The n e w e ng l a n d j o u r na l of
Clinical Problem-Solving
From the Department of Medicine, Oki-
nawa Miyako Hospital (M.M., S.S.), and
the Department of Medicine, Okinawa
Chubu Hospital (M.K.) — both in Okinawa,
Japan; Harvard Kennedy School, Cam-
bridge, MA (M.M.); the Department of
Medicine, Johns Hopkins University
School of Medicine, Baltimore (R.M.);
and the Departments of Medicine and
Pediatrics, University of Minnesota Medi-
cal School, Minneapolis (A.P.J.O.). Ad-
dress reprint requests to Dr. Mukaigawara
at Harvard Kennedy School, 79 John F.
Kennedy St., Cambridge, MA 02138, or at
mitsuru_mukaigawara@hks.harvard.edu.
N Engl J Med 2020;383:970-5.
DOI: 10.1056/NEJMcps1910306
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m e dic i n e
Caren G. Solomon, M.D., M.P.H., Editor
A Curve Ball
Mitsuru Mukaigawara, M.D., Reza Manesh, M.D., Mitsuyo Kinjo, M.D., M.P.H.,
Shuichi Sugita, M.D., and Andrew P.J. Olson, M.D.​​
In this Journal feature, information about a real patient is presented in stages (boldface type) to an expert
clinician, who responds to the information by sharing relevant background and reasoning with the reader
(regular type). The authors’ commentary follows.
A 70-year-old man presented to the emergency department after an episode of altered
mental status. He had been in his usual state of good health until 2 days before pre-
sentation, when he began having increased urinary frequency and decreased urine
volume after he ate a rice cake made with potato. He did not have nausea, vomiting,
diarrhea, constipation, abdominal pain, back pain, fever, or chills. On the day of
presentation, the patient’s son had noticed him standing in the doorway of the bath-
room at his home, appearing disoriented. When his son spoke to him, the patient’s
eyes rolled back and he fell to the floor. His son did not observe any jerking move-
ments and noted that the patient appeared slightly dazed after the event. Emergency
medical services brought him to the emergency department, where he was alert and
oriented on arrival.
Altered mental status commonly results from metabolic derangements, infections,
structural causes (e.g., subdural hematoma), toxicants (synthetic agents), or toxins
(naturally occurring agents). However, encephalopathy that results from most of
these causes is not self-limited, as it was in this case. Possible explanations for the
patient’s transient disorientation and possible loss of consciousness include syn-
cope (e.g., post-micturition syncope), seizure, and hypoglycemia. The acute onset
of lower urinary tract symptoms in an elderly man suggests a urinary tract ob-
struction, most commonly as a complication of benign prostatic hyperplasia.
The absence of gastrointestinal symptoms makes foodborne illness a less likely
cause.
The patient had a history of benign prostatic hyperplasia, hypertension, and asthma.
His medications included atenolol, amlodipine, and enalapril. He did not take any
over-the-counter medications, supplements, or herbal medicines. He was employed
as a taxi driver on a remote island in southern Japan, where he also worked in sugar-
cane fields one or more times each week. His son noted that the sugarcane harvest
period had ended several weeks before presentation and reported that his father had
visited the sugarcane fields less frequently since then. The patient noted that several
stray cats occasionally came near his house but said that he had had no direct contact
with them. He reported no insect bites, consumption of raw food, or contact with
saltwater or freshwater sources. The patient did not smoke tobacco and drank alco-
hol occasionally. He had not traveled recently and had not had contact with persons
who were sick.
