Pess Measles

7/30/2019 Pess Measles

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case records of themassachusetts general hospital

T h e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 357;6 www.nejm.org august 9, 2007 589

Founded by Richard C. CabotNancy Lee Harris, m.d., Editor Eric S. Rosenberg, m.d., Associate EditorJo-Anne O. Shepard, m.d.,Associate Editor Alice M. Cort, m.d.,Associate EditorSally H. Ebeling,Assistant Editor Christine C. Peters, Assistant Editor

From the Neurology Service (A.J.C., J.W.H.,M.P.F.) and the Departments of Radiol-ogy (J.W.H.) and Pathology (M.H.A.R.,M.P.F.), Massachusetts General Hospi-tal; and the Departments of Neurology(A.J.C., J.W.H.) and Pathology (M.H.A.R.,M.P.F.), Harvard Medical School.

N Engl J Med 2007;357:589-600.Copyright 2007 Massachusetts Medical Society.

Presentation of Case

A 20-year-old pregnant woman was admitted to this hospital at 26 weeks of gesta-tion because of dizziness, confusion, and difficulty walking.

Ten weeks before admission, the patient had a positive result on a home preg-nancy test and presented to a neighborhood health center for prenatal screening.Tests for sickle cell trait, syphilis, and human immunodeficiency virus (HIV) andhepatitis B and C virus antibodies were negative. Serologic tests for varicellazos-ter virus and rubella IgG were positive. Two weeks later, an endocervical specimenwas positive for Chlamydia trachomatis infection and negative for gonorrhea. Thepatient missed follow-up appointments, and treatment with azithromycin was

initiated 4 weeks later.Six weeks before admission, she moved into a shelter for pregnant women. Staff

members described her as happy, with a childlike affect, a poor memory, confu-sion, and odd movements of her head. During the next 2 weeks, nausea and vom-iting occurred daily and were controlled with metoclopramide. Four days beforeadmission, dizziness and weakness on the left side developed; she began to fall toher left and vomited several times. The next day, she went to the emergency de-partment of another hospital. On evaluation, the patient was oriented to locationbut not to date, day, or month, and she provided inconsistent information abouther medical history. The uterus was gravid, and the remainder of the physicalexamination was normal. An electrocardiogram revealed sinus tachycardia andcounterclockwise rotation with T waves in the right precordial leads. Urinalysis

showed a protein level of 30 mg per deciliter and a glucose level of 100 mg perdeciliter (5.6 mmol per liter). Tricyclic metabolites were present on toxicologyscreening of a urine specimen. Computed tomographic (CT) scanning of the headrevealed a slight, diffuse prominence of the ventricular system. There was no in-tracranial mass or other focal brain lesion.

On the second hospital day, the patient was alert, calm, cooperative, and ori-ented to person, location, and current events but was not aware of details of herlife. There were no tremors or extrapyramidal signs. Ultrasonographic examina-tion revealed normal fetal anatomy and growth, corresponding to a gestation of25 weeks 6 days. On the third day, the weakness, nausea, and vomiting had resolved,

Case 24-2007: A 20-Year-Old PregnantWoman with Altered Mental Status

Andrew J. Cole, M.D., John W. Henson, M.D., Michael H.A. Roehrl, M.D., Ph.D.,and Matthew P. Frosch, M.D., Ph.D.

Downloaded from www.nejm.org on March 1, 2010 . Copyright 2007 Massachusetts Medical Society. All rights reserved.


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n engl j med 357;6 www.nejm.org august 9, 2007590

and the patient was thought to have returned toher baseline mental status. She was dischargedto the shelter with a recommendation to sched-ule a follow-up neurologic evaluation. At theshelter, she was dizzy, had difficulty walking,and fell into a chair. That evening, she wasbrought to the emergency department of this

hospital.In the emergency department, the patient re-

ported feeling woozy and nauseated. She noteda mild headache of gradual onset, extending band-like across the brow. The history as given by thepatient was inconsistent; the history was thenprovided by staff members of the shelter, andmany details were lacking. The patient was anative of Cape Verde who had immigrated to thiscountry 3 years previously. She had had measlesat 4 months of age and varicella infection in child-hood. At 7 years of age, she injured her head in

a fall but was said to have recovered fully. Immu-nizations included polio vaccine and diphtheria,pertussis, and tetanus vaccine series; measles vac-cine (at 11 months of age); measles, mumps, andrubella vaccine combination; and hepatitis B vac-cine (between 2 and 3 years before admission, onenrollment in high school).

