The n e w e ng l a n d j o u r na l of m e dic i n e

Case Records of the Massachusetts General Hospital

Founded by Richard C. Cabot

Eric S. Rosenberg, M.D., Editor
Virginia M. Pierce, M.D., David M. Dudzinski, M.D., Meridale V. Baggett, M.D.,
Dennis C. Sgroi, M.D., Jo‑Anne O. Shepard, M.D., Associate Editors
Alyssa Y. Castillo, M.D., Case Records Editorial Fellow
Emily K. McDonald, Sally H. Ebeling, Production Editors

Case 5-2019: A 48-Year-Old Woman

with Delusional Thinking and Paresthesia
of the Right Hand
Charlotte Hogan, M.D., Brent P. Little, M.D., Jonathan C.T. Carlson, M.D., Ph.D.,
Oliver Freudenreich, M.D., Ana Ivkovic, M.D., and Jason M. Baron, M.D.​​

Pr e sen tat ion of C a se

Dr. Cary S. Crall (Psychiatry): A 48-year-old woman presented to the emergency de- From the Departments of Psychiatry (C.H.,
partment of this hospital with tingling of the right hand. O.F., A.I.), Radiology (B.P.L.), Hematology
(J.C.T.C.), and Pathology (J.M.B.), Massa‑
One hour before presentation, the patient felt an acute “prickling and tingling” chusetts General Hospital, and the Depart‑
sensation diffusely on the right palm while she was reaching for a can of soda out ments of Psychiatry (C.H., O.F., A.I.), Ra‑
of a vending machine. The sensation did not radiate to other areas of the hand or diology (B.P.L.), Hematology (J.C.T.C.),
and Pathology (J.M.B.), Harvard Medical
the arm, and it was not associated with decreased range of motion, tenderness, or School — both in Boston.
joint pain. Although she presented to the emergency department 1 hour after the
N Engl J Med 2019;380:665-74.
onset of symptoms, the tingling resolved before the examination, which took place DOI: 10.1056/NEJMcpc1807495
approximately 80 minutes after presentation. The patient stated that she had re- Copyright © 2019 Massachusetts Medical Society.

cently traveled to Boston from New York City to visit museums, and she requested
“accommodations” from medical personnel because she did not have a place to stay.
On examination, the temperature was 36.9°C, the blood pressure 141/89 mm Hg,
the heart rate 88 beats per minute, the respiratory rate 16 breaths per minute, and the
oxygen saturation 99% while the patient was breathing ambient air. The weight
was 70.9 kg, the height 160 cm, and the body-mass index (the weight in kilograms
divided by the square of the height in meters) 27.7. The patient was described as
having a labile affect, with rapid and tangential speech. The results of the remain-
der of the physical examination, including tests of neurologic function and examina-
tion of the muscles in the right hand and arm, were normal. The patient was
discharged from the emergency department with a list of local shelters and hotels.
Five hours after discharge, the patient felt recurrent tingling on the right palm,
primarily along the radial-nerve distribution, and she again presented to the emer-
gency department of this hospital. She reported that she had been unable to find
a shelter and that she feared hotel staff would perform “unwanted sleep studies” or
“gas” her. The results of the physical examination had not changed from several
hours earlier. The patient was described as disheveled, unkempt, malodorous, and

