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
Jo-Anne O. Shepard, M.D., Associate Editor
Sally H. Ebeling, Assistant Editor

Nancy Lee Harris, M.D., Editor
Alice M. Cort, M.D., Associate Editor
Emily K. McDonald, Assistant Editor

Case 19-2014: A 19-Year-Old Woman
with Headache, Fever, Stiff Neck,
and Mental-Status Changes
Mark P. Gorman, M.D., Sandra P. Rincon, M.D., and Virginia M. Pierce, M.D.

Pr e sen tat ion of C a se
Dr. Robin M. Jones (Neurology): A 19-year-old woman was admitted to the pediatric
intensive care unit of this hospital in the autumn because of headache, fever, photophobia, neck stiffness, and mental-status changes.
The patient had been well until 7 days before admission, when headache and
nausea developed. She was seen at the emergency department of a hospital in
Massachusetts 6 days before admission. The physical examination and laboratory
test results were normal. Intravenous fluids and ketorolac were administered, with
improvement. A diagnosis of tension or migraine headache was made, and she
returned to her college dormitory.
Two days later, the patient reportedly vomited and fainted after standing up.
She returned to the hospital that night; examination revealed a temperature of
38.4°C and was otherwise normal. The hematocrit, hemoglobin level, platelet count,
and results of renal- and liver-function tests were normal. Testing for mononucleosis, streptococcal pharyngitis, and influenza was negative, and urinalysis revealed blood that was consistent with menses. Intravenous fluids, ketorolac,
metoclopramide, and ondansetron were administered, with some improvement.
A diagnosis of possible migraine headache was made, and the patient returned to
her dormitory. The next day, the fever persisted, and the patient’s parents, who had
traveled from their home to be with her, administered amoxicillin (obtained from
relatives who were physicians) and ibuprofen. The day before admission, another
episode of syncope occurred, without head trauma, after the patient arose from
bed. She went to the emergency department of another hospital that is affiliated
with this hospital.
The patient reported a bilateral parietal headache that was the worst of her life,
fever, photophobia, chills, night sweats, nausea, vomiting, dizziness with position
changes, neck stiffness that had lasted for 2 days, a mild sore throat, and no cough
or abdominal pain. On examination, the temperature was reportedly below 37.1°C,
the blood pressure 97/64 mm Hg, the pulse 99 beats per minute, the respiratory

From the Department of Neurology,
Boston Children’s Hospital (M.P.G.), the
Departments of Radiology (S.P.R.) and
Pathology (V.M.P.), Massachusetts Gen­
eral Hospital, and the Departments of
Neurology (M.P.G.), Radiology (S.P.R.),
and Pathology (V.M.P.), Harvard Medical
School — all in Boston.
N Engl J Med 2014;370:2427-38.
DOI: 10.1056/NEJMcpc1400838
Copyright © 2014 Massachusetts Medical Society.

n engl j med 370;25 nejm.org june 19, 2014

The New England Journal of Medicine
Downloaded from nejm.org by Karen Tapia on December 28, 2015. For personal use only. No other uses without permission.
Copyright © 2014 Massachusetts Medical Society. All rights reserved.

2427

35–7.7 Venous Arterial Blood gases Specimen Fraction of inspired oxygen Unspecified 0. and the oxygen saturation 96% while she was breathing ambient air. No other uses without permission. and antibodies against Lyme disease. as were tests for Anaplasma phagocytophilum. For personal use only.1 7. 2015.45) 7.9 26 26 25.7 5. Age-adjusted† 4 Days before Admission to MGH. .3 (hemolyzed) 3. and results of renal. All rights reserved.0 Chloride (mmol/liter) 100–108 96 100 94 Carbon dioxide (mmol/liter) 23.0–31.org june 19.44 (ref 7.org by Karen Tapia on December 28. Lumbar puncture was performed. 1st Hospital 1 Day before Admission to MGH.8 3. 2nd Hospital On Admission.9 1.0 1.45 (arterial) 7. results of analysis of the cerebrospinal fluid (CSF) are shown Table 1.4 Calcium (mg/dl) 8.000 5800 4900 9200 Neutrophils 40–62 53 63 90 Band forms <10 1 <10 27–40 21 19 (ref 15–45) 6 Variable Blood White-cell count (per mm3) Differential count (%) Lymphocytes Atypical lymphocytes 6 Monocytes 4–11 18 16 (ref 0–15) 3 Eosinophils 0–8 0 1 1 Basophils 0–3 1 0 0 Erythrocyte sedimentation rate (mm/hr) 2 Sodium (mmol/liter) 135–145 130 134 129 Potassium (mmol/liter) 3.The n e w e ng l a n d j o u r na l rate 20 breaths per minute.* Reference Range. hemoglobin level.2 70–110 116 125 154 Glucose (mg/dl) Magnesium (mg/dl) 1. Laboratory Data. MGH 4500–13.5–10. 2014 The New England Journal of Medicine Downloaded from nejm. Polymerase-chain-reaction (PCR) testing for nu- of m e dic i n e cleic acid from Babesia microti was negative. Other test results are shown in Table 1.6 8.7–2.70 7.5 8.and liver-function tests were normal. The hematocrit.4–4. Adults. ehr­ lichia species.35–7.25 nejm. the remainder of the examination was normal.3 Cerebrospinal fluid Color Turbidity Colorless Colorless Clear Clear Xanthochromia 2428 None n engl j med 370. Copyright © 2014 Massachusetts Medical Society.53 Partial pressure of oxygen (mm Hg) 80–100 (arterial) 84 (ref 42–54) 350 Partial pressure of carbon dioxide (mm Hg) 35–42 (arterial) 39 (ref 38–52) 27 Bicarbonate (mmol/liter) 24–30 (arterial) pH 22 Base excess (mmol/liter) 0.

