Age: 20.0
Sex: F
Vaccine: HEP, MMR
Symptoms: Subacute sclerosing panencephalitis, Transferrin increased, Urine analysis abnormal, Varicella zoster virus serology positive, Venogram normal
Clinical narrative: It was report in a published article, title as stated above, that "A 20-year-old pregnant woman was admitted to this hospital at 26 weeks of gestation because of dizziness, confusion, and difficulty walking. Ten weeks before admission, the patient had a positive result on a home pregnancy test and presented to a neighborhood health center for prenatal screening. Tests for sickle cell trait, syphilis, and human immunodeficiency virus (HIV) and hepatitis B and C virus antibodies were negative. Serologic tests for varicella-zoster virus and rubella IgG were positive. Two weeks later, an endocerival specimen was positive for Chlamydia trachomatis infection and negative for gonorrhea. The patient missed follow-up appointments and treatment with azithromycin was initiated 4 weeks later. (She) was happy, with a childlike affect, a poor memory, confusion, and odd movements of her head. During the next 2 weeks, nausea and vomiting occurred daily and were controlled with metoclopramide. Four days before admission, dizziness and weakness on the left side developed; she began to fall to her left and vomited several times. The next day, she went to the ED of another hospital. On evaluation, the patient was oriented to location but not to date, day, or month, and she provided inconsistent information about her medical history. The uterus was gravid, and he remainder of the physical examination was normal. An EKG revealed sinus tachycardia and counterclockwise 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 per deciliter (5.6 mmol per liter). Tricyclic metabolites were present on toxicology screening of a urine specimen. CT scanning of the head revealed a slight, diffuse prominence of the ventricular system. There was no intracranial mass or other focal brain lesion. On the second hospital day, the patient was alert, calm, cooperative, and oriented to person, location, and current events but was not aware of details of her life. There were no tremors or extrapyramidal signs. Ultrasonographic examination revealed normal fetal anatomy and growth, corresponding to a gestation of 25 weeks 6 days. On the third day, the weakness, nausea and vomiting had resolved, and the patient was thought to have returned to her baseline mental status. She was discharged to the shelter with a recommendation to schedule a follow-up neurologic evaluation. At the shelter, she was dizzy, had difficulty walking, and fell into a chair. That evening, she was brought to the emergency department of this hospital. In the emergency department, the patient reported feeling "woozy" and nauseated. She noted a mild headache of gradual onset, extending bandlike across the brow. The history as given by the patient was inconsistent; the history was then provided by staff members of the shelter, and many details were lacking. She had had measles at 4 months of age and varicella infection in childhood. at 7 years of age, she injured her head in a fall but was said to have recovered fully. Immunizations included polio vaccine and diphtheria, pertussis, and tetanus vaccine series; measles vaccine felt (at 11 months of age); measles, mumps and rubella vaccine combination; and hepatitis B vaccine (between 2 and 3 years before admission, on enrollment in high school). She had no known allergies and did not use alcohol, illicit drugs, or tobacco. On examination in the ED, the patient was alert but somewhat uncooperative, with involuntary head movements. Her mental status was not formally assessed, but her level of cognitive function was said by a friend to be at baseline. The abdomen was soft, gravid, and not tender; the fetus appeared to be healthy. The 1st cranial nerve was not tested, and the 2nd through 12th nerves were intact. Strength was intact, and the gait was unsteady. The remainder of the examination was normal. After premedication with lorazepam at a dose of 1 mg to control involuntary movements, MRI of the brain was performed without administration of contrast material. On T2-weighted, FLAIR images, hyperintense signal was seen in the left hippocampus and parahippocampal gyrus as well as in the posterior limb of the left internal capsule. There was no evidence of restricted diffusion. Examination by a neurology consultant showed that the patient was oriented to person and place, with a childlike affect. Her speech was fluent, and naming was intact. She could read a short sentence 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 three items at 5 minutes on repeated examination. Smell and taste were not tested. The function of the other cranial never was intact. There were choreiform movements of the head and neck, poor performance of rapid alternating movements, and apraxia. Hypertonia and hyperreflexia with clonus were noted in the right leg. The gait was wide-based, with postural instability and leaning toward the left. She was unable to stand on one foot. She was admitted to the neurology service. On the second hospital day, a lumbar puncture was performed. An enzyme-linked immunosorbent assay for serum antibodies against HIV was negative. An EEG showed diffuse theta slowing and frontal intermittent rhythmic delta activity, which was more prominent in the right hemisphere than in the left. There was no epileptiform activity. Repeated MRI of the brain after the administration of gadolinium showed no changes and no evidence of abnormal enhancement. Acyclovir was administered IV. The next day, a serum