The patient had attended school through the10th grade and was unemployed. During the3 years before admission, she had lived with rela-tives, friends, and a boyfriend, as well as in shel-ters. She was single, and she no longer main-tained a social relationship with the father of thefetus. Her parents and seven siblings were alivebut not in contact with her at the time of admis-sion. No family medical history was available. Shehad no known allergies and did not use alcohol,illicit drugs, or tobacco.

On examination in the emergency department,the patient was alert but somewhat uncoopera-tive, with involuntary head movements. Her men-tal status was not formally assessed, but her levelof cognitive function was said by a friend to be at

baseline. The blood pressure was 107/81 mm Hg,the pulse 84 beats per minute, and the tempera-ture 36.3C; the respirations were 18 per minute,and the oxygen saturation was 100% while the pa-tient was breathing ambient air. Acneiform lesionswere present on her face. The abdomen was soft,gravid, and not tender; the fetus appeared to behealthy. The 1st cranial nerve was not tested, andthe 2nd through 12th nerves were intact. Strengthwas intact, and the gait was unsteady. The remain-der of the examination was normal.

Results of laboratory tests are shown in Table 1.After premedication with lorazepam at a dose of1 mg to control involuntary movements, magnet-ic resonance imaging (MRI) of the brain wasperformed without administration of contrastmaterial. On T2-weighted, f luid-attenuated inver-sion recovery (FLAIR) images, hyperintense signal

was seen in the left hippocampus and parahippo-campal gyrus as well as in the posterior limb ofthe left internal capsule. There was no evidence ofrestricted diffusion.

Examination by a neurology consultant showedthat the patient was oriented to person and place,with a childlike affect. Her speech was fluent,and naming was intact. She could read a shortsentence and do simple addition. She was left-handed, could write her name but not a sentence,and followed simple and complex commands.Her attention was variable, and testing of her

memory showed recollection of zero of threeitems at 5 minutes on repeated examination.There was mild asymmetry of the face with flat-tening of the right nasolabial fold. Smell andtaste were not tested. The function of the othercranial nerves was intact. There were choreiformmovements of the head and neck, poor perfor-mance of rapid alternating movements, and aprax-ia. Hypertonia and hyperreflexia with clonus werenoted in the right leg. The gait was wide-based,with postural instability and leaning toward theleft. She was unable to stand on one foot. She wasadmitted to the neurology service.

On the second hospital day, a lumbar punc-ture was performed. Results of cerebrospinalfluid analysis are shown in Table 2; other testresults are listed in Table 1. An enzyme-linked im-munosorbent assay for serum antibodies againstHIV was negative. An electroencephalogramshowed diffuse theta slowing and frontal inter-mittent rhythmic delta activity, which was moreprominent in the right hemisphere than in theleft. There was no epileptiform activity (Fig. 1).

Repeated MRI of the brain after the administra-tion of gadolinium showed no changes and noevidence of abnormal enhancement. Acyclovir wasadministered intravenously.

The next day, a serum Lyme antibody test, a testof a throat swab for Mycoplasma pneumoniaenucle-ic acid, and cultures of blood and urine werenegative; results of other tests are listed in Table 1.On the fifth day, the patients condition appearedto be improved. She was oriented and remem-bered details of her past; dysmetria and truncal



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case records of the massachusetts general hospital


ataxia were reduced. Results on a repeated elec-troencephalogram were unchanged. The nextday, a repeated lumbar puncture was performed(Table 2).