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 The n e w e ng l a n d j o u r na l
oriented to person and time. Examination re-
vealed inconsistent thought processes and delu-
sions of persecution. Urine toxicology screening
was negative for amphetamines, barbiturates,
benzodiazepines, cannabinoids, cocaine, opiates,
and phencyclidine, and serum toxicology screen-
ing was negative for salicylates, acetaminophen,
ethanol, and tricyclic antidepressants. A urine test
for human chorionic gonadotropin was negative.
Laboratory test results are shown in Table 1.
Imaging studies were obtained.
Dr. Brent P. Little: A radiograph of the right
hand and wrist (Fig. 1) showed no acute frac-
ture, dislocation, or soft-tissue abnormality; the
joint spaces were preserved, and there were no
joint erosions. Computed tomography (CT) of
the head (Fig. 2), performed without the admin-
istration of intravenous contrast material, revealed
no evidence of intracranial hemorrhage, mass, or
acute territorial infarct.
Dr. Crall: On evaluation by a psychiatrist, the
patient incorrectly named the city and state as
“Massatution” and “Boston,” respectively. Mental-
status examination was notable for attentiveness
to the interviewer, recall of two of five objects
after 5 minutes, and the inability to subtract se-
rial sevens and to repeat phrases. The patient’s
score on the Montreal Cognitive Assessment was
21 (reference range, 26 to 30) on a scale of 0 to
30, with lower scores indicating greater cogni-
tive impairment. She maintained eye contact and
had no abnormal movements. Her speech was
characterized by malapropisms and mispronun-
ciations and was pressured. Her mood was de-
scribed as happy, with a congruent affect. Her
thought processes were described as tangential
and disorganized. The results of the neurologic
examination, including tests of cranial-nerve
function, strength, and sensation to light touch,
were normal.
The patient reported no history of medical
problems. She said that she had previously been
a “volunteer client” at a psychiatric hospital in
New York City but had not undergone psychiatric
treatments or hospitalizations. A review of sys-
tems was negative for physical trauma, anorexia,
weight loss, loss of energy, weakness, bleeding
(menstrual cycles had stopped during the past
year), headache, ataxia, dizziness, seizure, syn-
cope, pain, depression, anhedonia, expansive
mood, distractibility, anxiety, memory difficul-
ties, sleep disturbance, auditory and visual hallu-
cinations, suicidal ideation, and homicidal idea­
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of m e dic i n e
tion. She took no medications and had no known
allergies to medications.
The patient reported the following informa-
tion. She was born in the southeastern United
States and grew up in an orphanage. She had
skipped grades in elementary and high school
because of high intelligence and then had ob-
tained doctoral degrees in psychology from
“Northwestern International University in Den-
mark” and “Panworld University in China.” Six
years earlier, she had moved to New York City,
where she lived in a downtown hotel. She was
employed as a scientist to perform online re-
search and volunteered for New York City hospi-
tals and the U.S. Navy. She was unmarried and
had no children, and she had no family or friends
who could provide collateral information. She did
not use alcohol, tobacco, or illicit drugs. Her
family psychiatric and medical history was un-
known, since she was adopted. She had no his-
tory of legal problems.
Because of concern about the patient’s in-
ability to protect herself in a new environment,
given her impaired judgment and disorganized
thinking, an order that authorized temporary in-
voluntary hospitalization was implemented.1 The
patient was admitted to the inpatient psychiatry
unit. Results of urinalysis and the venous blood
pH were normal; laboratory test results are shown
in Table 1. Additional imaging studies were ob-
tained.
Dr. Little: A chest radiograph showed clear
lungs. Magnetic resonance imaging (MRI) of the
head (Fig. 2), performed without the administra-
tion of intravenous contrast material, revealed
mild mucosal thickening in the paranasal sinus
without acute intracranial abnormality. There was
no evidence of infarct, such as intracranial mass,
cerebral edema, or restricted diffusion, and there
was no evidence of white-matter disease or vol-
ume loss.
Dr. Crall: Laboratory test results that were ob-
tained on the third hospital day are shown in
Table 1. Results of additional diagnostic tests
were received.
Differ en t i a l Di agnosis
Dr. Charlotte Hogan: This 48-year-old woman, who
presented with paresthesia of the right hand,
had normal results on physical examination and
imaging studies but had clinically significant psy-
chotic symptoms, including disorganized thought
 Case Records of the Massachuset ts Gener al Hospital

