Cardiovascular Diseases

Karl T. Weber, MD

Professor of Medicine

slide8

A warm summer evening, June 25, 1965, and resident in medicine, Nick Pinheiro, was seated at his favorite tasca in Porto enjoying Portugal’s outstanding sea fare and a bottle of chilled vinho verdi. This had become Nick’s usual haunt on Friday evenings and he now knew most of the staff including Carlos, a waiter whose hoarse voice and slurred speech made deciphering the evening’s specials a challenge.

vinho verde young wine
Vinho Verde (young wine)
  • Produced in the Minho region in the northwest of Portugal, mainly between the rivers Minho and Douro
slide12
The name of Porto comes from the Roman name "Portus Cale" (from late Latin) ; the ancient port of Cale: the name of an early settlement located at the mouth of the Douro River

The name of the country, Portugal, comes from that term too

slide15

Tonight, Carlos was quite troubled, mumbling that sharp, shooting pains in his feet and deep stabbing pains in his calves made tending tables difficult.

Also troublesome was brother Juan, a chef in Lisbon. Earlier in the week Juan was dismissed because too much salt had been added to meals he prepared. Carlos explained this was not because Juan was careless or that he had overindulged in his favorite wine. Instead, this incident was more likely related to Juan’s recent unsteadiness and faltering vision. Nick offered assistance, but Carlos politely declined and departed in a rather wide-based, stumbling gait.

nick pinheiro resident
Nick Pinheiro: Resident

Rami Khouzam

as…

Sherlock Holmes

carlos symptoms
Carlos’ Symptoms
  • Hoarse voice
  • Slurred speech
  • Sharp shooting pains in feet
  • Deep stabbing pains in calves
juan s symptoms
Juan’s Symptoms

Too much salt added to meals

Dismissed

juan s symptoms1
Juan’s Symptoms
  • Unsteadiness
  • Faltering vision
  • Wide-based, stumbling gait
slide23

Friday next again found Nick dining at the tavern reflecting on several of his patients while gazing out at the River Douro. His reverie was interrupted by the clatter of fallen dishes. Not ten feet away stood an embarrassed, unsteady Carlos. Nick rushed to his aid.

Carlos brushed the incident off as nothing more than a result of summer’s heat. Perhaps, too, he was weakened by diarrhea of several days’ duration, but this was an intermittent problem to which he had grown accustomed.

slide24

Nick found Carlos’ pulse to be irregular and insisted he call an ambulance. A second episode of near syncope convinced Carlos that hospitalization was unavoidable. Nick wondered if this episode could be explained solely by fluid loss and subsequent orthostasis. Why arrhythmia? Perhaps there was hypokalemia.

At the hospital, Nick found Carlos normotensive but indeed orthostatic and began intravenous fluids. Bedside ECG demonstrated right bundle branch block, left axis deviation and sinus rhythm with premature atrial contractions. Runs of atrial fibrillation were seen on rhythm strip.

carlos more symptoms
Carlos’ more Symptoms
  • Diarrhea (intermittent /? Chronic)
  • Irregular pulse
  • Near-syncope
  • Orthostasis
slide28

Carlos’ right pupil was dilated with irregular outline and fringed edges; it did not react to light or accommodation. Thyroid nonpalpable; neck veins not distended; lungs clear. Cardiovascular examination did not reveal cardiomegaly, gallop, or murmur. Pain and temperature sensations in both lower extremities were blunted while position and vibration sensations were lost in feet and ankles. Given Carlos’ orthostasis, Romberg’s test would have to wait.

carlos signs
Carlos’ Signs

PE:

- HEENT: Rt. pupil: dilated with irregular outline &fringed

edges. No reaction to light & accommodation

- Neck: Thyroid non-palpable, No JVD

- Lungs: CTA

- CVS: No cardiomegaly, gallop, or murmur

- Neuro: Bilat. LEs: Pain & Temperature sensation: blunted

Feet & ankles: Position & Vibration sensation: lost

adie s pupil
Adie’s pupil
  • - Constricts very slowly and incompletely, or not at all, to direct light and does not react to accomodation
  • - Degeneration of the ciliary ganglia and the postganglionic parasympathetic fibers that constrict the pupil and affect accommodation
  • - A manifestation of a mild dysautonomia and can also be associated with Shy-Drager syndrome, diabetes mellitus, and amyloidosis
slide32

Pertinent laboratory tests revealed: hemoglobin 10 g/dL with 3.9 million red blood cells/cm3; normal white cell count and differential, normal serum electrolytes and creatinine, albumin, and glucose; negative serology for syphilis; urine negative for porphyrins and Bence-Jones protein; cerebrospinal fluid protein 200 mg/dL, otherwise negative.

slide33

On rounds the following morning, Nick found Carlos sitting upright in bed with labored breathing and bilateral inspiratory rales on examination. A diuretic was given followed by sequential doses of oral digoxin over several hours. Why pulmonary congestion? Heart size and configuration on x-ray were normal. Since admission Carlos had received 3 liters of normal saline. Could he have occult constrictive pericardial disease? Perhaps intravascular volume was normal on admission and yet Carlos remained orthostatic.

more physical signs
More Physical Signs
  • Dyspnea
  • Bilateral inspiratory rales
  • Ventricular extrasystoles (following Digoxin)
slide35

Ventricular extrasystoles presenting as parasystole on bedside ECG were evident later in the day. In 1965, a parasystolic focus was thought to represent a ventricular ectopic site with fixed rate impulse generation and therefore having common inter-ectopic intervals, and a fusion of ectopic and normal foci known as fusion beats.

Marriott HJ. Practical Electrocardiography. 1962

slide36

Consuelo, Carlos’ 33-year-old frail and ill-appearing sister, came to visit him. Nick met with her in hopes of obtaining pertinent historical information and family history. Like Carlos and Juan, Consuelo too had become unsteady and walking was difficult, particularly at nights, when she often fell in attempting to reach the bathroom. And there was incontinence of urine and chronic constipation.

She mused, “Doctor, all seems to be failing me.” Only this morning, in preparing for her visit, she scalded her right foot unable to gauge the temperature of her bath water. She also reported that their father had died suddenly at age 45. Prior to his demise he had complained of progressive weakness of his legs, nausea, vomiting and constipation.

consuelo s problems
Consuelo’s Problems
  • Ill-appearing
  • Unsteady
  • Difficult walking
  • Urinary Incontinence
  • Chronic constipation
  • Temperature loss
carlos father1
Carlos’ Father
  • Progressive legs weakness
  • Nausea/ Vomiting/ Constipation
  • Sudden death at age 45
slide41

Nick had formed his differential diagnosis and was eager to discuss his thoughts on professor rounds.

What is the likely diagnosis?

summary of carlos family problems
Hoarse voice/ Slurred speech

Faltering vision

Sharp shooting pains in feet/ Temperature loss

Progressive legs weakness

Unsteadiness/ Stumbling gait

Near-syncope

Orthostasis

Irregular pulse

Nausea/ Vomiting/ Diarrhea/ Constipation

Urinary Incontinence

Ill-appearing sister

Sudden death at age 45

Summary of Carlos’ family problems
systems affected
Systems affected…

Inheritance

AD (likely)

Nervous System

Impaired Proprioception/ Deep sensation/ Motor function

Peripheral Neuropathy/ Ataxia

ANS

Orthostatic Hypotension

Adie’s pupil

Sphincteric disturbance

(Urinary incontinence/ Diarrhea/ Constipation)