Between the 7th and 18th hospital days, thepatients motor function gradually worsened,right-sided neglect developed, she became unable

to feed herself, her responsiveness and ability tofollow commands decreased, and she becameincontinent. She began lying in a fetal position,moaning and crying out unintelligible sounds.A skin test for tuberculosis, a test of a nasopha-ryngeal specimen for respiratory viral antigens,and a viral culture of a stool specimen were nega-tive. Nucleic acid testing for HIV RNA and testsfor antinuclear antibodies were negative. Levelsof free and total thyroxine were normal, and thethyroglobulin level was elevated (54.7 ng per milli-liter; normal range, 4 to 40). On the 12th day, the

acyclovir was discontinued, and ceftriaxone, ata dose of 2 g, was administered intravenously.A repeated electroencephalographic study showedincreased attenuation of background activity andless abundant frontal intermittent rhythmic deltaactivity. MRI on the 13th day showed new hyper-intense signal in the pons and middle cerebellarpeduncles with associated restricted diffusion ofwater on T2-weighted FLAIR images. Restricteddiffusion was also noted in the posterior limb ofthe left internal capsule. There was atrophy in theleft medial temporal lobe, with resolution of theabnormal hyperintense signal on FLAIR images.On the 14th day, a third lumbar puncture wasperformed.

On the 18th hospital day, a test result wasreceived.

Differential Diagnosis

Dr. Andrew J. Cole: I was involved in this patientscare from the time of her admission and am there-fore aware of the diagnosis. I will discuss the

case as it unfolded in order to illustrate the diag-nostic process and therapeutic decision makingthat took place. The patient lived semi-indepen-dently until she became pregnant 27 weeks beforeadmission. Her level of function at that time wasunknown, and because of the lack of informa-tion, it was not possible to determine either herlevel of function before her illness or the tempoof her disease.

Neurologic differential diagnosis relies primar-ily on the physical examination for localization

of lesions and on the history, especially the natureof onset and pace of progression, to identify thedisease process. This patients neurologic exami-nation showed abnormal cognitive function indi-cating dysfunction of the cortical and subcorticalgray matter, abnormal motor function indicat-ing dysfunction of the pyramidal motor system,

and choreiform movements indicating dysfunc-tion of the extrapyramidal motor systems. Thisexamination also showed a clumsy gait and dif-ficulty performing rapid alternating movements,indicating dysfunction of the cerebellum or itsconnections. With the limited information aboutthe pace of her disease, we needed to considerinherited, congenital, and acquired diseases thatcould be acute, subacute, or chronic, with static,episodic, or progressive tempos. We had to baseour differential diagnosis on the neurologic ex-amination, initial laboratory testing, and electro-

encephalographic and MRI studies.

Cerebrospinal Fluid Examination

The results of the cerebrospinal f luid analysis inthis patient showed a lymphocytic pleocytosiswith few red cells, a mildly elevated protein level,and a normal glucose level. These findings arecharacteristic of aseptic meningitis. We were thusconcerned about viruses, rickettsia, spirochetes,partially treated bacterial infection, a paramenin-geal focus of infection, certain autoimmune ill-nesses such as systemic lupus erythematosus orBehets disease, vasculitides, carcinoma, a reac-tion to the toxic effects of certain medicationssuch as nonsteroidal antiinflammatory drugs,and chemical meningitis related to the ruptureof a cyst. Although they were nonspecific, thecerebrospinal f luid findings provided support forthe possibility of acute or subacute infection orinf lammatory illness. The presence of an inflam-matory response made chronic degenerative diseas-es such as Huntingtons disease, Wilsons disease,and systems abiotrophies such as multisystem

atrophy unlikely.

Electroencephalographic Studies

The initial electroencephalogram was markedlyabnormal, but the findings were nonspecific(Fig. 1). The slow and attenuated posterior domi-nant rhythm suggests cortical gray-matter dis-ease, whereas the intermittent frontal rhythmicdelta activity suggests subcortical gray-matterdisease. The monomorphic slow waves also sug-gest that initially the subcortical white matter



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Table 1. Results of Laboratory Tests.*

VariableReference Range

for Adults On AdmissionOn Hospital

Day 2

Hematocrit (%) 36.046.0 (in women) 37.4 35.2

Hemoglobin (g/dl) 12.016.0 (in women) 13.2 12.1

White-cell count (per mm3) 450013,000 8,100 7,600

Differential count (%)