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The New England Journal of Medicine
 Clinical Problem-Solving

Decreased urine output in the context of benign vectorborne disease, caused by Orientia tsutsuga-
prostatic hyperplasia warrants prompt evaluation mushi, that is endemic in Japan — might be ini-
for urinary tract obstruction and associated kid- tially overlooked on examination. Facial flushing
ney injury. If the patient has acute renal injury, and edema, tachypnea, loose stool, and hypoten-
the use of an angiotensin-converting–enzyme sion prompt consideration of anaphylaxis, espe-
(ACE) inhibitor could have caused hyperkalemia, cially from an insect bite, given his work in
which could potentially have led to arrhythmia, sugarcane fields; the use of an ACE inhibitor and
which could, in turn, have caused his transient a beta-blocker may impair his physiologic re-
altered mental status and possible loss of con- sponse to hypotension. Anaphylaxis, however,
sciousness. Antihypertensive medications may would not explain the preceding increased uri-
cause orthostatic hypotension, although his al- nary frequency or limited urine output. Adrenal
tered consciousness was not clearly related to a crisis may also manifest with distributive hypo-
change in posture. Workers in sugarcane fields tension and confusion.
have a number of occupational hazards, including A toxidrome (a syndrome induced by a toxin
pesticide poisoning, vectorborne diseases, and or toxicant) should be considered, because his
lung cancer. occupation puts him at risk for accidental or
deliberate pesticide poisoning. A comprehensive
On physical examination, the patient’s tempera- occupational and environmental history is needed.
ture was 36.5°C, systolic blood pressure 55 mm Hg, Cholinergic toxicity from organophosphate in-
heart rate 100 beats per minute, respiratory rate secticides may result in confusion, hypotension,
28 breaths per minute, and oxygen saturation tachypnea, increased urinary frequency, and diar-
97% while he was breathing ambient air. His face rhea, although his tachycardia and the absence
was flushed and edematous. He had conjunctival of miosis and diaphoresis make this a less likely
injection in both eyes. His pupils were equal, nor- diagnosis. Anticholinergic toxicity may manifest
mal in size, and symmetrically responsive to light. with encephalopathy, blurred vision, flushing,
The mucous membranes were moist. He had mul- tachypnea, tachycardia, and urinary retention
tiple untreated dental caries. Cardiac examination but is typically associated with decreased bowel
showed no murmurs. The lungs were clear to sounds, mydriasis, and dry mucosa. Similarly,
auscultation. Rectal examination revealed an en- the presence of tachycardia and tachypnea and
larged, nontender prostate. Bowel sounds were the absence of miosis are inconsistent with opioid
normal. His arms and legs were warm and with- intoxication. His conjunctival injection suggests
out edema. There were several superficial abra- an allergic, infectious, or toxin- or toxicant-
sions, each 2 to 3 cm in length, on his right upper mediated process.
arm. No insect bites were present. He had one
greenish, loose bowel movement while in the The white-cell count was 20,500 per cubic milli-
emergency department. meter, with 81% neutrophils, 16% lymphocytes,
and 1% eosinophils. The hemoglobin level was
The patient’s altered mental status, tachycardia 12.5 g per deciliter, and the platelet count was
despite beta-blocker therapy, oliguria, tachypnea, 317,000 per cubic millimeter. The sodium level
and severe hypotension suggest shock, and urgent was 136 mmol per liter, potassium 5.2 mmol per
evaluation and treatment should be pursued. liter, chloride 101 mmol per liter, bicarbonate
Shock may result from cardiogenic, obstructive, 21 mmol per liter, blood urea nitrogen 55 mg per
hypovolemic, or distributive causes, or a com- deciliter (19.6 mmol per liter), and creatinine
bination of these. His warm extremities and 4.9 mg per deciliter (433 μmol per liter). The base-
flushed face point to vasodilatation and reduced line creatinine concentration was not known.
systemic vascular resistance, which suggest a The serum lactate level was 41.4 mg per deciliter
distributive cause of the severe hypotension. The (4.6 mmol per liter). The serum troponin level was
absence of fever does not rule out sepsis; poten- within normal limits. Urinalysis showed a spe-
tial sites of infection include the oral cavity, cific gravity of 1.019, as well as 5 white cells and
skin, and urinary tract. Blood cultures should be 20 red cells per high-power field, +3 protein, and
obtained. Eschar caused by scrub typhus — a no cellular casts. A urine toxicology screening test

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 The n e w e ng l a n d j o u r na l
was negative for benzodiazepines, cocaine, barbi-
turates, phencyclidine, amphetamines, metham-
phetamines, marijuana, morphine, and tricyclic
antidepressants.