obtained without the administration of contrast material. n engl j med 370. by PCR Negative Negative Epstein–Barr virus DNA.) Reference Range. truncal ataxia. † Reference values are affected by many variables. All rights reserved. Copyright © 2014 Massachusetts Medical Society. To convert the values for magnesium to millimoles per liter. by PCR Negative Negative Enterovirus RNA. in Table 1. The ranges used at MGH are age-adjusted for patients who are not pregnant and do not have medical conditions that could affect the results.25 nejm. Testing of throat specimens for group A streptococcus and of nasal specimens for influenza A and B viruses was negative. multiply by 0. 2429 .org by Karen Tapia on December 28. including the patient population and the laboratory methods used. She had neck stiffness. To convert the values for calcium to millimoles per liter. Urinalysis revealed a moderate amount of blood. multiply by 0. They may there­ fore not be appropriate for all patients. by PCR Negative Negative Borrelia burgdorferi DNA. (Continued. and ref the reference range at the second hospital. was normal. The patient received 3 liters of normal saline (administered intravenously over a period of 3 hours). as was a chest radiograph.05551.case records of the massachuset ts gener al hospital Table 1. To con­ vert the values for glucose to millimoles per liter. 2nd Hospital On Admission. by PCR Negative Negative West Nile virus RNA. A computed tomographic (CT) scan of the head. Age-adjusted† Variable 4 Days before Admission to MGH. PCR polymerase chain reaction.0°C. 2015. with 5 red cells per highpower field (2 days after menses). In the morning. For personal use only. and ketorolac. Overnight. She was admitted to the observation unit of the second hospital. by PCR Negative Negative Eastern equine encephalitis IgG antibodies <1:10 <1:10 Eastern equine encephalitis IgM antibodies <1:10 <1:10 * MGH denotes Massachusetts General Hospital. diphenhydramine. 2014 The New England Journal of Medicine Downloaded from nejm. multiply by 0.4114. MGH Red-cell count (per mm3) Tube 1 of 4 13 Tube 4 of 4 12 White-cell count (per mm3) Tube 1 of 4 253 (ref 0–5) Tube 4 of 4 327 (ref 0–5) Differential count for tube 4 of 4 (%) Lymphocytes 81 Atypical lymphocytes 2 Eosinophils 3 Macrophages 14 Protein (mg/dl) 137 (ref 20–50) Glucose (mg/dl) 52 (ref 40–75) Gram’s stain No organisms Culture No growth Herpes simplex virus DNA. and intermittent double vision and increasing difficulty with ambulation and urination occurred. 1st Hospital On Admission. metoclopramide.org june 19. the temperature rose to 39. she appeared drowsy and was disoriented with respect to the year. a urine pregnancy test was negative. Adults. No other uses without permission.250.

MRI Images of the Head. ondansetron. and effacement of the basal cisterns is present. The urethra was catheterized. Measurements of venous blood gases are shown in Table 1. ampicillin (2 g every 4 hours). acetaminophen. A fluid­attenuated inversion recovery (FLAIR) image shows diffuse sulcal hyper­ intensity (Panel B). but the basal cisterns were intact. Rincon: Magnetic resonance imaging (MRI) of the head was performed after the administration of gadolinium and revealed diffuse leptomeningeal enhancement (Fig. E. eczema. Jones: Acyclovir (10 mg per kilogram of body weight every 8 hours).25 Fluid-attenuated inversion recovery (FLAIR) images showed diffuse sulcal hyperintensity (Fig. and F). and oral fever blisters. FLAIR images show diffuse sulcal hyperintensity that has increased since the previous MRI examination. 2015. nejm. meclizine. show diffuse lepto­ meningeal enhancement (Panel A). obtained at the other hospital after the administration of gadolinium. 2014 The New England Journal of Medicine Downloaded from nejm. and ibuprofen were administered. rotatory nystagmus. these findings are consistent with cerebral edema. an indwelling catheter was placed. and a T2 ­weighted image shows ill­defined hyperintense signal abnormality and expansion of the medulla (Panel C. 1A). a PR interval of 92 msec. MRI images of the head were obtained with­ out the administration of gadolinium (Panels D. The strength and sensation were normal. On the patient’s admission to this hospital. For personal use only. Dr. numbness of the face and right arm. There was mild effacement of the sulci that was suggestive of cerebral edema. 1C). . 1B). The patient was transferred to this hospital and admitted to the pediatric intensive care unit. No other uses without permission. There is diffuse signal abnormality in the cerebellum and effacement of the cerebellar folia. findings consistent with diffuse cerebellar edema. MRI images of the head. T2-weighted images showed subtle. 2430 n engl j med 370. and 1 liter of urine was drained. All rights reserved. Effacement of the sulci has increased since the previous MRI examination. ill-defined signal abnormality and mild expansion of the medulla (Fig. She had a history of headache. and nonspecific T-wave abnormalities. arrow).org by Karen Tapia on December 28. Dr. Sandra P. and an inability to perform immediate recall of three words. Copyright © 2014 Massachusetts Medical Society.The n e w e ng l a n d j o u r na l A B D E of m e dic i n e C F Figure 1. An electrocardiogram showed sinus rhythm at a rate of 57 beats per minute.org june 19.