Table 1. Laboratory Data.*

On Evaluation,
Reference Range, Emergency On Admission,
Variable Adults† Department Psychiatry Unit Hospital Day 3
Sodium (mmol/liter) 135–145 140
Potassium (mmol/liter) 3.4–5.0 3.3
Chloride (mmol/liter) 98–108 104
Carbon dioxide (mmol/liter) 23–32 25
Glucose (mg/dl) 70–110 88
Urea nitrogen (mg/dl) 8–25 12
Creatinine (mg/dl) 0.6–1.5 0.63
Calcium (mg/dl) 8.5–10.5 8.9
Alkaline phosphatase (U/liter) 30–100 97
Bilirubin (mg/dl)
Total 0–1.0 0.2
Direct 0–0.4 <0.2
Alanine aminotransferase (U/liter) 7–33 97
Aspartate aminotransferase (U/liter) 9–32 24
Protein (g/dl)
Total 6.0–8.3 6.7
Albumin 3.3–5.0 4.4
Globulin 1.9–4.1 2.3
Ammonia (μmol/liter) 12–48 50
Antitreponemal antibody Negative Negative
Creatine kinase (U/liter) 40–150 247
Erythrocyte sedimentation rate 0–20 12
(mm/hr)
Lactate (mmol/liter) 0.5–2.0 1.3
Lactate dehydrogenase (U/liter) 110–210 325
Phosphorus (mg/dl) 2.6–4.5 2.9
Prolactin (ng/ml) 0.1–23.3 41.2
Thyrotropin (μIU/ml) 0.4–5.0 1.28
Vitamin B1 (nmol/liter) 70–180 96
Hematocrit (%) 36.0–46.0 32.1
Hemoglobin (g/dl) 12.0–16.0 10.0
White-cell count (per mm3) 4500–11,000 3130
Differential count (%)
Neutrophils 40–70 33.2
Lymphocytes 22–44 39.3
Monocytes 4–11 13.1
Eosinophils 0–8 14.1
Basophils 0–3 0.3
Platelet count (per mm3) 150,000–400,000 326,000
Red-cell count (per mm3) 4,000,000– 3,390,000
5,900,000
Mean corpuscular volume (fl) 80–100 82.3
Red-cell distribution width (%) 11.5–14.5 20.4

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. 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 bilirubin to micromoles per liter, multiply by 17.1. To convert the values for ammonia to micro‑
grams per deciliter, divide by 0.5872. 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 Massachusetts General Hospital are for adults who are not pregnant and do not have medical condi‑
tions that could affect the results. They may therefore not be appropriate for all patients.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

A B

Figure 1. Radiographs of the Hand.

Frontal and lateral radiographs of the right hand (Panels A and B, respectively) show no fracture, dislocation, bone
lesion, or soft‑tissue abnormality. The bone alignment is normal, the joint spaces are preserved, and there are no
bony erosions. No radiopaque foreign body is visible.

processes, persecutory and grandiose delusions, Primary Psychosis

pressured speech, and labile affect. In addition,
she had poor performance on cognitive tests,
including tests of executive function, memory,
and repetition, but her cognitive findings must
be considered in the context of attentional im-
pairment, as shown by her inability to subtract
serial sevens. Finally, laboratory tests revealed
normocytic anemia and an elevated prolactin
level. Given her disorganized thinking and the
lack of collateral information, we are left with-
out definitive knowledge regarding the time
course of her illness and the veracity of her
own report of medical history. Therefore, the
diagnosis must be based on the results of the
cross-sectional examination, which yield a broad
differential diagnosis that includes possible
primary and secondary causes of her psychotic
symptoms.
Could this patient have a primary psychotic dis-
order? The diagnosis of schizophrenia relies on
the development of at least two characteristic
symptoms over a 6-month period, along with
associated functional impairment. This patient
had delusions and disorganized speech. Subtle
clues suggest that she may have a chronic psy-
chotic disorder; for example, her comment that
she had been a “volunteer client” at a psychiatric
hospital suggests a history of psychiatric treat-
ment, and the unexplained elevated prolactin
level may be related to previous treatment with
antipsychotic medications.
The patient’s grandiosity and pressured speech
suggest a manic episode, but the presence of
these two symptoms alone does not establish
the diagnosis of bipolar disorder. Not enough
information has been provided to allow us to

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 Case Records of the Massachuset ts Gener al Hospital

A B

C D

Figure 2. Imaging Studies of the Head.

CT of the head was performed. An axial image (Panel A) shows no mass, mass effect, or intracranial hemorrhage.
The gray–white junction is preserved. There is no evidence of ischemic infarct. MRI of the head was also performed.
An axial T2‑weighted image (Panel B) and an axial fluid‑attenuated inversion recovery image (Panel C) show no intra‑
cranial mass, mass effect, or intraparenchymal signal abnormality. The ventricles and sulci are normal in size and
have normal morphologic features. An axial diffusion‑weighted image (Panel D) shows no restricted diffusion, and
the absence of this finding argues against an acute infarct.

