The

n e w e ng l a n d j o u r na l

of

HSC 3537: MEDICAL TERMINOLOGY

College of Health Professions and Social Work
Records
of the Massachusetts
Department Case
of Health
Sciences
Summer 2016

m e dic i n e

Name:
General Hospital

Founded
by Richard
C. Cabot
CASE STUDY (15% of final grade):
Due
Sunday,
July 17 by 11:59pm
EricS. Rosenberg,
M.D., Editor
Harris,
M.D.,
Editor
Directions:
This assignment
gives you a chance to read a real-life medicalNancyL.
case study
and
apply
the medical terminology you've
JoAnneO.
Editor
AliceM.
Cort, M.D.,
Editoror unusual clinical cases that can
learned
over theShepard,
course M.D.,
of theAssociate
semester.
Case studies present detailed
information
onAssociate
interesting
SallyH. Ebeling, Assistant Editor
EmilyK. McDonald, Assistant Editor
be used to educate health care providers on the presentation and diagnosis of an illness.

As you read through the case study, you will see comments inserted by the instructor with additional information about the case.
In addition, these comments contain the information you need to fill in the blanks with the missing term. There are 40 boxes total.
In each box, you will enter the correct medical term in each of the 40 boxes below using with a slash (/) to separate the prefix,
combining form, and suffix. These terms come from many chapters in the text, so it is a great opportunity to test what you learned
in the course. You may find that you don't understand all of the terms used in the case study, and that is ok! Use the information
you DO know to get an idea of what the clinicians are discussing and why.

Case 30-2015: A 50-Year-Old Man

with
Shock
In addition to the 40 blank boxes,
thereCardiogenic
are 5 questions to test your
comprehension of the case at the bottom of the last page.
Once completed,
you will Wheeler,
upload your
case JoshuaN.
study pdf toBaker,
CanvasM.D.,
by theDavidA.
deadline.Chad, M.D.,
ThurmanM.
M.D.,

JodiL. Zilinski, M.D., Stacey Verzosa, M.D., and DanielA. Mordes, M.D., Ph.D.

Good luck!

Pr e sen tat ion of C a se

Dr. Todd Herrington (Neurology): A 50-year-old man was transferred to this hospital
because of cardiogenic shock.
type 1answer had been made when the
A diagnosis of dilated nonischemic cardiomyopathy
patient was in his late 40s. When he was 48 years of age, a dual-chamber pacemaker and implantable cardioverterdefibrillator (ICD) was placed.
Dr. Jodi L. Zilinski (Echocardiology): Four months before admission, transthoracic
echocardiography
revealed a left ventricular ejection fraction of 40% (Fig.1A, 1B,
2
and 1C; and Videos 1 and 2, available with the full text of this article at NEJM.org).
Dr. Herrington: Several days before admission, malaise, fatigue, increasing dyspnea,
and chest tightness developed. One day before admission, the patient was
3
seen by his primary care provider. The systolic blood pressure was reportedly between 80 and 89 mm Hg, the pulse higher than 100 beats per minute, and the
oxygen saturation 77% while he was breathing ambient air. Emergency medical
services were called; on examination, the patients mentation was normal, and the
cardiac rhythm was rapid atrial fibrillation. During transport by ambulance to
4
another hospital, ventricular tachycardia
developed, and the patient became unresponsive and apneic. Cardiopulmonary resuscitation was begun, and the trachea
was intubated. In the emergency department, blood levels of magnesium and alkaline phosphatase were normal; other test results are shown in Table1. Ventricular
5
tachycardia was followed by transient pulseless electrical activity, with hypoten6
sion, hypoxemia, hypercapnia, and acidosis.
Oxygen, multiple external shocks,
epinephrine,
amiodarone, dopamine, and sodium bicarbonate were administered.
7
After approximately 25 minutes, atrial fibrillation was restored, and the blood
pressure rose to 98/20 mm Hg. Norepinephrine bitartrate, insulin, midazolam,
cisatracurium, furosemide, fentanyl, vasopressin, sodium bicarbonate, magnesium,
calcium gluconate, potassium chloride, potassium phosphate, heparin, and normal
saline were administered. The patient was admitted to the intensive care unit (ICU).
Dr. Zilinski: Transthoracic echocardiography revealed a left ventricular ejection
fraction of 15%, severe diffuse hypokinesis, regional wall-motion abnormalities,
mild left ventricular dilatation, normal wall thickness, and moderate mitral regurgitation, without pericardial
effusion.
8
Dr. Herrington: Chest radiographs reportedly showed increasing consolidation of
n engl j med 373;13nejm.org September 24, 2015

From the Departments of Neurology

(T.M.W., D.A.C.), Radiology (S.V.), and
Pathology (D.A.M.) and the Divisions of
Cardiac Surgery (J.N.B.) and Cardiology
(J.L.Z.), Massachusetts General Hospi
tal; and the Departments of Neurology
(T.M.W., D.A.C.), Surgery (J.N.B.), Medi
cine (J.L.Z.), Radiology (S.V.), and Pathol
ogy (D.A.M.), Harvard Medical School
both in Boston.
N Engl J Med 2015;373:1251-61.
DOI: 10.1056/NEJMcpc1415169
Copyright 2015 Massachusetts Medical Society.