CVS

Arrhythmias

Restrictive/ Constrictive Cardiomyopathy

differential diagnosis
Diabetes Mellitus

Riley-Day syndrome

Vasculitis/ Connective tissue diseases

Hyperthyroidism/ MEN

Syphylis

Lyme disease

Leprosy

Vitamin B12 deficiency

Freidreich’s ataxia

Fabry’s disease

Acute Intermittent Porphyria

Multiple Myeloma

Sarcoidosis

Amyloidosis

Differential Diagnosis
diabetes mellitus
Diabetes Mellitus

Inheritance

Type I:Offspring & Sibling 1-6 %, type II: 33-38 %, MODY: AD

Nervous System

Multiple mononeuropathy

Radiculopathy

ANS

Orthostatic hypotension

Diarrhea/ Gastroparesis

Bladder atony

CVS

Cardiomyopathy/ Arrhythmias

Hyperglycemia

Nephropathy/ Retinopathy

riley day syndrome familial dysautonomia hereditary sensory and autonomic neuropathy type iii
Riley-Day Syndrome (Familial dysautonomiaHereditary sensory and autonomic neuropathy - type III)

Inheritance

AR, Ashkenazi jews

Nervous System

Impaired pain sensation

Abnormal body temperature (high or low)

Incoordination, unsteady gait

Seizures/ Hypotonia

ANS

HTN (intermittent)

Orthostatic Hypotension

CVS

….

Feeding difficulties/ Poor sucking/ Sweating while eating/ Vomiting/ Scoliosis

vasculitis ct disorders sle ra
Vasculitis/ CT disorders (SLE/ RA)

Inheritance

HLA related, Immune complexes

Nervous System

Peripheral Neuropathy/ Ataxia

Seizures/ Psychosis

ANS

Orthostatic Hypotension

CVS

Arrhythmias

Angina/ CAD

Skin changes /Glomerulonephritis / Arthritis

  • Hematologic abnormality
hyperthyroidism men syndromes
Hyperthyroidism/ MEN Syndromes

Inheritance

AD

Nervous System

Periodic paralysis, Chorea

Nervousness, Irritability, HyperactivityInsomnia, Hand tremor

ANS

Orthostatic hypotension

CVS

Sinus tachycardia/ Atrial fibrillation

Cardiomyopathy/Angina

GI

Diarrhea/ Nausea & Vomiting

  • Weight loss/ Increase appetite
  • Heat intolerance/ PTH & Ca
syphilis
Syphilis
  • Inheritance
  • ? Congenital
  • Nervous System
  • Tabes dorsalis (loss of deep pain & proprioception) Stamping gait

General paresis/ Dementia/ Seizures

Argyll-Roberston pupil

  • GI
  • Vague GI symptoms
  • CVS
  • Myocardial granuloma(gumma)
  • Aortitis/ vasculitis
  • Skin changes/ Lymphadenopathy/ Arthritis/ Glomerulonephritis
  • Positive serology
lyme disease
Lyme disease

Inheritance

None

Nervous System

Radiculopathy

Cranial neuropathy (Bell’s palsy)

Meningoencephalitis

ANS

CVS

Arrhythmias/ Myopericarditis

AV Block

GI

Nausea/ Vomiting/ Abdominal pain

Arthralgia/ Arthritis/ Lymphadenopathy

leprosy hansen s disease
Leprosy (Hansen’s disease)

Inheritance

None

Nervous System

Impaired Proprioception/ Deep sensation/ Motor function

Peripheral Neuropathy/ Ataxia

ANS

Orthostatic Hypotension

Adie’s pupil

Sphincteric disturbance

(Urinary incontinence/ Diarrhea/ Constipation)

CVS

Arrhythmias

Constrictive Pericarditis

Cutaneous changes/ Decreased incidence

vitamin b 12 deficiency
Vitamin B12 Deficiency

Inheritance

None

Nervous System

Subacute Combined Degeneration

Impaired vibration & position

Impaired touch or pain perception

Ataxia/ Abnormal gait/ Romberg’s

Neuropathy

ANS

Orthostatic hypotension

GI

Glossitis/ Stomatitis/ Gastritis/GI symptoms

Urinary system

Urinary incontinence

Megaloblastic anemia

friedreich s ataxia
Friedreich’s Ataxia

Inheritance

AR (single patient in a family)