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 The n e w e ng l a n d j o u r na l of m e dic i n e

determine whether she had other characteristic Hallucinations are common, as are disorganized
features of bipolar disorder, such as racing thought processes. Although the patient had
thoughts, decreased need for sleep, increased goal- impaired attention, her psychotic symptoms and
directed activity, or a history of risky behaviors. her level of consciousness did not fluctuate, so
The combination of schizophrenia and a mood delirium is unlikely.
disorder, such as bipolar disorder, is called
schizoaffective disorder. Additional evaluation Infection
would be needed to assess whether the patient Infection of the brain can cause psychotic symp-
meets the criteria for a mood disorder and thus toms. However, the absence of fever, tachycardia,
schizoaffective disorder. Although some features leukocytosis, and abnormal findings on physical
of her presentation are highly suggestive of examination makes infection an unlikely cause
schizophrenia, this diagnosis alone does not of this patient’s altered mental status. Central
explain other important features, including the nervous system disease caused by syphilis is un-
hand tingling and anemia. likely, given the negative test for antitreponemal
antibody, although an examination of cerebro-
Secondary Psychosis spinal fluid would be needed to definitively rule
Substance Use out neurosyphilis. Testing for human immuno-
In addition to psychiatric disorders, a variety of deficiency virus (HIV) infection should also be
medical diseases initially manifest as psychosis. performed in this case.
The use of substances such as cocaine, amphet-
amines, and alcohol can precipitate an intoxica- Neurodegenerative Conditions
tion or withdrawal syndrome, which may lead to Disorders that are associated with dementia may
psychosis. In this case, however, urine and se- cause psychotic symptoms. Frontotemporal de-
rum toxicology screening tests were negative for mentia is characterized by irritability, poor im-
potential substances of abuse, and the results of pulse control, and social disinhibition, features
physical examination and the history were not that were not evident in this patient. Dementia
suggestive of a recent ingestion or a substance with Lewy bodies causes fluctuating cognitive
use disorder. and psychotic symptoms but also typically causes
parkinsonian features, which were not present
Endocrine and Metabolic Disorders in this patient. Finally, psychosis can occur in
Thyroid disorder and parathyroid disorder are patients with Huntington’s disease, but it would
endocrine abnormalities that can cause psycho- rarely develop before chorea.
sis, but these diagnoses are unlikely in this pa-
tient because of the normal thyrotropin level and Inflammatory Disorders
normal calcium level, respectively. The patient’s Systemic lupus erythematosus can cause psycho-
mildly elevated alanine aminotransferase level sis. However, this patient had only two clinical
could be suggestive of Wilson’s disease, but it is features that are suggestive of this diagnosis —
a rare disorder that is unlikely to develop at the a neurologic disorder and leukopenia — and
age of 48 years. In addition, the neuropsychiatric these features are neither sensitive nor specific.2
symptoms that are typical of Wilson’s disease On rare occasions, multiple sclerosis can cause
are depression and personality changes, rather psychosis, but this patient’s MRI study does not
than psychosis. Acute intermittent porphyria is show characteristic lesions. Finally, limbic en-
characterized by recurrent acute attacks of ab- cephalitis would be a consideration if the patient
dominal pain, peripheral neuropathy, and psy- were found to have subacute neuropsychiatric
chiatric symptoms. It is also a rare disorder and symptoms (occurring for <3 months) and at least
is unlikely in this patient, given that her only one additional characteristic feature (a new focal
physical symptom was paresthesia. neurologic finding, seizures, pleocytosis in cere-
brospinal fluid, or MRI findings suggestive of
Delirium encephalitis) and if alternative causes were ruled
Delirium is defined as acute, waxing and wan- out.3 Although we know the patient had a new
ing disturbances in attention and awareness that focal neurologic finding of paresthesia, we do not
are caused by an underlying medical condition. know whether her neuropsychiatric symptoms

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 Case Records of the Massachuset ts Gener al Hospital