Videos showing
transthoracic
echocardiography
are available at
NEJM.org

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LV
LV

LV
LV

RA

LA

LV
LV
RA

LA

Figure 1. Transthoracic Echocardiograms.

An echocardiogram was obtained 4 months before admission. Parasternal longaxis (Panel A) and shortaxis (Panel B)
views show dilatation but no hypertrophy in the left ventricle (LV), as well as impaired systolic function, with a left
ventricular ejection fraction of approximately 40% and without pericardial effusion. The apical fourchamber view
(Panel C) shows an elongated left atrium (LA), moderate left ventricular systolic dysfunction, an elongated right
atrium (RA), and mild right ventricular systolic dysfunction; the right ventricular systolic pressure was estimated to
be 20 mm Hg. Another echocardiogram was obtained at the time of the current presentation. The parasternal long
axis (Panel D) and shortaxis (Panel E) views show severe, diffuse left ventricular hypokinesis, with regional variation
and a left ventricular ejection fraction of 13%; these findings are consistent with ischemia that is superimposed on
a nonischemic cardiomyopathy. Changes in the perfusion rates for extracorporeal membrane oxygenation (ECMO)
were not associated with clinically significant changes in left ventricular ejection fraction or right ventricular function.
The apical fourchamber view (Panel F) shows severe diffuse left ventricular hypokinesis, as well as diffuse right
ventricular hypokinesis, with normal right ventricular size; there is no evidence of a pericardial effusion.

the right middle and upper lobes. The patient

was paralyzed, and mechanical ventilation was
continued. Furosemide and chlorothiazide were
9
administered for oliguria,
and broad-spectrum
antibiotic agents for presumed aspiration pneu1252

n engl j med 373;13

monia; venoarterial extracorporeal membrane

oxygenation (ECMO) was initiated for persistent
hypoxemia. On the second day, the patient was
transferred to this hospital and admitted to the
ICU. Medications on transfer included norepi-

nejm.org

September 24, 2015

Case Records of the Massachuset ts Gener al Hospital

nephrine, dopamine, fentanyl, midazolam, vasopressin, insulin, and cisatracurium.

The patient had muscle weakness that had
begun approximately 15 years earlier, when increasing weakness of his hands developed.
When the patient was 40 years of age, episodes
of lightheadedness occurred; a diagnosis of paroxysmal atrial fibrillation was made, and prophylactic anticoagulation with warfarin was begun. When he was 41 years of age, he noted
difficulty walking (with occasional stumbling),
gripping and releasing tools, and climbing stairs
10
and ladders. Electromyography,
which was performed at another hospital, reportedly revealed
brief-duration, low-amplitude, polyphasic motorunit potentials. During the next 3 years, his
symptoms worsened, and his left forearm was
fractured after a fall.
On examination when the patient was 44 years
of age, extraocular movements were normal,
11
and mild bilateral
ptosis, moderate bilateral
11
facial weakness, and slight thinning of the temporalis muscles were present. His speech had
anasal quality, without dysarthria or tongue
weakness. The muscle weakness was rated as 4
on the Medical Research Council (MRC) scale
(which ranges from 0 [paralysis] to 5 [normal
strength]) and involved the neck flexors, finger
extensors, and intrinsic muscles of the hands;
strength was normal in the proximal
muscles of
12
the arms. Muscle tone was normal throughout.
After the patient firmly grasped the examiners
hand, he had difficulty releasing his grip quickly. Tapping of the finger extensor muscles on the
dorsal forearm and on the abductor pollicis in
the thenar eminence produced muscle contrac13 tions that relaxed slowly. There was slight weakness of the hip flexor muscles, normal strength
in the quadriceps and hamstrings, and weakness of the dorsiflexors (MRC score, 3+) and
plantar flexors (MRC score, 4) of the feet. The
patient was able to point to a target with his
fingertip, perform the heelkneeshin test, and
carry out rapid, rhythmic tapping movements
with his hands and feet. Vibration sense was
mildly decreased in his toes. He rose from a
chair without the use of his arms and had a
high-stepping gait. Deep-tendon reflexes were
hypoactive in the arms and absent at the ankles.
Rombergs sign was absent. Over the course of
the next few years, weakness progressed. When
the patient was 47 years of age, he had difficulty
lifting 5-gallon buckets at work; examination

