Age: 13.0
Sex: M
Vaccine: MMR
Symptoms: Herpes simplex serology negative, Immunoglobulin therapy, Immunohistochemistry, Inflammation, Intensive care
Clinical narrative: Information has been received from a physician, author of a literature article, title as stated above, concerning a 13 year old male patient who on an unspecified date, was vaccinated with a dose of MMR II (dose, route and lot number not reported). Measles inclusion body encephalitis (MIRE) was a disease of the immunocompromised host and typically occurred within 1 year of acute measles infection or vaccination. In addition to acute encephalitis and subacute sclerosis panencephalitis in immunocompetent hosts, measles virus could cause measles inclusion body encephalitis (MIBE) in immunocompromised hosts. MIBE presented typically with focal and intractable seizures within 1 year of initial measles infection. The mortality rate was high, and no effective treatment existed. The patient was a 13-year-old boy who received a diagnosis of X-linked chronic granulomatous disease (CGD) at 2 years of age after serratia lymphadenitis. The patient traveled frequently to urban, most recently 4 years before this illness. He received 1 documented MMR at one year of age, and had no history of a measles-like illness or measles exposure at any time. A second MMR was not documented. Despite prophylactic therapy for CGD with trimethoprim-sulfamethoxazole and thrice-weekly y-interferon, he had multiple staphylococcal liver abscesses that required extensive surgical drainage. Poor compliance with interferon was documented. Because of the severity of his repeated infections, SCT was performed. The conditioning regimen comprised fludarabine (180 mg/m2), busulfan (6.4 mg/kg), and equine anti-thymocyte globulin (ATG). Because of fever and chills after equine ATG, he received rabbit ATC for the last 3 days. On day -1, he began graft-verus-host disease (GVHO) prophylaxis with cyclosporine (CsA) and on day 0 with mycophenolate mofetil. He received anti-infective prophylaxis with oral acyclovir, itraconazole, intravenous vancomycin, and weekly CMV-immune globulin. On SCT day +10, he was admitted for fever and neutropenia and treated with broad-spectrum antibiotics. On day +11, a pruritic, erythematous rash developed, and his CsA dose was increased to treat presumed GVHD. Rash and low-grade fever persisted, and conjunctivitis and photophobia developed. Skin biopsy was consistent with GVHD; oral steroids were started with improvement in the rash. By day +19, he had engrafted with 99% donor chimerism by variable N-terminal repeats. On day +23, he presented with fever, headache, and eye pain. Head computed tomography scan and ophthalmologic examination were normal. Lumbar puncture showed 13 white blood cells (WBCs; 30% neutrophils, 52% lymphocytes, and 18% monocytes), glucose of 50 mg/dL, and protein of 34 mg/dL. Bacterial fungal and viral cultures were negative; cryptococcal antigen was negative. His symptoms improved, and he was discharged on day +27. By day +33, he had worsening erythematous rash on his face, arms, and trunk, and corticosteroids were increased to treat GVHD. On day +38, he was admitted to Hospital with afebrile focal seizures involving his left hand. Immunosuppressive medications on admission included CsA, mycophenolate mofetil, and prednisone. CsA was stopped and tacrolimus was started for possible CsA-induced seizures. The seizures progressed to involve his chin and tongue despite anticonvulsant therapy with clonazepam and valproic acid. Electroencephalogram showed focal status epilepticus (epilepsia partialis continua) involving the right frontal cortex. No neurologic abnormalities were noted on brain magnetic resonance imaging (MRI). He was transferred to the intensive care unit, where a continuous infusion of midazolam followed by a phenobarbital coma were unsuccessful in completely controlling seizures. Subclinical seizures persisted despite phenobarbital levels >300 ug/mL. Lumbar puncture on day +43 was significant for glucose of 43 mg/dL, protein of 77 mg/dL, 51 WBCs/mm3 (88% lymphocytes, 8% monocytes, and 4% neutrophils), and 8 red blood cells/mm3. A repeat lumbar puncture on day +49 showed less inflammation, with glucose 59 mg/dL, protein 54 mg/dL, 9 WBCs/mm3, and 294 red blood cells/mm3. Spinal fluid cultures for bacteria, fungi, mycobacteria, and viruses were negative. Cryptococcal antigen was negative. Polymerase chain reaction (PCR) for herpes simplex virus (HSV) -1 and 2, human herpesvirus-6, enterovirus, Epstein-Barr virus, and arboviruses were negative. CMV antigenemia was negative. No antibodies to measles, mumps, varicella, adenovirus, HSV-1/2, or lymphocytic choriomeningitis virus were detected in the spinal fluid. Brain MRI on day +45 showed bilateral patchy areas of cortical swelling and signal abnormality, predominantly involving the frontal and temporal lobes, compatible with meningoencephalitis. A right frontal lobe lesion showed restricted diffusion. In retrospect, the initial MRI showed a small focus of signal abnormality in the right frontal cortex. Subsequent brain MRIs on day +49 and day +55 showed progressive involvement of the cerebral cortex and the basal ganglia. Treatment dose intravenous acyclovir was started on day +44 and was changed to intravenous gancyclovir on day +47. Brain biopsy on day +53 demonstrated numerous eosinophilic intranuclear inclusion bodies and minimal perivascular inflammatory reaction. Inclusions of varied sizes were seen in astrocytes, oligodendroglial cells, and neurons. Electron microscopic examination showed that the inclusions were clusters of relatively long, curved, tubular structures consistent with paramyxovirus nucleocapsids. Extensive demyelination of axons was seen. Immunohistochemistry for HSV-1/2, CMV, human immunodeficiency virus, adenovirus, and Epstein-Barr virus was negative. Measles studies of the brain tissue performed at the Centers for Disease Control and Prevention were positive by reverse transcriptase (RT)- PCR for wild-type measles virus, genotype D3, and by immunohistochemistry for measles nucleoprotein. Measles virus was isolated using the B95a marmoset lymphoblastoid cell line, and genotype D3 was confirmed by nucleotide sequence analysis of RT-PCR products. In addition, repeat skin biopsy on day +61 was consistent with GVHD. After demonstration of intranuclear inclusion bodies, intravenous ribavirin was initiated on day +57 (loading dose of 30 mg/kg, then 15 mg/kg every 6 hours for 16 doses, and then 7.5 mg/kg every 8 hours). Despite ribavirin and intensive supportive therapy, the patient's neurologic status continued to deteriorate, and brain death was determined on day +70. Ribavirin was discontinued. Life support was stopped with the family's agreement on day +92, and the patient died. No postmortem study was permitted. Immunohistochemistry and RT-PCR of the initial skin biopsy (day +15) were negative for measles virus. RT-PCR performed on the donor stem cells was negative for measles virus. MIBE occurred typically in immunocompromised patients within 1 year of measles infection. Patients usually presented with afebrile focal seizures and altered mentation. The seizures tended to be refractory to anticonvulsant therapy, and electroencephalogram often showed epilepsia partialis continua. The clinical features of the authors' patient was consistent with this picture. Imaging studies such as brain MRI and computed tomography were often normal. Diagnosis required brain biopsy. The diagnosis of MIBE could be confirmed by RT-PCR for measles virus RNA or by immunohistochemistry. The prognosis was poor, with a 76% mortality rate, and all survivors manifesting significant neurologic sequelae. This case was unusual given the absence of apparent recent measles exposure or vaccination. The patient had not traveled outside during the year before SCT. The authors' patient was born during the epidemic of 1989-1991 (birth year 1989) and had traveled only to foreign country, where the D3 genotype had not been endemic in recent years. An undiagnosed case of measles in the period 1989-1991 would suggest a latency period of 12 years, which was not typical of MIBE. The median length of time from acute measles infection or exposure to MIBE onset was 4 months. It was unlikely that the authors' patient's history of CGO placed him at increased risk for measles complications, but his SCT clearly did. The authors' patient might have had a measles infection or exposure that was not recognized, although this was unlikely with his close medical supervision and prolonged hospitalizations the preceding year. The authors' patient had a rash with conjunctival injection 27 days before the seizure onset, and skin biopsy suggested GVHO. The authors believed that the rash and conjunctivitis were not manifestations of measles because the skin biopsy obtained soon after rash onset was consistent histologically with GVHD, and immunohistochemistry and RT-PCR both were negative for measles virus. The authors also doubt that the stem cell donor was the source of measles infection as she had no history of measles-like infection or travel to an endemic area, and RT-PCR on the donor stem cells was negative for measles. MIBE had been reported 9 months after measles vaccination; however, the authors' patient received the measles vaccination many years before SCT, and the identification of genotype D3 was inconsistent with the well-established vaccine virus genotype (vaccine genotype was genotype A). This case demonstrated the diagnostic utility of a brain biopsy in cases of encephalitis of unknown cause, particularly in immunocompromised individuals. Early brain biopsy might enable diagnosis and early institution of antiviral therapy. The utility of ribavirin or other therapies was unknown in MIBE. Ribavirin inhibits measles replication in vitro and had been used with some success to treat measles infections in immunocompetent hosts The authors' patient, suggested the possibility of a long latency period between measles infection and onset of MIBE. The authors' case illustrated the importance of early brain biopsy in cases of obscure encephalitis or encephalopathy in the immunocompromised host. Additional information has been requested.