Differ en t i a l Di agnosis Dr. raw meats or unpasteurized dairy products. 2431 . She had no known allergies. vancomycin. and the trachea was intubated. subarachnoid hemorrhage. or connective-tissue disease. or use illicit drugs. her immunizations were current. She was transiently se- dated and paralyzed. decreased sensation to light touch on the right arm. and results of renal. or mosquito or tick bites. or n engl j med 370. She closed her eyes with equal strength and resisted opening them. MRI of the spine was performed without the administration of contrast material. All rights reserved. the left pupil was difficult to assess because of ocular movements. the patient was awake. 1D. Additional diagnostic tests were performed. MRI images of the head were also obtained without the administration of contrast material (Fig. During the first 30 minutes after her arrival. findings consistent with diffuse cerebellar edema. Her eyes were open most of the time.25 nejm. ill-defined hyperintense signal abnormality and mild expansion of the spinal cord from the cervicomedullary junction to the conus medullaris (Fig. as were blood levels of phosphorus. farm or domestic animals. A sensory examination. Mark P. she was unable to follow commands and had increasingly slurred and nonsensical speech. she answered “yes” or “no” to questions but often cried out in Chinese or with unintelligible words. was raised in the southern United States. proximal weakness. these findings are consistent with cerebral edema. The hematocrit. There was nuchal rigidity. Magnetic resonance angiography of the intracranial circulation. and lipase. Cerebellar testing was not performed owing to the patient’s overall neurologic status. On examination. Moderate palpebral conjunctival injection and shotty nontender cervical lymphadenopathy were seen. She was of East Asian descent. Copyright © 2014 Massachusetts Medical Society. The changes in the spinal cord are most prominent in the central gray matter (Fig. Gorman: This 19-year-old. autoimmune disease. She had had no travelrelated exposures. had not traveled recently. ataxia. revealed no hemodynamically significant stenosis. and 1F). with a greater decrease in tone in the left leg than in the right leg. the patient’s condition worsened. revealed decreased sensation on the left side of the face. previously healthy. For personal use only. The right pupil was normal. FLAIR images also showed diffuse signal abnormality in the cerebellum and effacement of the cerebellar folia. and reported no exposures to sick persons. obtained without the administration of contrast material. She did not smoke. The right plantar reflex was flexor. presumably immunocompetent. amylase. intact sensation to light touch on the left arm. 1E. and the left plantar reflex was absent. she had taken biotin for acne. and withdrawal from a mild noxious stimulus to the legs. Dr. and mild effacement of the basal cisterns was present. hemoglobin level. alert. The reflexes were brisk throughout. No other uses without permission. and lived in a college dormitory in Massachusetts. and azithromycin were also administered. with constant slow upward ocular movements and predominantly upward deviation. 2014 The New England Journal of Medicine Downloaded from nejm. ceftriaxone. she reportedly had had a diarrheal illness.case records of the massachuset ts gener al hospital Two weeks before admission. fully immunized. showed no acute intracranial abnormality.and liver-function tests were normal.org by Karen Tapia on December 28. The vital signs were normal. 2B). Diffuse effacement of the sulci had increased since the previous MRI examination. which was limited because of her fluctuating attention span and pain from nuchal rigidity. albumin. A solution of 20% mannitol (25 g) was administered intra­ venously. and the remainder of the examination was normal. with two or three beats of clonus at the right ankle. Before this illness. performed with the use of a three-dimensional time-of-flight technique. animal or insect contacts. Dr. T2-weighted images showed diffuse. She was not sexually active. There was no family history of multiple sclerosis. Additional test results are shown in Table 1. 2A). platelet count. Her strength was 4−/5 in shoulder extension (antigravity with little resistance) and 2/5 in hip flexion (an inability to overcome gravity). altered mental status. and oriented with respect to her name and her father but not the place or time. meningeal signs. Jones: An arterial catheter and a right femoral central catheter were placed. 2015. Rincon: A CT scan of the head. FLAIR images showed diffuse sulcal hyperintensity that had increased since the previous MRI examination.org june 19. and urinary retention that developed over a period of 7 days in the autumn in Massachusetts. globulin. drink alcohol. female college student presented with fever. acyclovir. red-cell indexes.