An electrocardiogram showed sinus tachycar-
dia. Point-of-care transabdominal ultrasonogra-
phy in the emergency department did not show
bladder distention or hydronephrosis. Point-of-
care transthoracic echocardiography showed nor-
mal left ventricular ejection fraction without wall-
motion abnormality, valvulopathy, or pericardial
effusion. Computed tomography of the chest and
abdomen revealed ground-glass opacities in the
right upper lung field. No bladder distention, hydro-
nephrosis, or fat stranding was noted.
Central venous access was obtained through
catheterization of the femoral vein, and infusions
of normal saline and norepinephrine were initi-
ated. Blood and urine cultures were obtained.
The neutrophil-predominant leukocytosis sug-
gests infection or a stress response. The lactic
acidosis is consistent with hypoperfusion and
anaerobic metabolism. The primary consider-
ation remains septic shock with multiple sites of
possible infection, including the skin, oral cavity,
and lungs. The oliguric renal failure can proba-
bly be explained, at least in part, by renal hypo-
perfusion due to hypotension. The proteinuria
and hematuria prompt consideration of glomer-
ulonephritis; there are no red-cell casts, but their
absence does not rule out the diagnosis.
The patient’s normal echocardiogram further
supports a presumed diagnosis of distributive
(rather than cardiogenic or obstructive) shock.
Broad-spectrum antibiotics should be initiated
for possible sepsis. Nonseptic causes of distribu-
tive shock, such as anaphylaxis and adrenal cri-
sis, remain possible.
The opacities in the right lung field combined
with renal failure may suggest a pulmonary–­
renal syndrome, such as antiglomerular base-
ment membrane disease. However, the focal na-
ture of the opacities and the absence of cough,
dyspnea, and hemoptysis make pulmonary–renal
syndrome a less likely cause.
A lumbar puncture, which was performed in the
emergency department, showed 10 red cells,
1 monocyte, a glucose level of 140 mg per deciliter
(7.8 mmol per liter), and a protein level of 37 mg
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of m e dic i n e
per deciliter. Gram’s staining of cerebrospinal
fluid (CSF) showed no organisms. After the CSF
culture results were obtained, empirical antibiotic
treatment with cefotaxime, clindamycin, and
minocycline was initiated to cover likely causes,
including toxic shock syndrome and scrub typhus.
Treatment with norepinephrine was continued,
and 4 liters of lactated Ringer’s solution were ad-
ministered. The patient was admitted to the inten-
sive care unit. The next morning, vasopressin and
epinephrine were added, but hypotension per-
sisted, with systolic blood pressures ranging from
50 to 60 mm Hg. Hydrocortisone (100 mg) was
administered intravenously, but there was no ap-
parent improvement in blood pressure. A fever
(temperature, 39°C) developed in the patient.
Tachypnea was noted, and arterial blood gas
analysis revealed a pH of 7.20, partial pressure
of carbon dioxide 48 mm Hg, partial pressure of
oxygen 148 mm Hg, bicarbonate level 18.1 mmol
per liter, and lactate level 4.4 mg per deciliter
(0.49 mmol per liter). The patient’s trachea was
intubated for airway protection, and continuous
venovenous hemodialysis was initiated, given the
concern for an unidentified toxin or toxicant.
The cause of the patient’s hypotension remains
unclear. The normal echocardiogram, normal
troponin level, and absence of a history of vol-
ume loss make a primarily cardiogenic, obstruc-
tive, or hypovolemic cause of shock unlikely. The
normal serum sodium level and hydrocortisone-
refractory hypotension lessen the likelihood of
adrenal crisis, and the lack of response to epi-
nephrine argues against anaphylaxis. In addition
to blood cultures, serologic testing and poly-
merase-chain-reaction assays to evaluate for
rickettsial infections, including O. tsutsugamushi,
are indicated. Scrub typhus typically manifests
as an acute febrile illness, with or without a
rash, within 10 days after a person is bitten by
an infected chigger. A toxidrome, including anti-
cholinergic toxicity, remains a possibility, given
the patient’s employment in the sugarcane fields
and potential exposure to pesticides.