reportedly revealed weakness of the neck flexors

(MRC score, 4), wrist and finger extensors
14
(MRC scores, 4), and finger flexors and distal
leg muscles (MRC scores, 3+) and normal
strength in the deltoid, biceps, triceps, hip flexors, quadriceps, and hamstrings. Deep-tendon
reflexes were absent.
15 apnea,
The patient also had obstructive sleep
sudden sensorineural hearing loss in the left ear
(which had begun when he was 45 years of age and
which was unresponsive to glucocorticoid therapy),
16
hypertension,
hyperlipidemia,
morbid obesity, cho17
lelithiasis
(which
had
required
cholecystectomy),
19
18
problems with ejaculation, noninsulin-dependent
type 2 diabetes mellitus, gastroesophageal reflux
disease, depression, vitamin B12 and vitamin D
deficiencies, and episodes of pneumonia that
were thought to be related to aspiration.
Medica20
tions that he was taking before this acute illness
included warfarin, pravastatin, pioglitazone, met
formin, ketoconazole, atenolol, citalopram, furosemide, pantoprazole, and bupropion (all daily),
as well as a vitamin B12 supplement (monthly)
and a vitamin D supplement (weekly). He reportedly had allergies to morphine, codeine, and
tramadol. He was married and lived with his
wife and children. He worked in a retail store. He
drank alcohol occasionally and did not smoke.
His father and one sister had an undefined neuromuscular problem. His father had had lung
cancer, and his mother uterine cancer; both died
when they were in their 70s. One of his children
had scoliosis
and a neuromuscular disorder
21
similar to that of the patient.
On examination, the patient was sedated and
paralyzed. Coarse breath sounds in the lungs
and active bowel sounds were present. There was
22
trace edema
of both legs, and the abdomen was
soft and nondistended. The pupils were sluggishly
reactive; oculocephalic and corneal reflexes were
absent. The arms and legs had minimal withdrawal and possible posturing. The blood levels
of magnesium and amylase
were normal; other
23
test results are shown in Table1. Sodium bicarbonate, insulin, glucose solution, and furosemide were administered, and urine output increased (450 mm3 of urine over a 2-hour period).
A cannula was placed for distal perfusion,
and
24
ECMO was continued.
25
Dr. Stacey Verzosa: A chest radiograph
(Fig.2)
showed bilateral diffuse consolidation that was
most confluent in the left lower lung, an enlarged cardiac silhouette, bilateral layering pleu-

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Table 1. Laboratory Data.*

Reference Range,
Adults

On Admission,
Other Hospital

Day of Transfer,
Other Hospital

On Admission,
This Hospital

Day 3,
This Hospital

Hematocrit (%)

41.053.0

40.4

31.6

32.3

28.5

Hemoglobin (g/dl)

13.517.5

13.4

450011,000

9900

150,000400,000

Variable

White-cell count (per mm3)

Platelet count (per mm3)

10.9

10.2

9300

11,700 (1 nucleated
red cell per 100
white cells)

28,500

195,000

132,000

142,000

61,000

Fibrinogen (mg/dl)

150400

Activated partial-thromboplastin time

(sec)

21.033.0

41.5

69.5

82.4

116.0

Prothrombin time (sec)

11.013.7

29.6

40.1

41.7

16.6

2.8

3.8

4.2

1.4

181

193

Prothrombin-time international
normalized ratio

579

Activated clotting time (sec)

90130

Sodium (mmol/liter)

135145

141

143

141

137

Potassium (mmol/liter)

3.44.8

2.9

5.5

5.8

3.6

Chloride (mmol/liter)

100108

106

110

104

103

Carbon dioxide (mmol/liter)

23.031.9

21

22

23.1

23.6

14

10

Plasma anion gap (mmol/liter)

Urea nitrogen (mg/dl)
Creatinine (mg/dl)
Estimated glomerular filtration rate
(ml/min/1.73 m2)
Glucose (mg/dl)

315
825

11

21

25

40

0.601.50

1.23

2.07

2.13

2.79

33

24

60
70110

398

88

106

130

Total

0.01.0

2.0

2.9

3.3

4.0

Direct

0.00.4

1.6

2.6

4.2

4.2

2.4

2.0

1.8

2.2

5.1

4.0

Bilirubin (mg/dl)

Protein (g/dl)
Total

6.08.3

Albumin

3.35.0

Globulin
Phosphorus (mg/dl)

2.7

2.7

2.34.1
2.64.5

3.9

Calcium (mg/dl)

8.510.5

7.4

Ionized calcium (mmol/liter)

1.141.30

7.8

7.9

8.2

1.06

1.18

Aspartate aminotransferase (U/liter)

1040

68

7626

455

Alanine aminotransferase (U/liter)

1055

44

2958

447

Alkaline phosphatase (U/liter)

45115

109

96

Lactate dehydrogenase (U/liter)

110210

363

8856

Lipase (U/liter)

1360

Creatine kinase (U/liter)

101

138

462

Troponin I (ng/ml)

0.33

4.08

Iron (g/dl)

45160

195

Total iron-binding capacity (g/dl)

230404

208

Ferritin (ng/ml)

30300

Lactate (mmol/liter)