possibly suggesting a postinfectious process. she did not have the slow downward eye movements that are consistent with ocular bobbing. 2014 The New England Journal of Medicine Downloaded from nejm. 2015. Throat soreness and cervical lymphadenopathy are nonspecific findings.25 nejm. The leptomeningeal enhancement dietary exposures. For personal use only. General examination revealed conjunctivitis. No other uses without permission. The MRI images confirm the clinical localization and show additional medullary involvement. which may be contributing to the altered mental status. arrow). conjunctival injection can indicate uveitis. a condition associated with pontine damage and a poor prognosis. which can occur with viral infections of the central nervous system such as adenovirus and West Nile virus. rotatory nystagmus.count and increased protein content in the lepto- 2432 n engl j med 370. A sentation. All rights reserved. Copyright © 2014 Massachusetts Medical Society. A T2 ­weighted im­ age shows diffuse. arrow). the increased white-cell diarrheal illness had occurred 2 weeks before pre.The n e w e ng l a n d j o u r na l of m e dic i n e Figure 2. although the history may be and increased sulcal signal on FLAIR images limited because of her altered mental status. Imaging of the entire spine revealed diffuse involvement of the spinal cord. which are consistent with reverse ocular dipping. the cerebellum. a condition associated with diffuse cerebral dysfunction caused by potentially reversible metabolic encephalopathies or infectious encephalitides. proximal weakness (with decreased tone and increased reflexes). truncal ataxia. but they could suggest upper respiratory pathogens such as Mycoplasma pneu­ moniae or viruses. The presence of uveitis would narrow the differential diagnosis to uveomeningeal syndromes. ill­defined hyperintensity and mild expansion of the cervical spinal cord (Panel A. and the spinal cord. with signal abnormality extending inferiorly to the level of the conus medullaris (not shown). A suggest inflammation.org june 19.org by Karen Tapia on December 28.1 Overall. abnormal eye movements. . and urinary retention. MRI Images of the Spine. and the sensory examination unreliable. MRI of the cervical spine was performed without the administration of contrast material. which requires formal ophthalmologic examination for detection. the brain-stem examination was largely normal. The patient had slow B upward eye movements. Alternatively. The neurologic symptoms and signs include mental-status changes. An axial T2 ­weighted image shows that the signal ab­ normality in the spinal cord predominantly involves the central gray matter (Panel B. the neurologic findings suggest multifocal localization involving the cortex diffusely.

and no cause was identified in the remaining 63%. the hyperreflexia. For personal use only. Copyright © 2014 Massachusetts Medical Society. No other uses without permission. but serologic testing for this agent should be performed because it is more sensitive. pneumoniae. Recommended Diagnostic Tests. All rights reserved. pneumoniae is a strong contender.4 Among those patients.3 Many infectious causes have been eliminated on the basis of the available test results. Antinuclear antibodies Antiphospholipid antibodies Neuromyelitis optica Human immunodeficiency virus Infectious Causes Bartonella Results of the California Encephalitis Project can help to focus the search for infectious causes.25 nejm.6 and hyponatremia. Medullary and spinal cord hyperintensity suggests inflammation. Of the 1570 patients who participated in the study that was published in 2006. a possible infectious cause was identified in 13%. gastrointestinal symp- Varicella–zoster virus Tuberculosis Blood antiaquaporin 4 IgG antibodies Blood antibodies Blood IgM and IgG CSF PCR Purified protein derivative * CSF denotes cerebrospinal fluid. such infections could include enteroviruses and West Nile virus. Effacement of cerebral sulci and cerebellar fissures suggests diffuse cerebral and cerebellar edema. The patient had a negative PCR test for West Nile virus. which could suggest a poliomyelitis-like viral infection. herpes simplex virus.5 predominant abnormalities in the central gray matter on spinal MRI. However. White-matter abnormalities are notably absent on MRI.org june 19. the time of year.8 Noninfectious Causes Small-vessel vasculitis of the central nervous system is a possible noninfectious cause and would require a brain biopsy for definitive diagnosis. West Nile virus.7. young immunocompetent persons tend not to have neuroinvasive complications of West Nile virus infection. The laboratory findings include hyponatremia and a normal erythrocyte sedimentation rate. this patient’s CSF and MRI findings were more severe than would be expected with this diagnosis. The following viral causes were each identified in at least 1% of patients: enterovirus. However. varicella–zoster virus. and Epstein–Barr virus. it is notable that eosinophils accounted for 3% of the cells in the CSF. The spinal cord changes are most prominent in the central gray matter. it was considered a possible cause and not a confirmed or probable one in nearly all cases. pneumoniae infection. In an immunized host. In addition. Several features are present that could be indicative of West Nile virus infection. Of the remaining possibilities. The differential diagnosis at this juncture is described in Table 2. Gorman Ophthalmologic consultation Creatine kinase Mycoplasma pneumoniae Blood IgM and IgG Respiratory PCR CSF PCR (if other tests are positive) West Nile virus Blood IgM and IgG CSF IgM and IgG Adenovirus Blood IgM and IgG CSF PCR (if blood test is positive) Vasculitis C-reactive protein von Willebrand factor antigen Meningoencephalomyelitis The patient’s presentation is most consistent with meningoencephalomyelitis with an infectious or inflammatory cause. 2014 The New England Journal of Medicine Downloaded from nejm.case records of the massachuset ts gener al hospital meninges and subarachnoid space are confirmed by the CSF analysis. and the absence of neutrophils in the CSF are not consistent with West Nile virus infection.org by Karen Tapia on December 28. M. Table 2.* Disease or Pathogen in the Differential Diagnosis General Test Recommended by Dr. 2433 . In this patient. Extensive testing for infectious diseases was negative. but the absence of peripheral eosinophilia and clear risk factors makes eosinophilic meningoencephalomyelitis with a parasitic cause an unlikely diagnosis. n engl j med 370. The patient’s age falls within the age range of the 111 patients in the California Encephalitis Project who received a diagnosis of encephalitis due to M. The most commonly identified cause was M.2 a confirmed or probable cause of encephalitis was identified in 24% (the cause was infectious in 16% and noninfectious in 8%). toms (as seen in this patient) were surprisingly as common as respiratory symptoms. including focal weakness. 2015.