Acidemia contributes to refractory hypoten-
sion through impaired cardiac contractility, ar-
terial vasodilatation, and decreased response to
endogenous and pharmacologic catecholamines.
The mild anion gap is attributable to lactic aci-
dosis and renal failure.
 Clinical Problem-Solving
Figure 1. Desquamation.
Two days after admission, desquamation developed on
the patient’s palms (shown), face, axillae, and genital
area.
Continuous venovenous hemodialysis was main-
tained for 3 days, after which the patient’s hypo-
tension gradually resolved. Around the same
time, desquamation developed in the face, palms,
axillae, and genital area (Fig. 1). Blood, urine, and
CSF cultures remained negative. Serologic tests
for rickettsiosis were negative. Six days after ad-
mission, all vasopressors were discontinued, and
the patient’s trachea was extubated. Ten days after
admission, while he was in the general ward, he
began to have diffuse alopecia.
Whether the improvement in his condition rep-
resents the natural course of an unidentified
illness, removal of a toxin or a toxicant by con-
tinuous venovenous hemodialysis, or response to
antimicrobial therapy is unclear. Desquamation
may follow toxic shock syndrome caused by
Staphylococcus aureus or Streptococcus pyogenes. Sero-
logic tests for infections should be interpreted
with caution, because results may be falsely
negative early in the illness. Cultures are often
negative in cases of sepsis.
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Diffuse alopecia after a life-threatening ill-
ness is a clue to the diagnosis. Diffuse hair loss
is categorized on the basis of the phase of hair
cycle that is interrupted. The most common
cause is acute telogen effluvium owing to an
abrupt shift of hair follicles from anagen to telo-
gen phases, which occurs 2 to 3 months after an
inciting factor such as a major systemic illness
(including toxic shock syndrome), initiation of a
medication, or nutritional deficiency. The pa-
tient’s rapid hair loss is consistent with anagen
effluvium, which typically results within 2 weeks
after an insult to the hair follicle in the anagen
phase without transition of hair follicles to the
telogen phase; the most common culprits are
chemotherapeutic agents, but an unrecognized
toxin or toxicant could have the same effect.
I suspect a toxidrome, especially given the
patient’s potential exposure to pesticides as a
sugarcane worker. Toxic causes of anagen efflu-
vium include heavy metal (e.g., thallium) and
boric acid poisoning. Boric acid is used in pes-
ticides, and acute intoxication manifests with
nausea, vomiting, blue-green diarrhea, diffuse
erythematous rash, seizure, coma, acute renal
failure, and circulatory collapse. Many of these
features match the salient findings of the pa-
tient’s presentation.
While treating the patient empirically for toxic
shock syndrome, the medical team continued to
ask the patient and his family about any potential
toxic exposures, including ingestion of wild
mushrooms and plants, but none were reported.
However, his family was concerned about the rice
cake he ate before admission, because his symp-
toms started after he ate it. The patient confirmed
that he ate one rice cake, approximately 10 cm in
diameter, that had a bitter flavor. About 3 weeks
after admission, the patient’s family told the med-
ical team that the purported rice cake was poten-
tially a pesticide ball made of boric acid and
mashed potato, used to kill cockroaches. Every
year, local farmers make the cockroach-killing
balls and distribute them to the neighborhood.
That year, distribution of the pesticide balls had
coincided with a regional religious festival in
which residents bring home edible souvenirs. The
patient’s family speculated that he might have ac-
cidentally eaten a pesticide ball laden with boric
acid. The diagnosis of boric acid toxicity was con-
nejm.org September 3, 2020 973
 The n e w e ng l a n d j o u r na l
firmed by measurement of serum boric acid levels
in blood samples obtained before hemodialysis
(773 μg per milliliter) and after (11 μg per millili-
ter). The patient was discharged home 4 weeks
after admission, at which point his serum creati-
nine level had normalized (0.89 mg per deciliter
[78.7 μmol per liter]). Nine months later, I hap-
pened to ride in the patient’s taxi. The patient was
feeling well and was continuing to drive his taxi
and work on a farm.