0.52.2

1254

16,575
5.9

2.2

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Case Records of the Massachuset ts Gener al Hospital

Table 1. (Continued.)
Reference Range,
Adults

Variable

On Admission,
Other Hospital

B-type natriuretic peptide (pg/ml)

Day of Transfer,
Other Hospital

On Admission,
This Hospital

Day 3,
This Hospital

210

Blood gases
Source

Arterial

Arterial

Unspecified

Unspecified

Unspecified

1.00

1.00

1.00

Unspecified, 7.327.45;
Arterial, 7.357.45

7.15

7.34

7.30

7.41

Partial pressure of carbon dioxide

(mm Hg)

Unspecified, 3550;
Arterial, 3542

70

39

49

40

Partial pressure of oxygen

(mm Hg)

Unspecified, 4090;
Arterial, 80100

27

157

325

269

Bicarbonate (mmol/liter)

24.7

20.8

Base excess (mmol/liter)

4.0

3.2

-0.4

Oxygen saturation (%)

33

Fraction of inspired oxygen

pH

99

* To convert the values for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for creatinine to micromoles per liter,
multiply by 88.4. To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for bilirubin to micromoles
per liter, multiply by 17.1. To convert the values for phosphorus to millimoles per liter, multiply by 0.322. To convert the values for calcium
to millimoles per liter, multiply by 0.250. To convert the values for ionized calcium to milligrams per deciliter, divide by 0.250. To convert
the values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791. To convert the values for lactate to milligrams per
deciliter, divide by 0.1110.
Reference values are affected by many variables, including the patient population and the laboratory methods used. The ranges used at Massa
chusetts General Hospital are for adults who are not pregnant and do not have medical conditions that could affect the results. They may
therefore not be appropriate for all patients.
If the patient is black, multiply the value by 1.21.
The reference value from the other hospital is unavailable.

ral effusions, and the presence of medical devices, including a dual-chamber pacemaker and
ICD and an ECMO catheter.
26
Dr. Herrington: Electroencephalography
revealed alternation of low-amplitude bursts with
near-complete suppression of cerebral activity.
Continuous venovenous hemofiltration was begun, without improvement in neurologic function. Overnight, multiple units of red cells and
fresh-frozen plasma were transfused, and albumin was administered. Heparin,
insulin, vaso27
pressin, and norepinephrine were administered.
Results of a cosyntropin stimulation test were
normal. On the second day, computed tomography of the head revealed no evidence of hemorrhage or mass lesions.
28
Dr. Zilinski: Repeat transthoracic echocardiography revealed severe diffuse left ventricular hypokinesis, with regional variation and a left
ventricular ejection fraction of 13% (Fig.1D, 1E,
and 1F; and Videos 3 and 4).
Dr. Herrington: Fentanyl and midazolam were
discontinued, and hydrocortisone was administered, without improvement in the patients level
of consciousness. Portable electroencephalogra-

Figure 2. Chest Radiograph.

A chest radiograph shows an enlarged cardiac silhou
ette. There is bilateral diffuse consolidation that is
most confluent in the left lower lung (arrow), a finding
that is consistent with pulmonary edema and super
imposed aspiration. A dual-chamber pacemaker and
implantable cardioverterdefibrillator (ICD), an ECMO
catheter (arrowhead), a SwanGanz catheter in the
right pulmonary artery, a catheter in the left internal
jugular vein, an endotracheal tube, and a nasogastric
tube are in place.

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phy revealed generalized slowing with near-total

suppression of cerebral activity and without evidence of epileptiform abnormalities. Additional
laboratory test results are shown in Table1. On
the fifth hospital day, in consultation with the
patients family, mechanical respiratory support
was withdrawn and comfort measures were instituted; shortly thereafter, the patient died.
An autopsy was performed.

Differ en t i a l Di agnosis
Dr. Thurman M. Wheeler: In summary, this 50-yearold man had a 15-year history of progressive
distal weakness, delayed relaxation of muscle,
and cardiac arrhythmias.
I will review his pre29
sentation as a timeline and discuss possible
causes in view of what was known about his
course as it unfolded.
35 to 43 Years of Age

When the patient was between 35 and 43 years

of age, progressive weakness in his hands developed, followed by difficulty grasping and releasing objects, walking (with occasional stumbling),
and climbing stairs and ladders. Evaluation for
multiple episodes of lightheadedness led to a
diagnosis of paroxysmal
atrial fibrillation, and
30
warfarin therapy was initiated.
The progressive involvement of the hands and
apparent sparing of the arms are indicative of
distal weakness. The difficulty walking (with
stumbling) is nonspecific, and it is unclear
whether the weakness of the legs is proximal,
distal, or both. It is also unclear whether the
paroxysmal atrial fibrillation is related to the
process causing the patients weakness.
What are the causes of progressive distal
weakness in adults? It can be localized to the
motor neuron, peripheral nerve, or muscle.
Motor-neuron disorders include amyotrophic
lat31
eral sclerosis and spinal muscular atrophy.
Many
32
types of peripheral neuropathies
can cause distal
33
weakness. Primary muscle disorders typically
feature proximal weakness that begins earlier
and is more severe than distal weakness. However, several muscular dystrophies or inherited
or acquired myopathies can be manifested by
progressive distal weakness.
In this patient, electromyography revealed
brief-duration, low-amplitude, polyphasic motorunit potentials. This pattern can be seen in severe denervation, when axons are entering a phase
1256