encephalitis due to M. even though they had not had a febrile illness in the 2434 of m e dic i n e preceding 2 to 4 weeks. 2014 The New England Journal of Medicine Downloaded from nejm. patients with neuromyelitis optica are more likely than patients with other demyelinating disorders to have eosinophils in the CSF. which is outlined n engl j med 370. Neuromyelitis optica should also be considered. and asymptomatic carriage. pneumoniae–associated encephalitis. pneumoniae–­ associated encephalitis. I would perform further testing.14 How­ ever. particularly when older methods. pneumoniae.The n e w e ng l a n d j o u r na l However. In fact. PCR assays detected M. pneumoniae infection is the most likely diagnosis. of the 301 pediatric patients with acquired demyelinating disorders who participated in a Canadian prospective study. this patient had many more white cells in the CSF than would be expected with this diagnosis. In a 2010 review of previously published cases of central nervous system disease associated with M. but these tests have poor specificity.12 leptomeningeal enhancement was present in only 3%. Patients with neuromyelitis optica can present with longitudinally extensive myelitis without optic neuritis. However. antibody titers can take weeks to months to normalize.18 Thus. The presence of leptomeningeal enhancement may argue against a demyelinating disorder.17 Encephalitis due to antiNMDA receptor antibodies is a very unlikely diagnosis in this patient.18 The antiGalC antibodies may be induced through molecular mimicry between GalC in myelin and epitopes in M. such as complement fixation. anti-galactocerebroside (GalC) antibodies have been detected in the blood.9. particularly those with evidence of demyelination on MRI. teens.15 Furthermore. convalescent infection. pneumoniae. according to the definition established in 2007 by the Interna­ tional Pediatric Multiple Sclerosis Study Group. extensive leptomeningeal enhancement is rarely described with neuromyelitis optica. and thus neuromyelitis optica is an unlikely diagnosis in this case. and cerebral involvement with encephalopathy can be present. hyperintense lesions in the white matter are seen on MRI images in nearly all patients with small-vessel vasculitis of the central nervous system. In addition. because she did not have seizures or a movement disorder and the MRI findings were much more extensive than those typically seen in patients with this diagnosis.10 In addition. these findings suggest the possibility of a direct M. pneumoniae On the basis of the epidemiology of encephalitis in the United States and this patient’s age. .org by Karen Tapia on December 28.11 patients must have multifocal hyperintense lesions in the white matter to receive this diagnosis. particularly in younger patients. However. To determine the diagnosis in this patient.16 After a known infection with M. Encephalitis Due to M. 2015. even when the central nervous system is not directly infected. with the use of either culture or PCR.13 Also. pneumoniae in the CSF in only 2% of the 111 patients in the California Encephalitis Project who received a diagnosis of encephalitis associated with M. other diagnoses must be considered even when a patient with encephalitis has a positive test for antibodies against M. For personal use only. pneumoniae may be important in the pathogenesis of some cases of encephalitis. pneumoniae and had received a diagnosis of M. tests performed for the detection of M. pneumoniae. but they were not seen in this patient’s MRI images. 4 of 10 patients in the California Encephalitis Project who ultimately received a diagnosis of encephalitis associated with anti–Nmethyl-d-aspartate (NMDA) receptor antibodies (once testing for the anti-NMDA receptor antibodies became available) had previously had positive tests for antibodies against M. pneumoniae infection of the central nervous system. Copyright © 2014 Massachusetts Medical Society. enzyme immunoassays. pneumoniae. pneumoniae. are used. All rights reserved. and young adults who participated in the study had positive tests for IgM antibodies against M. pneumoniae in brain tissue in 3 patients (2 with encephalitis and 1 with acute disseminated encephalomyelitis) and in the CSF in approximately 50 patients. the CSF. This diagnosis is often made on the basis of the results of serologic tests. and enzyme-linked immunosorbent assays (ELISAs) — at least 20% of the Israeli children.25 nejm. or both (with the use of ELISA) in some patients with M. pneumoniae.org june 19.15 In one study evaluating eight commercially available serologic tests — particle agglutination assays. there are several caveats. No other uses without permission. pneumoniae in respiratory specimens cannot distinguish among acute infection.10 The presence of encephalopathy and multifocal neurologic symptoms and signs after a systemic infection could suggest acute disseminated encephalomyelitis.15 the authors reported the detection of M.4 Therefore. M.9.