were subacute and we have not ruled out more condition could independently explain the pa-
likely alternative causes. tient’s mental status, but neither would fully ex-
plain all the features of her presentation. A diag-
Neurologic Disorders nosis of schizophrenia would not explain the
On the basis of the results of CT and MRI of the paresthesia or anemia, and a diagnosis of vita-
head, we can rule out a space-occupying lesion min B12 deficiency may not explain the possible
and stroke as the cause of this patient’s psycho- history of psychiatric illness. It would not be
sis. In cases of unexplained neuropsychiatric unusual for a patient to have both schizophrenia
symptoms, epilepsy is a consideration. Seizure and vitamin B12 deficiency; this combination of
activity can cause an elevated prolactin level im- diagnoses is common in patients with severe
mediately after the event. Three forms of psycho- mental illness and can result in exacerbated psy-
sis are associated with epilepsy: ictal psychosis, chotic symptoms.8 To establish this diagnosis,
postictal psychosis, and interictal psychosis. In- I would recommend obtaining the vitamin B12
terictal psychosis can result in chronic psychotic level, as well as plasma homocysteine and serum
symptoms if the patient has a history of uncon- methylmalonic acid levels.
trolled seizures, particularly in the context of
epilepsy involving the temporal lobe.4 This pa- Dr . Ch a r l o t te Ho g a n’s
tient did not have any other characteristic fea- Di agnose s
tures of temporal-lobe seizures, such as an epigas-
tric “rising” sensation, déjà vu, an aura of taste or Vitamin B12 (cobalamin) deficiency.
smell, stereotyped movements, or postictal con- Probable schizophrenia.
fusion. Therefore, seizures are an unlikely diag-
nosis in this case, although it would be reason- Di agnos t ic Te s t ing
able to obtain an electroencephalogram after
other, more likely diagnoses have been ruled out. Dr. Jason M. Baron: Laboratory testing revealed a
low plasma vitamin B12 level (67 pg per milliliter;
Nutritional Deficiencies reference range, >231). There was marked eleva-
Many vitamin deficiency syndromes are associ- tion in the plasma homocysteine level (93.0 μmol
ated with neuropsychiatric manifestations. How- per liter; reference range, 0.0 to 14.2) and the
ever, vitamin B12 (cobalamin) deficiency is most serum methylmalonic acid level (13.58 μmol per
likely to cause the symptoms that were seen in liter; reference range, ≤0.40). The serum folate
this patient. Vitamin B12 deficiency can cause a level was normal.
range of neuropsychiatric symptoms, including Vitamin B12 and folate are required for metabo-
psychosis, personality changes, and affective lism of homocysteine to methionine, whereas
symptoms, in addition to cognitive impairment.5 vitamin B12 but not folate is required for metabo-
It commonly causes paresthesia. Furthermore, lism of methylmalonyl–coenzyme A (methyl-
vitamin B12 deficiency typically causes macro- malonic acid linked to coenzyme A) to succinyl–
cytic anemia. This patient had normocytic ane- coenzyme A. Thus, isolated folate deficiency can
mia, which could be explained by concomitant produce an elevation in the homocysteine level
iron deficiency. Her elevated red-cell distribution but not in the methylmalonic acid level.9 In con-
width, elevated lactate dehydrogenase level, and trast, isolated vitamin B12 deficiency can produce
mild leukopenia are consistent with pernicious an elevation in both the methylmalonic acid
anemia.6 Alternatively, the patient could have level and the homocysteine level,9 the pattern
vitamin B12 deficiency along with anemia that is that was seen in this patient. Taken together,
entirely unrelated, since it is common for pa- this patient’s vitamin B12, methylmalonic acid,
tients with neuropsychiatric manifestations of and homocysteine levels are consistent with vita-
vitamin B12 deficiency to have a normal hemato- min B12 deficiency.
crit and mean corpuscular volume.7 Serologic testing was positive for intrinsic-
factor antibodies, a finding that supports the
Summary diagnosis of pernicious anemia as the cause of
The two most likely diagnoses in this patient are vitamin B12 deficiency. The presence of intrinsic-
vitamin B12 deficiency and schizophrenia. Each factor antibodies is highly specific but some-