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of regeneration and motor-unit potentials are

nascent, but it is more typical of a chronic myopathy. The progression of weakness that had occurred for several years before the electromyographic examination and the absence of
compelling evidence of severe denervation suggest that a myopathy is a more likely diagnosis in
this patient than is motor-neuron disease or peripheral neuropathy.
44 Years of Age

When the patient was 44 years of age, a detailed

neurologic examination revealed severe distal
weakness that involved the limbs and some
muscles of the face, head, and neck. Results of a
sensory examination were mostly normal, thus
confirming a motor process. The patient had difficulty releasing his grip quickly, and tapping of
the muscles of the forearm or thenar eminence
produced muscle contractions that faded slowly;
these findings suggest abnormal muscle activity
and are important clues to the diagnosis. At this
time, the patient reported that he had type 2 diabetes mellitus and that his father, sister, and one
of his children had a similar neuromuscular
disorder; this family history is suggestive of an
autosomal dominant inheritance pattern.
What causes abnormal muscle activity? Disorders of the central nervous system, motor nerve,
axon terminal, or muscle all may cause muscle
stiffening. The description of abnormal muscle
activity in this case is classic for myotonia, which
refers to delayed muscle relaxation due to repetitive action potentials. Voluntary activity, percussion, or insertion of an electromyography
needle may induce myotonia.
A few disorders feature prominent clinical
myotonia. In myotonic dystrophy and myotonia
congenita, myotonia is caused by dysfunction of
the muscle chloride channel. In paramyotonia
congenita and hyperkalemic periodic paralysis,
myotonia results from dysfunction of the muscle
sodium channel. Myotonic dystrophy is 10 times
as common as any of these other disorders.1 The
patient was taking pravastatin and furosemide,
which have been associated with experimental,
electrical, or clinical myotonia and may have
exacerbated his symptoms.2-4
The only disorder associated with prominent
clinical myotonia and progressive distal weakness is myotonic dystrophy.1 Myotonic dystrophy
is commonly associated with cardiac-conduction
defects and arrhythmias, features that are seen

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Case Records of the Massachuset ts Gener al Hospital

in this patient. These features, in addition to the

family history that is suggestive of an autosomal
dominant inheritance pattern, would provide a
unifying diagnosis in this case. Genetic testing
is indicated to confirm the diagnosis.
Late 40s and 50 Years of Age

When the patient was in his late 40s, a diagnosis

of nonischemic cardiomyopathy was made, and a
dual-chamber pacemaker and ICD was implanted.
The left ventricular ejection fraction was 40%.
When the patient was 50 years of age, he had
a cardiac arrest; ventricular fibrillation with pulseless electrical activity lasted for 25 minutes. Atrial
fibrillation was restored, but he had persistent
34
hypotension; vasopressors
and ECMO were administered. In the ICU, he had poor neurologic
function despite discontinuation of sedative
medications. The absence of corneal and oculocephalic reflexes, the presence of minimal withdrawal and possible posturing in response to
pain in the arms and legs, and the evidence of
generalized slowing with near-total suppression
of cerebral activity on electroencephalography
35
were all suggestive of anoxic encephalopathy.
In summary, the combination of myotonia,
progressive distal weakness, wasting of the temporalis muscles, muscle weakness involving the
face and neck, cardiac arrhythmias, abnormal
findings on electromyography, and family history is suggestive of myotonic dystrophy.
Myotonic Dystrophy

This patient most likely has myotonic dystrophy,

which is the most common muscular dystrophy
in adults and the most prevalent overall, with an
incidence of approximately 1 per 7000 to 8000 persons. It is associated with an autosomal dominant inheritance pattern, which is consistent with
this patients family history. He could have either
myotonic dystrophy type 1 or myotonic dystrophy
type 2. Myotonic dystrophy type 1 is caused by an
expansion of CTG repeats in the dystrophia
myotonica protein kinase (DMPK) gene.5 Myotonic dystrophy type 2 is caused by an expansion
of CCTG repeats in the zinc finger protein 9 (ZNF9)
gene (now known as the CCHC-type zinc finger,
nucleic acid binding protein [CNBP] gene).6 Although many clinical features of these subtypes
overlap, distal weakness (which was seen in this
patient) predominates in myotonic dystrophy
type 1, whereas proximal weakness predominates
in myotonic dystrophy type 2. Cardiac involvement