DR . for possible infectious encephalitis? There are known adverse effects of glucocorticoids. a compatible clinical presentation. Since tests for IgM antibodies against M. Dr. pneumoniae after in­ fection and by the imperfect sensitivity and specificity of available assays.19 However. these can be discontinued if the patient has negative tests for infectious diseases. While awaiting the test results. these findings are consistent with a recent infection. pneumoniae.case records of the massachuset ts gener al hospital in Table 2. in combination with antimicrobials. In a specimen collected on day 75 of her illness. pneu­ moniae is complicated both by the persistence of antibodies against M. 2015. with a maximal dose of 1 g per day) for 5 days. Two major questions remain regarding this patient’s diagnosis and treatment.org june 19.25 nejm.20 Because of the lack of evidence. In this patient. Copyright © 2014 Massachusetts Medical Society.19. and the team’s diagnosis was similar to that of Dr. Azithromycin is a reasonable treatment option for possible M. G OR M A N’S DI AGNOSIS Meningoencephalomyelitis. All rights reserved. and the estimated relative contribution of direct infectious and inflammatory mechanisms. including airway management and maintenance of normal body temperature and glucose and sodium levels. 2014 The New England Journal of Medicine Downloaded from nejm. The IgM antibody response peaks approximately 3 weeks after infection and then begins to decline. although there is a lack of clear evidence of its benefit in central nervous system disease. First. IgM antibodies remained detectable by enzyme immunoassay. should glucocorticoids be administered as empirical treatment for a possible autoimmune disorder of the central nervous system or as an adjunctive treatment. although I acknowledge the lack of definitive published evidence for this approach. and a negative laboratory evaluation for alternative infectious causes. Clinically evident increased intracranial pressure should be managed with attention to fluid and sodium balance and with an infusion of mannitol or hypertonic saline. Virginia M. but a confirmatory indirect immunofluorescence assay was negative for IgM antibodies. No other uses without permission. I would provide supportive care. compatible neuroimaging features.21 Ultimately.10 but I would not recommend biopsy in this case because of the atypical MRI and CSF findings. the decision to administer glucocorticoids is made on a case-by-case basis and must take into account disease severity. with careful monitoring. M A R K P. For personal use only. most likely due to Mycoplasma pneumoniae and less likely due to West Nile virus.23 Serum specimens collected from this patient on days 9 and 13 of her illness were positive for IgM antibodies against M. data regarding herpes simplex virus–associated encephalitis suggest a benefit to the administration of glucocorticoids in combination with acyclovir. I would administer methylprednisolone (at a dose of 30 mg per kilogram per day. pneu­ moniae infection. pneumoniae can have both false negative and false positive results. Pathol o gic a l Discussion Dr. asso­ ciated conditions. there is no single laboratory test with sufficient sensitivity and specificity to establish the diagnosis of a central nervous system disease associated with mycoplasma infection. Pierce: Currently. should a leptomeningeal and brain biopsy be performed to assess for small-vessel vasculitis of the central nervous system? This diagnosis is increasingly recognized and would require an intensive treatment regimen that would not otherwise be prescribed. the serologic diagnosis is most reliable when the IgG antibody titer in a convalescentphase serum specimen is four times as high as the IgG antibody titer in an acute-phase serum specimen. The interpretation of serologic tests for M. Although broad-spectrum antimicrobial agents are initially indicated. 2435 .22. possibly due to Mycoplasma pneumoniae. Second. Testing of the three specimens (col- n engl j med 370. and concerns have been raised that they could delay clearance of infectious agents. Gorman. but it may persist for several months. suggesting a decline in the IgM antibody response. Cl inic a l Di agnosis Parainfectious meningoencephalomyeloradiculitis. Nancy Lee Harris (Pathology): We asked Dr. Jones to share with us the clinical diagnosis that was determined by the treatment team at that time.org by Karen Tapia on December 28. this diagnosis relies on laboratory studies.

She was having to study more than she was used to and was frustrated with what she perceived to be diminished cognitive n engl j med 370. and 75 of her illness) for IgG antibodies was positive. more conventional time. Ten weeks after admission. a trial of IVIG was administered for glucocorticoid-refractory severe parainfectious encephalomyelitis. 13. the specimens were tested independently rather than in parallel. PCR testing for M. and since index values are not directly related to antibody levels. therefore. Results of sero- 2436 of m e dic i n e logic tests for Epstein–Barr virus. as were serum antibody tests for arboviruses (including La Crosse virus. Tracey A. Cho (Neurology): Once we received the test results for antibodies against mycoplasma. Because of the severity of the patient’s clinical deficits and the diffuse abnormalities on her MRI scan. Taken together. western equine encephalitis virus. pneumoniae have been reportedly inconsistent among patients with central nervous system disease that is attributed to mycoplasma infection. Dr. unrevealing laboratory evaluation for alternative causes of her illness. Louis encephalitis virus.25-27 CSF PCR testing for M. Despite the administration of intravenous glucocorticoids. pneumoniae is not widely available. she was living with her parents and taking classes at a local college. and her mental status and strength improved steadily. Second. and all three specimens had similar index values. and a CSF PCR test for varicella–zoster virus. The patient had an extensive. even when the testing is performed early in the clinical course. the compatible clinical and neuroimaging findings. Another factor to consider in the interpretation of this patient’s serologic test results is the administration of intravenous immune globulin (IVIG) on days 13 through 17 of her illness. the patient had minimal alertness and was unable to follow commands even when she was not receiving sedatives. 2015. no clinical trials have determined adequate treatment for this disease. For personal use only. Bartonella henselae. pneumoniae infection. the tapering of the glucocorticoid treatment was lengthened. she had moderate asymmetric weakness and clonus but was walking with crutches. St.The n e w e ng l a n d j o u r na l lected on days 9. levofloxacin was administered. the acute-phase and convalescent-phase specimens may have been collected too far apart to show the peak antibody response. and the patient had had recurrent paresthesias after glucocorticoids had been tapered. to our knowledge.org by Karen Tapia on December 28. The patient underwent aggressive physical therapy. or the natural history of the illness. tests for syphilis. although assays that have not been approved by the FDA are offered at some institutions and reference laboratories. and extensive negative laboratory evaluation for alternative infectious causes are most likely indicative of a diagnosis of parainfectious encephalomyelitis associated with M. The performance characteristics of these assays vary. Gastrostomy and tracheostomy were performed for supportive care. quintana were not consistent with recent infection.org june 19. Her condition began to improve after she received the IVIG. severe flaccid paraplegia developed.24 After considering the half-life of IVIG. This treatment strategy was based largely on anecdotal evidence because. Harris: Dr. Each dose of IVIG is derived from plasma from thousands of donors and thus may contain antibodies that are specific for infectious agents. No other uses without permission. . the improvement could have been due to the IVIG treatment. and West Nile virus). 2014 The New England Journal of Medicine Downloaded from nejm.25 nejm. I think the likelihood is probably low that donor antibodies in the IVIG affected the test results obtained on day 75. It is difficult to draw conclusions about the timing of infection based on these index values for several reasons. results from separate testing cannot be directly compared. The results of PCR testing of CSF for M. Cho. but interpretation would have been more challenging if the convalescent-phase serologic testing had been attempted at an earlier. and B. Other antibiotic agents had already been discontinued. We administered adjunctive high-dose glucocorticoids for presumed parainfectious inflammation of the central nervous system. eastern equine encephalitis virus. Antibody and nucleic acid amplification testing for human immunodeficiency virus was negative. Eighteen weeks after admission. Copyright © 2014 Massachusetts Medical Society. First. pneumoniae was performed on a CSF sample collected on day 21 of the patient’s illness and was negative. late effects of the glucocorticoid treatment. and the reference standard to which they should be compared is unknown. serologic test results. would you tell us how the patient was treated and her current condition? Dr. Some of the literature reports worsening symptoms after the discontinuation of glucocorticoids. All rights reserved.