Neutrophils 4062 72

Lymphocytes 2740 21

Monocytes 411 6

Eosinophils 08 1

Basophils 03 0

Platelet count (per mm3) 150,000350,000 236,000 192,000

Mean corpuscular volume (m3) 80100 89

Erythrocyte sedimentation rate (mm/hr) 125 26

Glucose (mg/dl) 70110 78 73

Sodium (mmol/liter) 135145 135 137

Potassium (mmol/liter) 3.44.8 3.5 3.4

Chloride (mmol/liter) 100108 106 104

Carbon dioxide (mmol/liter) 23.031.9 26.0 25.2

Urea nitrogen (mg/dl) 825 8 4

Creatinine (mg/dl) 0.61.5 0.5 0.6

Bilirubin (mg/dl)

Total 0.01.0 0.1

Direct 00.4 0.0

Protein (g/dl)

Total 6.08.3 7.7 7.4Albumin 3.35.0 3.5

Globulin 2.64.1 4.2

Phosphorus (mg/dl) 2.64.5 3.0

Magnesium (mmol/liter) 0.71.0 0.75

Calcium (mg/dl) 8.510.5 9.2

Creatine kinase (U/liter) 40150 (in women) 62

Alkaline phosphatase (U/liter) 30100 96

Aspartate aminotransferase (U/liter) 932 18

Alanine aminotransferase (U/liter) 730 15

Lipase (U/dl) 1.36.0 7.5Amylase (U/liter) 3100 79

Rapid plasma reagin Nonreactive

Human chorionic gonadotropin, quantitative(IU/liter)


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was relatively spared. Dr. Henson, may we reviewthe radiologic studies?

Dr. John W. Henson: Axial T2-weighted FLAIRimages from the MRI studies of the brain on theday of admission, performed without the admin-istration of gadolinium, revealed a region of hy-perintense signal in the left medial temporal lobe(Fig. 2A) and subtle increased signal in the pos-terior limb of the left internal capsule corre-sponding to the location of the corticospinaltract. These foci did not show restricted diffu-

sion or abnormal enhancement on a gadolinium-enhanced study performed the next day. The ap-pearance of the pons was unremarkable, and noother clinically significant findings were noted.Magnetic resonance venography of the head wasnormal.

By day 13, there had been marked changes.There was a region of abnormal signal in thepons (Fig. 2B), with areas of restricted diffusionon the diffusion-weighted image and apparent-

diffusion-coefficient maps. The hyperintensity ofthe left medial temporal lobe had resolved, andthere was volume loss in the region of the hippo-campal formation. There was restricted diffusionin the left corticospinal tract (Fig. 2C); no abnor-mal enhancement was detected. These findingswere interpreted as resulting from a subacute en-cephalitis caused by an infection or an autoim-mune disorder.

Dr. Cole: In summary, this patient has a distur-bance of cognitive function, pyramidal tract and

cerebellar dysfunction, and a choreiform-move-ment disorder, and both laboratory tests and elec-troencephalographic and imaging studies suggestan infectious or autoimmune encephalitis.

Disorders of Movement

Chorea is a hyperkinetic movement disorder thatmay result from a number of neurologic diseases;it may appear or worsen during pregnancy, a con-dition known as chorea gravidarum. Most patients

Table 1. (Continued.)

VariableReference Range

for Adults On AdmissionOn Hospital

Day 2

Anticardiolipin IgM antibodies (MPL units) 015 10.6

Ceruloplasmin (mg/dl) 2750 84

Iron (g/dl) 30160 61

Iron-binding capacity (g/dl) 228428 464

Vitamin B12 (pg/ml) >250 430

Ferritin (ng/ml) 10200 9

Transferrin (mg/dl) 188341 361

Antistreptolysin O (IU/ml) 6.00)

Herpes simplex virus type 2 antibody IgG Negative

* To convert the values for glucose to millimoles per liter, multiply by 0.05551. To convert the values for urea nitrogento 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 total and direct bilirubin to micromoles per liter, multiply by 17.1. To convert the values forphosphorus to millimoles per liter, multiply by 0.3229. To convert the values for magnesium to milliequivalents perliter, multiply by 2. To convert the values for calcium to millimoles per liter, multiply by 0.250. To convert the valuesfor iron and iron-binding capacity to micromoles per liter, multiply by 0.1791. To convert the values for vitamin B12topicomoles per liter, multiply by 0.7378.