(which was also seen in this patient) is common

in myotonic dystrophy type 1 and can result in
asymptomatic electrocardiographic abnormalities,
36
progressive heart block, atrial tachyarrhythmias,
ventricular tachyarrhythmias,
nonischemic
car36
diomyopathy, and sudden death.7 On the basis of
this patients clinical presentation, I would predict that the diagnostic test was genetic analysis
and that this test confirmed the diagnosis of
myotonic dystrophy type 1 through the identification of an expansion of CTG repeats.
Although there is no current therapy for this
patient or his children that would alter the disease course, establishing the diagnosis is key to
helping anticipate, identify, and treat coexisting
conditions. For example, yearly electrocardiographic examinations are recommended to identify those who may benefit from pacemaker and
ICD placement, which was performed in this
patient. However, it is unknown whether such
preventive measures reduce the mortality associated with myotonic dystrophy type 1.7 This patient may have benefited from mexiletine treatment, but its use for myotonic dystrophy type 1
is controversial because of concerns about potential proarrhythmic effects on the heart.8,9 Therapies targeted at the genetic defect are also a
possibility. This patients symptoms result from
expression of an expansion of CUG repeats in
DMPK messenger RNA (mRNA) that causes gainof-function toxic effects.10 In clinically affected
tissues, RNA from the mutant DMPK gene interacts with nuclear proteins to induce misregulated alternative splicing of pre-mRNA in several
dozen genes.11 Therapeutic approaches designed
to reduce the toxic effects of mutant DMPK RNA
are in development, but none have reached clinical application at this time.12 If the treatments are
successful, this patients affected family members
may benefit. Going forward, genetic counseling
will be important for this patients family.

Dr . Thur m a n M. W heel ers

Di agnosis
Adult-onset myotonic dystrophy type 1.

Di agnos t ic Te s t ing
a nd M a nagemen t
Neurologic Evaluation and Management

Dr. David A. Chad: I first saw this patient at the

Muscular Dystrophy Association (MDA) clinic at

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University of Massachusetts Memorial Medical

Center when he was 44 years of age. At that
time, he had moderately severe weakness, a gait
disorder, excessive daytime somnolence, heightened sensitivity to anesthetic agents after surgery for fracture repair (i.e., slow recovery from
37
anesthesia), cardiac involvement, dysphagia,
aspiration, and diaphragmatic weakness; one of his
children was also affected by muscle weakness.
Diagnostic testing included electromyography,
which revealed evidence of myotonia that was
characterized by repetitive muscle-fiber action
potentials that waxed and waned in frequency
and amplitude and produced a sound when amplified that was reminiscent of a revving motorcycle engine. The combination of weakness,
multisystem complications, clinical and electromyographic evidence of myotonia, and an autosomal dominant inheritance pattern made a
compelling case for a diagnosis of myotonic
dystrophy type 1.
Before the patients visit to the MDA clinic,
genetic testing for suspected myotonic dystrophy
type 1 was performed. As Dr. Wheeler predicted,
the testing showed an expansion of the unstable
CTG repeats in the untranslated region of the
DMPK gene, at chromosome 19q13.3. There are
normally 5 to 34 CTG repeats at this locus, but
patients with myotonic dystrophy type 1 have hundreds to thousands of CTG repeats. This patient
had 306 CTG repeats, thus confirming the suspected diagnosis of myotonic dystrophy type 1.13
Persons with 35 to 49 CTG repeats are asymptomatic, but the number of repeats may be
expanded in the next generation and cause a
disease phenotype.13 Persons with 50 to 150 CTG
repeats often have mild disease (characterized
by myotonia and cataracts), an age of onset of
20 to 70 years, and a normal or moderately reduced life expectancy. Those with 150 to 1000
CTG repeats, such as this patient, typically have
moderate or severe disease (characterized by weakness, myotonia, cataracts, and multisystemic
involvement), an age of onset of 12 to 30 years,
and a reduced life expectancy. Those with more
than 1000 CTG repeats have the most severe
disease, which is congenital and characterized
by hypotonia, contractures, feeding difficulties,
respiratory insufficiency, and delayed motor and
mental development. However, it is important to
note that there is considerable variation in the
correlation between the number of repeats and
disease severity, and thus attempts to predict
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disease severity on the basis of the number of

repeats may not be particularly helpful.14
A clinical phenomenon that is more characteristic of myotonic dystrophy type 1 than of
myotonic dystrophy type 2 is anticipation, which
is defined as the lowering of age of onset, worsening of disease severity, or both in successive
generations.14 The biologic basis for anticipation
is the intergenerational expansion of the unstable CTG repeats, which is more likely to occur
in maternal transmissions than in paternal transmissions. The earlier onset of symptoms in the
patients child than in the patient may be explained by anticipation.
In this case, we recommended continued cardiac surveillance, assessment for anklefoot
orthosis (to mitigate foot drop), a sleep study to
evaluate for sleep apnea, and vocational counseling to help in his desire (and the medical necessity) for a job change. At a follow-up visit to the
MDA clinic 1 year later, the patient reported
hearing loss (an occasional complication of myo38
tonic dystrophy type 1 that resembles presbycusis).15 He also reported that he had been feeling
more refreshed after sleep since beginning treatment with continuous positive airway pressure
for sleep apnea and that he had found employment in which he no longer needed to hold a
paintbrush or climb a ladder.
Management of Cardiogenic Shock