BMC Neurol 2008.68:105360.43:1565-77. Stokic DS. Glaser CA.66:361-5. Disclosure forms provided by the authors are available with the full text of this article at NEJM. CSF findings in 250 patients with serologically confirmed West Nile virus meningitis and encephalitis.. that I owe the success of my recovery. Beyond viruses: clinical profiles and etiologies associated with encephalitis. eds. M. Jarius S. PATHO GIC A L DI AGNOSIS Parainfectious encephalomyelitis associated with systemic mycoplasma infection. 3. 8. et al.] 11. Northrop JL. Goldsmith. References 1. et al. Calamia KT.D. 10th ed. 2012:518-21. Cerebrospinal fluid findings in aquaporin-4 antibody positive neuromyelitis ­optica: results from 211 lumbar punctures. Spec­ trum of pediatric neuromyelitis optica. Tenembaum S. Landry ML. AJNR Am J Neuroradiol 2005. an incredibly humbling process. 5. Treatment of small vessel primary CNS vasculitis in children: an open-label cohort study. Janice A. and friends. Waites K. For me. J Neuropathol Exp Neurol 2009. [Erratum. J Child Neurol 2013.H.4:97-104.26:1986-95. Clin Infect Dis 2006. O’Mahony J. Lowe. and John Patrick T. Gavali S. I am thankful for having been able to experience firsthand the patient’s perspective. Clin Microbiol Infect 2006. Hutton GJ. This case was presented at the Harvard Medical School postgraduate course “Primary Care Pediatrics. Goody RJ. We thank C..P. The clinical spectrum of ocular bobbing and ocular dipping. M..28:1421-9. Kimberlin DW. Menon S. Arnold DL. Elbers J. Warnock DW. 2015. Talkington DF. The Patient: Although this discussion was about what had happened to me. M. Ruiz S.28:184-97. Drug insight: steroids in CNS infectious diseases — new indications for an old therapy. IL: American Academy of Pediatrics. 7. 22. Hutchinson C.org by Karen Tapia on December 28. Honarmand S. Sadovnick AD. Manual of clinical microbiology. these obstacles never seemed insurmountable with the constant encouragement of my enormous support group. Yagi S. Neurology 2007. Pediatrics 2008. Clin Microbiol Rev 2009. Greenspan.62:442-51. Bar-Or A. Tunkel AR. Evaluation of eight commercial tests for Mycoplasma pneumoniae antibodies in the absence of acute infection.org june 19. Ron M. Co. and Lindsay Carter. Front Neurol 2012. 10. Brown RD Jr. et al. Glaser CA. and the hard work that they have invested in my well-being. Salvarani C. Primary central nervous system vasculitis: analysis of 101 patients. 4. Bitnun A. Austrian and Dutch trial. which included my family.122(5):e1039-e1047. 12. et al. Consensus definitions proposed for pediatric multiple sclerosis and related disorders. Peter T.. Jorgensen JH. Corkill M. Neurology 2006. Krupp LB.120:305-13. Anderson LJ. Schiffman JS.12:685-8.D. Red Book: 2012 report of the Committee on Infectious Diseases. et al. Martinez-Torres F. Christie LJ. 9.case records of the massachuset ts gener al hospital abilities. Tyler KL. Kleinschmidt-DeMasters BK. M. multinational. progressing from a 20-year-old infant back to a competent young adult was. However. Halliday W. Christie LJ. Paul F. because I have no memories of it. Ann Neurol 2007. 17.306:82-90. 15. Baker CJ. Myco­ plasma and ureaplasma. It is to these people. All rights reserved. Richardson SE.3:37. Petropoulou KA. No potential conflict of interest relevant to this article was reported. M. et al. Hunter JV. Funke G. In: Versalovic J.68:Suppl 2:S7-S12. Pape J. Fitch MT. Marrie RA. Ruggierri PM. West Nile virus infections.D.D. My memories are mostly of the daily challenges I had. Graeff-Teixeira C. Protocol for German trial of Acyclovir and corticosteroids in Herpes-simplexvirus-encephalitis (GACHE): a multicenter. Currently. randomized. 6.25 nejm.51: 725-7. nurses. et al. West Nile virus meningoencephalitis: MR imaging findings.9:107884. Leis AA. Prayson RA. placebo-controlled German. it was a bit strange to hear about the initial and worst part of my illness. Nir-Paz R. Gordon SM. da Silva AC. Honarmand S. J Neurol Neurosurg Psychiatry 1988. Taylor-Robinson D. therapists.. No other uses without permission. Update on eosinophilic meningoencephalitis and its clinical relevance. I can confidently say that my parents’ memories and probably also my doctors’ memories of my case are far worse than the ones I have. 19.9:1045. 2011:970-85. Banwell B. Carroll KC. Mycoplasma pneumoniae and other Mycoplasma species infections. Washing­ ton. from finding a means of communicating when I had a tracheostomy to regaining my strength and relearning to walk.8:40. 2014 The New England Journal of Medicine Downloaded from nejm. double-blind. 2. Long SS. Honarmand S. but she was receiving straight A’s in her courses. Copyright © 2014 Massachusetts Medical Society. Radner A. J Neuroimmunol 2007. Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Mehler MF. Gable MS. Because I aspire to be a doctor someday (becoming the patient first was certainly not included in my premed plan). I will never forget feeling the satisfaction of achieving small goals and the extensive love and support I felt from everyone around me. Pritsch M. Banwell B. In: Picker­ ing L.” directed by Ronni L. Glaser CA. 21. 189:129-31. and still is. Lotze TE. Bloch KC. Ross B.D. Gyure KA. Neuromuscular manifestations of West Nile virus infection. 18. Mycoplasma pneumoniae: innocent bystander or a true cause of central nervous system disease? Curr Infect Dis Rep 2010. M. 29th ed. doctors. Lancet Neurol 2010. Block C. 2437 .12:282-90. Anti-galactocerebroside testing in Mycoplasma pneumoniae-associated encephalitis. 13.D. Nat Clin Pract Neurol 2008. The management of encephalitis: clinical practice guidelines by the Infectious n engl j med 370. M. I will ask her to share her experience with the audience. for help with organizing the conference. Pediatric encephalitis: what is the role of Mycoplasma pneumoniae? Pediatrics 2007. Elk Grove Village. 16.org. J Neurol Sci 2011. DC: ASM Press. Masquerades of acquired demyelination in children: experiences of a national ­demyelinating disease program. Franciotta D. 23. van de Beek D.22:322-48. 14. Yoshi­ mura K.. Chanley Dudley. the patient is back in school full time. Michael-Gayego A. Lancet Neurol 2010. et al. Eur J Clin Microbiol Infect Dis 2009. 20. For personal use only. eds.