Lyme antibody test, a test of a throat swab for Mycoplasma pneumoniae nucleic acid, and cultures of blood and urine were negative. On the fifth day, the patient's condition appeared to be improved. She was oriented and remembered details of her past; dysmetria and truncal ataxia were reduced. Results on a repeated EEG were unchanged. The next day, a repeated lumbar puncture was performed. Between the 7th and 18th hospital days, the patient's motor function gradually worsened, right-sided neglect developed, she became unable to feed herself, her responsiveness and ability to follow commands decreased, and she became incontinent. She began lying in a fetal position, moaning and crying out unintelligible sounds. A skin test for tuberculosis, a test of a nasopharyngeal specimen for respiratory viral antigens, and a viral culture of a stool specimen were negative. Nucleic acid testing for HIV RNA and tests for antinuclear antibodies were negative. Levels of free and total thyroxine were normal, and the thyroglobulin level was elevated (54.7 ng per milliliter). On the 12th day, the acyclovir was discontinued, and ceftriaxone, at a dose of 2 g, was administered IV. A repeated EEG study showed increased attenuation of background activity and less abundant frontal intermittent rhythmic delta activity. MRI on the 13th day showed new hyperintense signal in the pons and middle cerebellar peduncles with associated restricted diffusion of water on T2-weighted FLAIR images. Restricted diffusion was also noted in the posterior limb of the left internal capsule. There was atrophy in the left medical temporal lobe, with resolution of the abnormal hyperintense signal on FLAIR images. On the 14th day, a third lumbar puncture was performed. On the 18th hospital day, a test result was received. The patient lived   semi-independently until she became pregnant 27 weeks before admission. Her level of function at that time was unknown, and because of the lack of information, it was not possible to determine either her level of function before her illness or the tempo of her disease. This patient's neurological examination showed abnormal cognitive function indicating dysfunction of the cortical and subcortical gray matter, abnormal motor function indicating dysfunction of the pyramidal motor system, and choreiform movements indicating dysfunction of the extrapyramidal motor systems. This examination also showed a clumsy gait and difficulty performing rapid alternating movements, indicating dysfunction of the cerebellum or its connections. The results of the cerebrospinal fluid analysis in this patient showed a lymphocytic pleocytosis with few red cells, a mildly elevated protein level, and a normal glucose level. These findings are characteristic of aseptic meningitis. Although they were nonspecific, the cerebrospinal fluid findings provide support for the possibility of acute or subacute infection or inflammatory illness. The presence of an inflammatory response made chronic degenerative disease such as Huntington's disease, Wilson's disease and systems abiotrophies such as multisystem atrophy unlikely. The initial EEG was markedly abnormal, but the findings were nonspecific. The slow and attenuated posterior dominant rhythm suggests cortical gray-matter disease, whereas the intermittent frontal rhythmic delta activity suggests subcortical gray-matter disease. The monomorphic slow waves also suggest that initially the subcortical white matter was relatively spared. Axial T2-weighted FLAIR images from the MRI studies of the brain on the day of admission, performed without the administration of gadolinium, revealed a region of hyperintense signal in the left medical temporal lobe and subtle increased signal in the posterior limb of the left internal capsule corresponding to the location of the cortispinal tract. These foci did not show restricted diffusion or abnormal enhancement on a gadolinium-enhanced study performed the next day. The appearance of the pons was unremarkable, and no other clinically significant findings were noted. Magnetic resonance venography of the head was normal. By day 13, there had been marked changes. There was a region of abnormal signal in the pons, with areas of restricted diffusion on the diffusion-weighted image and apparent-diffusion-coefficent maps. The hyperintensity of the left medial temporal lobe had resolved, and there was volume loss in the region of the hippocampal formation. There was restricted diffusion in the left corticospinal tract; no abnormal enhancement was detected. These findings were interpreted as resulting from a subacute encephalitis caused by an infection or an autoimmune disorder. In summary, this patient has a disturbance of cognitive function, pyramidal tract and cerebellar dysfunction, and a choreiform-movement disorder, and both laboratory tests and EEG and imaging studies suggest an infectious or autoimmune encephalitis. This patient had only a minimally elevated antistreptolysin-antibody titer, with no other evidence of recent streptococcal infection or cardiac disease. The antiphospholipid-antibody syndrome2 may be primary or secondary to systemic lupus erythematosus, and it may become manifest during pregnancy. This patient had no symptoms or signs of systemic lupus. antiphospholipid-antibody testing and all laboratory studies for lupus were negative. Herpes simplex encephalitis was initially considered as one of the acute infectious encephalitis because of the abnormality detected in the left hippocampus on MRI. The negative results on cerebrospinal fluid testing for herpes simplex virus nucleic acid and the lack of response to