C om men ta r y
The patient presented with refractory shock that
persisted despite the administration of fluids,
vasopressors, and antibiotics. Distributive shock
commonly results from a bacterial infection but
can also be associated with noninfectious causes.
Although the leading hypotheses in this case
were septic shock1 and toxic shock syndrome,
several features made a noninfectious cause
more likely. The patient did not have a response
to antimicrobial treatment, the cultures remained
sterile, there was no clear source of infection,
and the patient’s condition improved rapidly with
renal-replacement therapy. In addition, desqua-
mation in toxic shock syndrome typically devel-
ops 10 to 21 days after the onset of symptoms,2
whereas desquamation in this patient developed
only 3 days after admission. The occurrence of
diffuse alopecia within 2 weeks after the onset
of illness pointed toward toxin or toxicant expo-
sure, especially given the patient’s occupational
history. The medical team continued to investi-
gate this point, which led the patient and his
family to make the connection between inges-
tion of the rice cake and boric acid toxicity.
Boric acid is used in the manufacture of ce-
ramics, glass, and pesticides,3 as an antiseptic
for burns, and for treatment of vulvovaginal
candidiasis.4 Accidental ingestions have been
reported globally, most commonly in children.5
In a large retrospective series of cases from two
poison centers, the median age of affected pa-
tients was 2 years, and 80% of the cases were in
patients younger than 6 years of age.6 However,
13.5% of affected patients were adults.6 Adult
exposure may be accidental3 or intentional.7 The
fatal dose of boric acid in adults is approxi-
mately 15 to 20 grams.3 The fatal concentration
of boric acid in the blood is reported to be ap-
proximately 1000 μg per milliliter,8 although
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of m e dic i n e
some patients with higher blood concentrations
have survived.3
Patients with boric acid toxicity are often
asymptomatic but can present with gastrointes-
tinal,6 dermatologic,9 renal,7 and systemic mani-
festations, such as hypotension10 and metabolic
acidosis.7 In the right clinical context, bluish-
green vomitus or diarrhea has been reported to
be suggestive of boric acid toxicity, although
bluish-green vomitus can also occur in the con-
text of copper sulfate and paraquat toxicities.11
Skin manifestations include a diffuse erythema-
tous rash involving the axillae, inguinal areas,
and the face that occurs within 1 to 2 days after
exposure, followed by diffuse desquamation 2 to
3 days after the development of the rash.6 These
cutaneous features are classically described as a
“boiled lobster” appearance.12 Anagen effluvium
may also occur.13 Oliguric renal failure due to
acute tubular necrosis8 has been documented in
severe cases. No specific antidote is available,
and high-quality supportive care is necessary.3
Because of its low molecular weight, boric acid
can be removed effectively with hemodialysis.
One case report showed that the total body
clearance was as high as 3.5 liters per hour with
hemodialysis.14 Aggressive diuresis with furose-
mide is an alternative treatment option; in an-
other case report, the condition of a patient who
could not undergo hemodialysis improved with
diuresis.3
This case highlights that a toxic exposure
can masquerade as septic shock and calls atten-
tion to the dangerous practice of mixing poi-
son with food for pest control. It also under-
scores the importance of taking a detailed
environmental, dietary, and occupational his-
tory to avoid striking out when thrown a curve
ball. In this case, the clinical evidence support-
ing a toxic exposure resulted in the eventual
identification of the pesticide ball as the cause
of the patient’s illness.
No potential conflict of interest relevant to this article was
reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.
We thank Takeshi Kasama, M.Sc., from the Earth-Life Sci-
ence Institute at Tokyo Institute of Technology, for analyzing the
serum boric acid concentration; Hiromi Fujita, Ph.D., from Ma-
hara Institute of Medical Acarology, for analyzing serologic tests
for rickettsiosis; and Morito Ikeda, M.D., and Yusuke Yamanaka,
M.D., from the Department of Medicine, Okinawa Miyako Hos-
pital, and Kiyoshi Kinjo, M.D., Masashi Narita, M.D., and Izumi
Nakayama, M.D., from the Department of Medicine, Okinawa
Chubu Hospital, for their contributions.
 Clinical Problem-Solving

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