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 The n e w e ng l a n d j o u r na l
what insensitive for pernicious anemia.10,11 In
contrast, the presence of parietal-cell antibodies
is highly sensitive but nonspecific for this diag-
nosis.10,11 Patients with pernicious anemia some-
times have elevated indirect bilirubin and lactate
dehydrogenase levels due to hemolysis12; this
patient had an elevated lactate dehydrogenase
level and a normal indirect bilirubin level.
The patient had mild anemia with a low-
normal mean corpuscular volume. Vitamin B12
deficiency classically leads to macrocytic anemia
with an elevated mean corpuscular volume.9 Iron
studies revealed a mildly elevated total iron-
binding capacity (480 μg per deciliter [86 μmol
per liter]; reference range, 230 to 404 μg per
deciliter [41 to 72 μmol per liter]) and a low-
normal ferritin level (16 μg per liter; reference
range, 10 to 200), findings that suggest a mild
concurrent iron deficiency. It is possible that the
iron deficiency, which classically leads to micro-
cytic anemia, was countering the effect of the
vitamin B12 deficiency on red-cell volume, there-
by causing the low-normal mean corpuscular
volume. All these laboratory findings, particu-
larly when they are interpreted in the context
of the clinical symptoms, support the diagnosis of
pernicious anemia.
Discussion of M a nagemen t
Hematology Management
Dr. Jonathan C.T. Carlson: The characteristic hemato-
logic and neuropsychiatric effects of vitamin B12
deficiency can develop independently, creating a
need for clinical and diagnostic vigilance. In one
study, among patients who presented with neu-
ropsychiatric symptoms due to vitamin B12 de-
ficiency, 24% had a normal hematocrit and 18%
had a normal mean corpuscular volume at pre-
sentation.13 However, less than 2% of the pa-
tients had a mean corpuscular volume of 84 fl or
less and nearly all the patients had a decrease in
the mean corpuscular volume with vitamin B12
repletion and had morphologic abnormalities on
a peripheral-blood smear; these findings suggest
that a low vitamin B12 level may have a physio-
logical effect on hematopoiesis even when the
complete blood count is relatively normal.
This patient’s elevated red-cell distribution
width suggests that a substantial fraction of the
red cells were markedly microcytic, with a red-
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of m e dic i n e
cell volume of 64 fl or less. Although such a
degree of microcytosis can be seen with severe
iron deficiency, the patient’s iron levels were
borderline and her anemia was relatively mild.
As such, I speculate that she may have had an
underlying hemoglobinopathy that contributed
to the low mean corpuscular volume and par-
tially obscured the diagnosis of B12 deficiency.
Treatment of pernicious anemia consists of a
repletion phase with weekly parenteral doses of
vitamin B12 (cyanocobalamin or hydroxocobala-
min), followed by a maintenance phase with
monthly intramuscular doses that are continued
indefinitely. Parenteral administration bypasses
the impairment of oral vitamin B12 absorption
that is a hallmark of pernicious anemia. For pa-
tients with acute neuropsychiatric impairment,
an intensive regimen (intramuscular doses of
1000 μg every 24 to 48 hours until symptoms
resolve or plateau) has been suggested.14 The
biochemical effect of repletion on methylmalo-
nic acid and homocysteine levels and on hema-
topoietic effects (i.e., a rise in the reticulocyte
count) should be evident within 5 to 10 days.
Difficulties of Establishing a Diagnosis
in a Patient with Severe Mental Illness
Dr. Oliver Freudenreich: This case involving a patient
with presumed severe mental illness shows a
common clinical dilemma: Are reported somatic
and psychiatric symptoms attributable to a psy-
chiatric cause, or are they due to an undiagnosed
medical disease? In patients with severe mental
illness, several factors may combine to make the
diagnosis of a medical disease difficult. The pa-
tient may provide an unreliable history because
of paranoia, disorganized thinking, or negative
or cognitive symptoms. There is often a lack of
collateral information. The problem is com-
pounded by a fragmented health care system, in
which the emergency department is used as a
point of entry. In addition, some doctors may
not have experience in treating patients with
severe mental illness and may make incorrect
assumptions about the patients. “Diagnostic
overshadowing” is a well-recognized phenome-
non in which somatic symptoms are preferentially
attributed to psychiatric disease.15 A systematic
approach that addresses the following three
questions may help to guard against premature
symptom attribution and diagnostic errors.
 Case Records of the Massachuset ts Gener al Hospital
First, does the patient have a known psychi-
atric diagnosis? The type of psychiatric symptom
on a mental-status examination is not helpful,
because there are no pathognomonic symptoms
that can be used to differentiate between a
medical and a psychiatric disease.16 In this case,
a long-standing history of severe mental illness
is possible, but we cannot make a psychiatric di-
agnosis without reliable (i.e., independent) infor-
mation about the patient’s course of illness over