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 medicalconditions that could affect the results. The ranges therefore may not be appropriate for all patients.



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Table 2. Results of Cerebrospinal Fluid Tests.

Test* Normal Range Hospital Day 2 Hospital Day 6 Hospital Day 14

Opening pressure (mm H20) 17

Appearance Colorless Colorless, slightlyturbid

Pink, slightly turbid Slightly pink, clear

Red-cell count (per mm3)

Tube 1 None 650 2250 2360

Tube 4 None 28 2438 1100

White-cell count (per mm3)

Tube 1 05 40 100 36

Tube 4 05 37 46 10

Differential count (%)

Neutrophils

Tube 1 None 0 6 7

Tube 4 None 0 6 4

Lymphocytes

Tube 1 None 82 80 61

Tube 4 None 88 82 76

Reactive lymphocytes

Tube 1 None 11 0 18

Tube 4 None 3 0 8

Monocytes

Tube 1 None 7 7 9

Tube 4 None 9 4 9

Other hematic cells (%) Large mononuclear cellswith abundant cyto-plasm and nucleoli

Large mononuclear cellswith basophilic cyto-plasm and promi-

nent nucleoliTube 1 None 7 5

Tube 4 None 6 3

Unidentified cells (%)

Tube 1 None 0

Tube 4 None 2

Protein (mg/dl) 555 66 100 76

Glucose (mg/dl) 5075 53 73 65

Venereal Disease Research Laboratory test Nonreactive Nonreactive

IgG (mg/dl) 0.08.0 38.9

Albumin (mg/dl) 11.050.9 16.4

Oligoclonal bands on agaroseelectrophoresis

None seen in 80 concentrate

Several seen in 63concentrate

Grams stain No organisms No organisms No organisms

Acid-fast bacilli stain No organisms No organisms

Varicellazoster virus (PCR) None detected None detected

Enterovirus RNA (PCR) None detected

Cytomegalovirus DNA None detected None detected

EpsteinBarr virus DNA None detected None detected



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with this condition present during the secondtrimester with an isolated movement disorder thatresolves after delivery. The most common causesare acute rheumatic fever (Sydenhams chorea) andthe antiphospholipid-antibody syndrome. We alsoconsidered other illnesses associated with chorea,including systemic lupus erythematosus, Hunting-tons chorea, and Wilsons disease, although thelatter two illnesses were ruled out by the cerebro-spinal fluid and other findings.

Sydenhams chorea is a late complication ofinfection with group A streptococcus; the onsetoccurs months after acute infection. Most casesoccur in childhood, but up to 30% of patientsmay have recurrent chorea months or years afterthe initial episode.1 This patient had only a mini-mally elevated antistreptolysin-antibody titer, withno other evidence of recent streptococcal infectionor cardiac disease. The antiphospholipid-antibodysyndrome2 may be primary or secondary to sys-temic lupus erythematosus, and it may becomemanifest during pregnancy. This patient had no

symptoms or signs of systemic lupus, but lupusconfined to the central nervous system is well rec-ognized and may worsen during the course ofpregnancy. Antiphospholipid-antibody testing andall laboratory studies for lupus were negative.

Acute Viral Encephalitis

Herpes simplex encephalitis was initially consid-ered as one of the acute infectious encephalitidesbecause of the abnormality detected in the left

hippocampus on MRI. Unlike the arboviral en-cephalitides and West Nile virus encephalitis,which occur in the summer and fall, when mos-quitoes are abundant, herpes simplex encephali-tis occurs sporadically throughout the year. Thenegative results on cerebrospinal f luid testing forherpes simplex virus nucleic acid and the lack ofresponse to acyclovir made this diagnosis unlike-ly. Other common causes of viral encephalitis,including enteroviral and echoviral infections, aswell as infection with coxsackievirus, typically pro-

l

Figure 1. Electroencephalogram Obtained on the Second

Hospital Day.

The electroencephalogram is markedly abnormal,

showing modest slowing of the posterior dominant

background rhythm with bursts of frontal intermittentrhythmic delta activity (arrows), sometimes maximal

on the right and other times relatively symmetric bilat-erally. There are no epileptiform features and no period-

ic discharges.