acyclovir made this diagnosis unlikely. This patient's clinical and cerebrospinal fluid findings were not consistent with paraneoplastic encephalitis. This patient did not have a recent history of immunizations or a viral infection or evidence of optic neuritis, and the imaging findings were not typical of acute disseminated encephalomyelitis. The cerebrospinal fluid findings were an important clue to the diagnosis in the case. Although the protein level in the initial cerebrospinal fluid specimen was modestly elevated, the IgG component was markedly elevated. Cerebrospinal fluid levels of total protein, albumin, and IgG obtained on the second hospital day are shown. Agarose-gel electrophoresis of cerebrospinal fluid revealed oligoclonal bands in the gamma region. The cerebrospinal fluid to serum mass concentration quotients for albumin and IgG concentrations were QA1b=4.7x10-3 and QIgG=26.1x10-3, corresponding to an IgG index of 5.6. On the basis of an analysis developed by Reiber, this patient's results indicated markedly increased intrathecal IgG synthesis (intrathecal production fraction, 87.7%) without evidence of clinically significant blood-brain barrier dysfunction. The mass concentration ratio of IgG to total protein in the cerebrospinal fluid was 58.9%. This patient did not have syphilis, as shown by negative results on serologic testing and a symptom complex that was inconsistent with the disease. Examination of the cerebrospinal fluid shows pleocytosis and a moderately elevated protein level, with up to 50% of the cerebrospinal fluid protein composed of immunoglobulins. The diagnosis is confirmed by a high antirubella-antibody titer in the cerebrospinal fluid. In summary, this patient presented with a subacute progressive neurologic disease characterized by widespread dysfunction of the central nervous system, inflammatory features in the cerebrospinal fluid, and an extremely high level of cerebrospinal fluid IgG. My colleagues and I favored the diagnosis of subacute sclerosing panencephalitis, a delayed consequence of her infection with measles at 4 months of age. This condition may have been exacerbated by her pregnancy. Specimens of serum and cerebrospinal fluid from the 14th hospital day were sent for testing for levels of antibodies against measles. The measles-specific cerebrospinal fluid to serum IgG antibody index was elevated at 31.8. Measles-specific IgM antibodies were not detected in the serum. This profile indicates a chronic immune response to measles infection in the cerebrospinal fluid compartment. The results confirm the diagnosis of subacute sclerosing panencephalitis in the patient. The disease was a late consequence of persistent infection with measles virus. When we made the diagnosis in this patient, she was 28 weeks of gestation, and her condition was deteriorating rapidly. We believed that an attempt at treatment was in the best interest of the patient and her fetus. We treated her with interferon and inosine pranobex for 8 weeks, without any clear clinical benefit. After the delivery of a healthy baby by elective cesarean section at 34 weeks gestation, a decision was made to discontinue treatment with the consent of the patient's mother. The patient died 6 weeks later. The autopsy revealed inflammatory infiltrates containing macrophages, plasma cells, and lymphocytes around vessels, with neuronal destruction and reactive gliosis that were most prominent in the brain stem. No viral inclusions of the type usually seen in acute measles encephalitis were seen in the nuclei or cytoplasm of any cell types (neurons, glia, or vascular endothelial cells). In the cerebral cortex, neuronal populations were perserved, but there was marked gliosis with reactive astrocytes. The brain stem was softened by the pathologic process, but the hemispheric white matter was firmer than normal; this was most evident when the brain was cut in the fresh state. This firmness corresponds to the sclerosis in the name, subacute sclerosing panencephalitis. The subcortical white matter also showed reactive gliosis and extensive microglial activation. These findings are nonspecific, but together with the serologic studies, they are consistent with a diagnosis of subacute sclerosing panencephalitis. Immunohistochemical analysis for measles virus nucleoprotein antigen was negative. Molecular diagnostic studies performed to detect portions of the measles genome were negative in repeated attempts at amplification of regions of the measles nucleoprotein gene. Weak signals were detected in a real-time reverse-transcriptase-polymerase-chain-reaction assay, but there were insufficient amounts of amplified DNA product to perform a sequence analysis. As a result, it was not possible to definitively establish the presence of measles virus in this case. Two years before admission, the patient was seen in the emergency department of another hospital because of an episode of loss of consciousness that was associated with rolling of the eyes and arching of the back. On examination, there were intermittent involuntary movements of the head and neck and jerking movements of the arms. Deep-tendon reflexes were brisk and symmetric. CT scanning of the head and an electroencephalogram were normal. Further testing showed an early pregnancy, which was electively terminated. During the next 20 months, the patient was lost to medical follow-up, and it is not known whether the abnormal movements stopped. Anatomical Diagnosis: Subacute sclerosing panencephalitis secondary to measles virus infection. A copy of the published article is attached as further documentation of the patient's experience.