time. Pernicious anemia alone could conceivably
be the cause of her psychiatric presentation.
Second, is there an undiagnosed medical dis-
ease? A balanced workup that includes broad
screening for organ dysfunction, supplemented
with specific testing for signs of easily treatable
diseases (i.e., tests for abnormal thyrotropin,
vitamin B12, and folate levels and for HIV anti-
body and antitreponemal antibody), is a good
starting point; it would have led to identification
of the underlying medical problem in this pa-
tient.17 Further workup is guided by the clinical
scenario and would be done discriminately, so
as to avoid false positive results. In this case,
information about the response to treatment
with vitamin B12 and collateral information about
the patient’s history are needed to help us deter-
mine that either her presentation can be fully
explained by vitamin B12 deficiency or severe
mental illness (schizophrenia) is also indepen-
dently present.
Third, if severe mental illness is present, does
it contribute to the medical problem? Patients
with severe mental illness are at high risk for
medical complications and death.18 It is difficult
for patients with untreated or poorly treated
psychiatric illness, particularly those who are
affected by structural inequalities and poverty,
to lead healthy lives and obtain timely medical
care.19 In this case, for example, a poor diet
might have contributed to the patient’s anemia.
Increasing provider competence in diagnosing
medical problems early and providing standard
treatment for patients with serious mental ill-
ness would help to reduce stigma and to ensure
equitable care.20
Dr. Ana Ivkovic: The most crucial component in
the management of vitamin B12 deficiency is early
recognition, which enables treatment that may
prevent progression to demyelinating nervous
system disease. Although many clinicians would
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consider the diagnosis of vitamin B12 deficiency
in such a case as this one, some may be unaware
of the complexity in diagnosing and managing
this condition.
It is helpful to be mindful of risk factors,
which are not always obvious to or known by
patients. Severe vitamin B12 deficiency is most
commonly caused by autoimmune gastritis, which
manifests as pernicious anemia, as in this case.
Vitamin B12 deficiency can also arise from other
malabsorptive conditions (e.g., inflammatory
bowel disease, atrophic gastritis, or pancreatic
insufficiency), develop after certain procedures
(e.g., bariatric surgery or ileal resection), occur
with the use of restricted diets (e.g., veganism)
or certain medications (e.g., proton-pump inhibi-
tors or metformin), or arise from hypermeta-
bolic states (including pregnancy) or inborn er-
rors of metabolism. Acute vitamin B12 deficiency
has been associated with abuse of nitrous oxide
(“whippets”).
In addition to testing at-risk populations, we
would generally test anyone with new-onset or
worsening neuropsychiatric symptoms — such
as depression, psychosis, cognitive impairment,
mania, catatonia, or visual hallucinations, as seen
in the Charles Bonnet syndrome21 — for vita-
min B12 deficiency. Hematologic abnormalities
are not always present and may be inversely re-
lated to neuropsychiatric disturbance.13
Because the presentation of patients with vita-
min B12 deficiency can vary, it is especially im-
portant to have reliable screening tests. Unfor-
tunately, there is no standard diagnostic test.
Although many clinicians administer an isolated
serum test to screen for vitamin B12 deficiency,
the test is imperfect.22-24 Moreover, the serum
vitamin B12 level does not always correspond to
the level of intracellular or functional vitamin
B12 deficiency.25-27
Dr. Crall: After this patient received 1 week of
daily vitamin B12 injections, a repeat vitamin B12
level was more than 2000 pg per milliliter. Be-
fore discharge, a repeat homocysteine level was
14.0 μmol per liter. The patient had complete
resolution of her neurologic symptoms.
Treatment with valproic acid and olanzapine
was initiated. The patient’s thought processes
became increasingly more organized, and in-
somnia resolved. When the patient was shown
pictures of her family, she maintained that she
673
 Case Records of the Massachuset ts Gener al Hospital

had no family relations, stating, “Even if they
were my family, they wouldn’t want anything to
do with me anyway.” She declined all aftercare
services and was discharged with plans to return
to New York City.
Fina l Di agnosis
Pernicious anemia (vitamin B12 deficiency).
This case was presented at Psychiatry Grand Rounds.
Dr. Freudenreich reports receiving consulting fees and advi-
sory board fees from Alkermes and Janssen, consulting fees,
advisory board fees, and lecture fees from Neurocrine, lecture
fees and fees for content development from Global Medical Edu-
cation, grant support from Saladax and Otsuka, and consulting
fees from Novartis and Roche; and Dr. Baron, receiving grant
support, paid to his institution, from IBM and consulting fees
from Roche Diagnostics. No other 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.

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Copyright © 2019 Massachusetts Medical Society.

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