Dr. Joshua N. Baker: This patient presented to another hospital with profound shock, with pulmonary edema and possible aspiration pneumonia.
Venoarterial ECMO, which is typically used for
the treatment of cardiogenic shock, was quickly
administered to provide biventricular support,
oxygenation, and carbon dioxide removal. The
evidence for its effectiveness in cardiogenic shock
varies widely, depending on the study and the
cause of the cardiogenic shock; associated survival rates range from 20% to 80%.16-21
At this hospital in collaboration with specialists in heart failure, neurology, medical ethics,
and palliative care we have determined that
the absolute contraindications to the use of ECMO
for the treatment of cardiogenic shock are neurologic injury from which recovery is deemed unlikely, active or uncontrolled malignant tumors,
an age older than 80 years, and any other major
medical problem that makes eventual recovery
impossible. In this case, it was initially thought
that neurologic recovery would be possible.

n engl j med 373;13nejm.org September 24, 2015

Case Records of the Massachuset ts Gener al Hospital

Cerebral and coronary malperfusion can be a

major complication of peripheral femoral venoarterial ECMO. Through this process, venous return from the right atrium is captured by a cannula in the femoral vein, and then oxygen-rich
blood is delivered to the central arterial bed
through a cannula in the femoral artery; both
the left and the right ventricles are unloaded.
However, if gas exchange in the lungs is poor
and the blood flow from the heart is pulsatile,
deoxygenated blood from the left side of the
heart can flow into the coronary arteries and
cerebral circulation. It is thus possible to have
seemingly adequate flow during venoarterial
ECMO and still generate severe myocardial and
39
cerebral ischemia.
Measurement of the partial
pressure of oxygen (Po2) in the right radial artery
is helpful in monitoring for this possible complication. If the right radial arterial Po2 is low, it
may be necessary to change the ventilator settings, insert additional cannulas for maximal
venous drainage, direct venting of the left atrium
or left ventricle, or perform a combination of
these tasks.
Unfortunately, this patient had pulsatile flow
from the heart, despite receiving ECMO, for at
least 24 hours before he was transferred to this
hospital. On arrival, it became clear to us that he
had hypoxic
cerebral damage.
40

Pathol o gic a l Discussion

Dr. Daniel A Mordes: An autopsy was performed,
and specimens of multiple muscles were obtained
for pathological examination. A frozen section
of the right deltoid revealed marked variation in
fiber size, with an increased number of internalized nuclei (Fig.3A). An enzymatic stain for
ATPase at pH 4.3, which stains type I fibers a
dark color and type II fibers a light color, revealed that the atrophic fibers were predominantly type I (Fig.3B). A stain for ATPase at pH
9.4, which stains type I fibers a light color and
type II fibers a dark color, had similar results.
Grouping by fiber type, which is typically associated with neurogenic processes, was absent. The
intercostal muscles had features that were similar to those of the deltoid, although they were
less pronounced. The right tibialis anterior muscle had evidence of end-stage muscle atrophy,
with replacement of most of the muscle fibers
with fatty tissue and fibrosis. Scattered, rounded,
atrophic fibers, often with internalized nuclei,

were present in a background of dense collagen

(Fig.3C). Electron microscopy was performed,
but ringed fibers (or ringbinden), which are
often seen in patients with myotonic dystrophy
type 1, were not present. Overall, these muscles
had severe myopathic changes and atrophy of
predominantly type I fibers.
These histopathological features, taken together with the clinical features of progressive
weakness and myotonia, are diagnostic of myotonic dystrophy type 1. In addition to the changes in the skeletal muscle, dilated cardiomyopathy
(Fig.3D), hemorrhagic diffuse alveolar damage
in the lungs, and evidence of ischemic injury in
many organs, including the liver and brain, were
present. Atrophy and fibrosis of the cardiacconduction systems have been associated with
myotonic dystrophy,22 but in this case, there was
no myocardial fibrosis; there was nonspecific
hypertrophy of cardiomyocytes. The cause of death
was myotonic dystrophy type 1, with cardiomyopathy, cardiac arrest, and subsequent diffuse
alveolar damage and generalized ischemia.
Dr. Nancy Lee Harris (Pathology): Are there
questions for any of our discussants?
Dr. Thomas N. Byrne (Neurology): Do some patients with this disease present to a cardiology
clinic with cardiac manifestations before they
present with muscular manifestations? Should
cardiologists consider this disorder in the differential diagnosis for cardiac arrhythmias and
cardiomyopathy?
Dr. Wheeler: Yes, and I would urge cardiologists to look for evidence of weakness that could
be related to a neuromuscular disorder in such
patients, especially since there are some preventive measures for the cardiac problems. That said,
it is unclear whether placement of a pacemaker
and ICD reduces mortality, since the most common cause of death associated with this disorder
is respiratory failure due to weakness of the
muscles of respiration.
A Physician: In my clinic, we see wasting of the
muscles. Does myotonia cause atrophy of muscle
cells?
Dr. Wheeler: The myotonic discharges in myotonic dystrophy are caused by dysfunction of a
chloride channel protein that results from misregulated alternative splicing of the chloride
channel mRNA. The expansion of CUG repeats
in mutant DMPK mRNA causes missplicing of
pre-mRNA from at least several dozen other
genes besides the chloride channel. The mecha-