Table 2. (Continued.)

Test Normal Range Hospital Day 2 Hospital Day 6 Hospital Day 14

Human herpes virus type 6 DNA (PCR) None detected

Herpes simplex virus (PCR) None detected None detected None detected

Mycoplasma pneumoniae (PCR) None detected

Encephalitis antibodiesEastern equine encephalitis None detected

West Nile virus IgM None detected

Cultures

Routine No growth No growth No growth

Fungal No growth No growth

Adenoviral No growth

Enteroviral No growth

Mycobacterial No growth

* PCR denotes polymerase chain reaction.



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duce prominent signs of meningeal irritation, withphotophobia, meningismus, nausea, and head-ache, but only minimal signs of focal cerebral dys-function, which may be fleeting and are not pro-gressive. Serologic tests in this patient ruled outthese agents.

Subacute Encephalitides

Paraneoplastic Encephalitis

Paraneoplastic limbic encephalitis may precedethe appearance of a tumor by months or even years.Psychiatric symptoms, memory failure, confusionand drowsiness, disordered respiration, ataxia, andcranial-nerve palsies have been reported. There

may be a modest increase in protein in the cere-brospinal fluid, but few cells are detected. Thispatients clinical and cerebrospinal fluid findingswere not consistent with paraneoplastic enceph-alitis.

Postinfectious Encephalitis

Several infections may be associated with postin-fectious encephalitis syndromes, including mea-sles, mumps, and rubella; inf luenza; EpsteinBarrvirus; and varicellazoster virus. Acute dissemi-nated encephalomyelitis may occur after a varietyof viral infections and after the administration ofrabies and smallpox vaccines.3 It usually beginswith nonspecific symptoms such as fever, head-ache, stiff neck, vomiting, and anorexia. Neuro-logic examination may show optic neuritis, ataxia,and focal weakness; seizures and decreased con-sciousness may develop. This patient did not havea recent history of immunizations or a viral infec-tion or evidence of optic neuritis, and the imag-ing findings were not typical of acute disseminat-ed encephalomyelitis.

The cerebrospinal fluid findings were animportant clue to the diagnosis in this case. Al-though the protein level in the initial cerebrospi-nal f luid specimen was modestly elevated, the IgGcomponent was markedly elevated. Dr. Roehrl,would you discuss the analysis and implicationsof this finding?

Dr. Michael H.A. Roehrl: Cerebrospinal fluid lev-els of total protein, albumin, and IgG obtainedon the second hospital day are shown in Table 2.

A

B

C

l

Figure 2. Brain Imaging Studies.

An axial T2-weighted FLAIR image (Panel A) obtained

on the day of admission showed a region of abnormal,hyperintense signal in the lef t hippocampus (arrow) and

in the posterior limb of the left internal capsule (not

shown). On the 13th hospital day, there was a new re-gion of hyperintense signal on T2-weighted FLAIR images

in the pons and middle cerebellar peduncles (Panel B,arrow) and restricted diffusion in the middle cerebellar

peduncle and posterior limb of the internal capsule asshown on the diffusion-weighted images (Panel C, arrow).



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Agarose-gel electrophoresis of cerebrospinal fluidrevealed oligoclonal bands in the gamma region(Fig. 3A). The cerebrospinal f luid to serum massconcentration quotients for albumin and IgGconcentrations were Q

Alb= 4.7103 and Q

IgG=

26.1103, corresponding to an IgG index of 5.6(normal value,


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ing panencephalitis has decreased with wide-spread vaccination against measles; however, itpersists in places where measles vaccination isuncommon.18 The incidence of this condition isincreased as much as 10 times in patients inwhom measles develops before the age of2 years; this patient had measles at 4 months of

age. The illness may present during pregnancy,possibly as a result of altered immune status.8,19

In summary, this patient presented with asubacute progressive neurologic disease charac-terized by widespread dysfunction of the centralnervous system, inflammatory features in thecerebrospinal fluid, and an extremely high levelof cerebrospinal fluid IgG. My colleagues and Ifavored the diagnosis of subacute sclerosing pan-encephalitis, a delayed consequence of her infec-tion with measles at 4 months of age. This condi-tion may have been exacerbated by her pregnancy.