27. Clin Microbiol Infect 2004. IgG. Socan M. Bencina D. Jazbec J. Radiographic. neurologic. Narita M. 2015.org by Karen Tapia on December 28.and IgA-specific enzyme immunoassays in blood donors and patients. averaging 50-60 slides per set. 24. Each set is supplied on a compact disc and is mailed to coincide with the publication of the Case Record. . 26. 33:916-7.32(2): E31-E35. which began in January. MA 02114 (telephone 617-726-2974) or e-mail Pathphotoslides@partners. Application forms for the current subscription year.10: 1094-8. tables. Dovc P. gross specimens. Hess RD. as well as unpublished text slides. All rights reserved.48: M51-4. Neurological symptoms in patients whose cerebrospinal fluid is culture. 2014 The New England Journal of Medicine Downloaded from nejm. including digital images. Pike M. For personal use only. Department of Pathology. Clin Infect Dis 2001.47:303-27. Clin Infect Dis 2008.org june 19. and photomicrographs. Clin Mol Pathol 1995. Sillis M. 2438 n engl j med 370. Fink CG. not only those published in the Journal. are included. or individual sets may be purchased for $50 each. Butler L. shown at the live Clinicopathological Conference (CPC) that is the basis of the Case Record. Read SJ.25 nejm. This slide set contains all of the images from the CPC. may be obtained from the Lantern Slides Service. and diagrams. 25. Two distinct patterns of central nervous system complications due to Mycoplasma pneumoniae infection. Csángó PA. Ravnik I. Yamada S. Boston. The cost of an annual subscription is $600. Copyright © 2014 Massachusetts Medical Society. Pedersen JE. with identifying legends. Neurological disease associated with Mycoplasma pneumoniae infection: PCR evidence against a direct invasive mechanism. Every year 40 sets are produced. Zakotnik B.and/or polymerase chain reaction-positive for Mycoplasma pneumoniae. Copyright © 2014 Massachusetts Medical Society. and cardiac studies. Massachusetts General Hospital. No other uses without permission. Comparison of four Mycoplasma pneumoniae IgM-.case records of the massachuset ts gener al hospital Diseases Society of America.org. Lantern Slides Updated: Complete PowerPoint Slide Sets from the Clinicopathological Conferences Any reader of the Journal who uses the Case Records of the Massachusetts General Hospital as a teaching exercise or reference material is now eligible to receive a complete set of PowerPoint slides. Clin Infect Dis 2001.