Nervous System

Progressive ataxia

Sensory loss, and Loss of DTRs

Nystagmus/ Dysarthria

Stocking-glove neuropathy

CVS

Hypertrophic cardiomyopathy

Arrhythmias (Atrial fibrillation/ Ventricular tachycardia)

Skeletal deformities (kyphosis, scoliosis)

  • +/- accompanying diabetes
fabry s disease
Fabry’s disease

Inheritance

X-linked recessive

Nervous System

Chronic neuropathic pain/ acroparesthesias

ANS

Hypohidrosis

CVS

Restrictive cardiomyopathy

  • Lysosomal storage disease
  • Corneal and lenticular opacities/ angiokeratomas
acute intermittent porphyria aip
Acute Intermittent Porphyria (AIP)

Inheritance

AR

Nervous System

Neuropathy

Quadriplegia/ Hallucinations/ Paranoia/ Anxiety/ Depression/ Confusion

CVS

Tachycardia/ HTN

GI

Nausea/ Vomiting/ Constipation

Abdominal pain/ Hyponatremia

Liver & Kidney affection

Positive urine porphyrins

multiple myeloma poems
Multiple Myeloma/ POEMS

Inheritance

  • Familial clusters of two or more first-degree relatives and in identical twins (Median age at diagnosis is 65 years)

Nervous System

Peripheral neuropathy

Radiculopathy

GI

Nausea/ Vomiting/ Constipation

Anemia/ Hypercalcemia

  • Renal failure/ Organomegaly
  • Bone pains/ Bence Jones proteins
  • POEMS
  • P: Polyneuropathy
  • O: Organomegaly
  • E: Endocrinopathy
  • M: M-protein
  • S: Skin changes
sarcoidosis
Sarcoidosis
  • Inheritance
  • ?? HLA-B8
  • Nervous System
  • Multiple mononeuropathy syndrome
  • Facial paralysis
  • ANS
  • ….
  • CVS
  • Restrictive cardiomyopathy
  • Respiratory disease/ Hypercalcemia/ Cutaneous manifestations/ Ocular disease/ Lymphadenopathy
slide58

Familial Amyloid Polyneuropathy

Inheritance

AD, Insiduous onset in young adults

Nervous System

Impaired Proprioception/ Deep sensation

Peripheral Neuropathy/ Ataxia

ANS

Orthostatic Hypotension/ Adie’s pupil

Sphincteric disturbance:

Diarrhea/ Constipation

Urinary Incontinence

CVS

Arrhythmias

Restrictive/ Constrictive Cardiomyopathy

autopsy report deceased c p 35 year old male

Autopsy report; deceased: C.P., 35 year old male

Reported by: Louisa Balazs, M.D., Ph.D. Department of Anatomic Pathology

external examination
External examination
  • Moderately cachectic young male
  • Pupils are irregular in diameter and
  • shape
  • Normal chest AP diameter
  • Concave abdomen
  • Lower extremities: mild skin atrophy,
  • few ecchymoses and scars
thoracic cavity
Thoracic cavity
  • Hydrothorax, bilateral, 200 ml, straw-yellow
  • Lungs: moderate edema and congestion
  • Hydropericardium, 50 ml, straw-yellow
  • Parietal and visceral pericardium:
  • smooth and glistening
heart
Heart
  • Heart weight: 390 gr
  • Left ventricle wall thickness: 1.7 cm
  • Right ventricle wall thickness: 0.5 cm
  • Myocardium: diffusely pale, waxy
  • Ostia and valves: normal
  • Coronary arteries: diffusely rigid wall,
  • no endothelial thickening
abdominal cavity
Abdominal cavity
  • 300 ml ascites, straw-yellow
  • Mildly distended stomach
  • Mildly distended small bowel
  • Moderately distended large bowel,
  • foci of mucosal hyperemia
abdominal cavity1
Abdominal cavity
  • Liver: 2,100 gr, mildly firm, pale brown,
  • no cirrhosis
  • Spleen: 350 gr, firm, fine, white nodularity
  • Kidneys: 210 gr, capsules are nonadherent, surface finely granular, cortical-medullary demarcation is distinct
  • Pancreas: no gross pathology
  • Adrenals: no gross pathology
other gross findings
Other gross findings
  • Central nervous system: no extra- or intracerebral hemorrhage, no infarct
  • Spinal cord: unremarkable
  • Peripheral nerves: slightly firm on palpation
microscopic investigation
Microscopic investigation
  • Heart: interstitial deposition of waxy, eosinophilic, homogenous “material”
  • Cardiac muscle atrophy, mild, diffuse
  • Coronary arteries: deposition of above mentioned material into the vascular wall
  • Conduction system: deposition of the above mentioned material and fibrosis
microscopic investigation1
Microscopic investigation
  • Internal organs: scattered, foci of extracellular deposition of homogenous, acidophilic material into the interstitium and vascular wall
  • Peripheral nerves: vascular and interstitial deposition of eosinophilic material, axonal degeneration
conclusion
Conclusion
  • Immediate cause of death: cardiac arrhythmia secondary to amyloid deposition into the heart conduction system
  • Underlying disease:
  • Familial amyloidotic polyneuropathy causing variable deposition of mutant form of amyloid trans-thy-retin (ATTR)
slide77

In 1952 Corino Andrade reported on 74 patients belonging to 12 different families living in Povoa de Varzim, a fishing town in the Porto region of Portugal. Patients presented with a puzzlesome constellation of symptoms and signs not unlike Carlos and his family.

The illness had a long history in the region where it was known as “Mal dos pèsinhos” or foot disease. Features included: insidious onset in young adults; peripheral neuropathy predominantly of lower extremities with impaired sensory and motor functions; and autonomic dysfunction (e.g., Adie’s pupil, sphincteric disturbance, orthostatic hypotension). Vitreous opacities blurred vision. Postmortem studies would demonstrate generalized amyloidosis.

slide78

Infiltration of the heart’s conduction tissue by amyloid fibrils and subsequent fibrosis (e.g., surrounding the AV node) leads to abnormalities of atrioventricular and intraventricular conduction and appear after the onset of progressive neuropathy.

Amyloid deposition in atria can account for atrial arrhythmias while in perivascular and interstitial spaces of the ventricles and corresponding fibrosis account for a restrictive cardiomyopathy with diastolic dysfunction that can simulate constrictive pericarditis.

slide79

In 1981, it was reported that digitalis selectively binds to amyloid fibrils leading to heterogenous concentrations of this sodium-potassium ATPase inhibitor within the myocardium. This perhaps provides substrate for abnormal automaticity, or spontaneous impulse formation, and parasystole—an ectopic, fixed rate, asynchronously discharging pacemaker tissue.

slide80

Today, it is recognized that familial amyloidotic polyneuropathy, a rare systemic disorder of the peripheral nervous system, involves a genetic variant of normal prealbumin, or transthyretin. Transthyretin transports thyroxine in the circulation. Its variant form causes autosomally dominant inherited forms of amyloidosis when it is deposited as amyloid fibrils accounting for peripheral neuropathy, cardiac amyloidosis, amyloid kidney and ocular disturbances.

slide81

More than 30 amyloidogenic mutations in the transthyretin gene have been described. The mutated transthyretin in which valine has been replaced by methionine at position 30, the Met-30 variant, is most common. Most transthyretin is produced by the liver.

In selected patients, liver transplantation has been effective in eliminating the source of variant transthyretin, reducing circulating concentration of transthyretin and ameliorating the disease.

slide82

“Moratorium on Mayhem

Lest There be a Requiem”