n engl j med 373;13nejm.org September 24, 2015

1259

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n e w e ng l a n d j o u r na l

of

m e dic i n e

Figure 3. Muscle Specimens Obtained at Autopsy.

A hematoxylin and eosin stain of a section of the right deltoid (Panel A) shows marked variation in fiber size and
frequent fibers with internalized nuclei (arrows), features indicative of a myopathic process. An enzymatic stain of
the right deltoid for ATPase at pH 4.3 (Panel B), which stains type I fibers a dark color and type II fibers a light col
or, shows frequent atrophic type I fibers and also highlights variation in fiber size. A hematoxylin and eosin stain of
the right tibialis anterior muscle (Panel C) shows endstage muscle atrophy, with extensive replacement of muscle
by fatty tissue and fibrosis. A gross photograph of a longitudinal section of the heart (Panel D) shows dilated cardio
myopathy, with severe dilatation of all four chambers. An ICD lead is present.

nism involves the sequestration of splicing regulator proteins in the muscleblind-like (MBNL)
family through the expansion of CUG repeats,
resulting in formation of nuclear inclusions and
loss of MBNL activity. However, except for the
effects of the dysfunctional chloride channel
protein, the downstream effects of most of the
splice variants associated with myotonic dystrophy type 1 are unknown. Insulin resistance,
which is common in patients with myotonic
dystrophy type 1 and was present in this patient,
may be related to inappropriate splicing of the
insulin-receptor transcript in muscle. Muscle
wasting may result from one of many splice variants acting alone or in combination with several
others, or it could occur independently of splicing. In addition to muscle, motor neurons in
1260

n engl j med 373;13

patients with myotonic dystrophy type 1 also

have nuclear inclusions, suggesting that dysfunction of nervemuscle communication may contribute to muscle weakness and wasting.23 The
cause of the muscle wasting is unknown, but it
is thought to be unrelated to myotonia itself.
A Physician: What is the time course for the
presentation of myotonia versus weakness?
Dr. Wheeler: The time course is highly variable.
Myotonia is the symptom that most commonly
leads to recognition of myotonic dystrophy type
1 and is usually worst in the weakest muscles, at
least initially. As the muscle wasting progresses
and becomes severe, the clinical myotonia tends
to go away. This patient had clinical myotonia in
his hands, which were the weakest muscles on
examination, but electrophysiologically, he had

nejm.org

September 24, 2015

Case Records of the Massachuset ts Gener al Hospital

more diffuse myotonic discharges, including

A nat omic a l Di agnosis
some in muscles that were strong.
Dr. Nagagopal Venna (Neurology): How does Myotonic dystrophy type 1, with associated carmyotonic dystrophy affect the cardiac-conduc- diomyopathy, cardiac arrest, and generalized
tion system?
ischemia.
Dr. Wheeler: That is unknown. Some speculate
This case was presented at Neurology Grand Rounds.
No potential conflict of interest relevant to this article was
that missplicing of cardiac troponin T mRNA
reported.
may play a role. Myocardial fibrosis and degenDisclosure forms provided by the authors are available with
eration of the cardiac-conduction system also the full text of this article at NEJM.org.
We thank Dr. Thomas Byrne and members of the Neurology
have been described in patients with myotonic
CPC Committee for assistance with organizing the conference,
dystrophy type 1 and may be contributing and Dr. Matthew Frosch (Neuropathology) for assistance with
factors.
preparation of the pathological discussion.
References
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Ribonuclear foci at the neuromuscular
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Copyright 2015 Massachusetts Medical Society.

41. List four body

systems
for the
patient
theScase
study.
Lantern
Slides Udescribed
pdated: Complete
Power
PointinSlide
ets from
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42. What
theCPC,
mans
initial
symptoms
theJournal.
onsetRadiographic,
of the disease?
imageswere
from the
not only
those
published at
in the
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43. Based on the physician discussion, how did the patient contract the disease?

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44. How could they confirm the disease?

n engl j med 373;13nejm.org September 24, 2015

45. What was the patients diagnosis?

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