Specimens of serum and cerebrospinal fluid fromthe 14th hospital day were sent for testing oflevels of antibodies against measles.

Dr. Roehrl: The measles-specific cerebrospinalfluid to serum IgG antibody index was elevated at31.8 (normal value, 1:800,000 1:81,920

Mumps

IgM Negative Negative

IgG 1:512 1:32



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sclerosing panencephalitis. The subcortical whitematter also showed reactive gliosis and extensivemicroglial activation (Fig. 4C). These findings are

nonspecific, but together with the serologic stud-ies, they are consistent with a diagnosis of sub-acute sclerosing panencephalitis.

Fixed and frozen specimens of brain tissuewere sent to Dr. William Bellini at the Centers forDisease Control and Prevention for immunohisto-chemical and molecular diagnostic studies.14,2830

Immunohistochemical analysis for measles virusnucleoprotein antigen was negative. Moleculardiagnostic studies performed to detect portionsof the measles genome were negative in repeatedattempts at amplification of regions of themeasles nucleoprotein gene. Weak signals weredetected in a real-time reverse-transcriptasepolymerase-chain-reaction assay, but there wereinsufficient amounts of amplified DNA productto perform a sequence analysis. As a result, it wasnot possible to definitively establish the presenceof measles virus in this case.

Dr. Nancy Lee Harris(Pathology): Dr. Cort, whoprepares the case histories for these exercises,was able to obtain some additional history, whichwas not available to the patients caregivers.

Dr. Alice M. Cort(Internal Medicine): Two yearsbefore admission, the patient was seen in theemergency department of another hospital be-cause of an episode of loss of consciousness thatwas associated with rolling of the eyes and arch-ing of the back. On examination, there were in-termittent involuntary movements of the head andneck and jerking movements of the arms. Deep-tendon reflexes were brisk and symmetric. CTscanning of the head and an electroencephalo-gram were normal. Further testing showed anearly pregnancy, which was electively terminated.During the next 20 months, the patient was lostto medical follow-up, and it is not known whetherthe abnormal movements stopped.

Dr. Harris: Dr. Cole, is it possible that subacutesclerosing panencephalitis began during this pa-tients previous pregnancy, stabilized, and thenworsened with the second pregnancy?

Dr. Cole: Subacute sclerosing panencephalitisis almost always a chronically progressive disease,although plateaus in the clinical course have beendescribed. The duration of the disease can beyears, however, and in retrospect, her symptoms2 years earlier may have been an earlier manifes-tation of the same disease. The effect of the pa-tients treatment on the appearance of the brainat autopsy and on the ability to detect viral anti-gens or DNA is not known.

A

B

C

l

Figure 4. Findings in the Brain at Autopsy.

A marked inflammatory inf iltrate around the vessels and

neuronal destruction are most prominent in this sectionof the brain stem, which contains macrophages, plasma

cells, and lymphocytes; there is prominent perivascularcuffing by lymphocytes (Panel A, hematoxylin and eosin).

In the cerebral cortex, neuronal populations are preserved,

but a marked gliosis is present (Panel B, immunohisto-chemical analysis for glial fibrillary acidic protein). Marked

microglial activation is present in the subcortical whitematter with rod-shaped CD68-positive cells (Panel C,

arrows; hematoxylin and eosin) (inset, immunohisto-chemical staining for CD68).



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Anatomical Diagnosis

Subacute sclerosing panencephalitis secondaryto measles virus infection.

Dr. Cole reports receiving consulting fees from GlaxoSmithKline,Abbott Laboratories, and Supernus Pharmaceuticals and lecture feesfrom GlaxoSmithKline, Abbott Laboratories, and Ortho-McNeil;

Dr. Henson, consulting fees from GlaxoSmithKline; and Dr. Frosch,consulting fees from Biogen Idec and Bristol-Myers Squibb. Noother potential conflict of interest relevant to this article was re-ported.

We thank Dr. Mandakolathur R. Murali, director of the ClinicalImmunology Laboratory, Department of Pathology, MassachusettsGeneral Hospital, for the analysis of the immunologic findingsin the cerebrospinal fluid.

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