¹Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

²Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

³Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

⁴Department of Radiology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

⁵Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

Correspondence to: Dr N L Antunes, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA

Epilepsia partialis continua (EPC) is a condition defined by prolonged focal myoclonus. Often resistant to therapy, EPC in children is frequently present in Rasmussen encephalitis, a form of chronic encephalitis of uncertain etiology. We discuss a child who developed bilateral EPC 5 months after a bone marrow transplant. Neuroimaging studies showed signal abnormalities on both sensory-motor areas. An extensive search failed to reveal the etiology of the disorder, but treatment with a broad-spectrum anti-viral agent was associated with resolution of the process. An unidentified infectious agent may be responsible for an encephalitis of the motor strip in immunosuppressed patients. Bone Marrow Transplantation (2000) 26, 917-919.

epilepsia partialis continua; bone marrow transplant; encephalitis

A type of myoclonus in which one group of muscles, usually the flexors of the hand and fingers, is continuously involved in rhythmic monophasic contractions is called epilepsia partialis continua (EPC).¹ In children, EPC is the characteristic manifestation of Rasmussen encephalitis, but can also be encountered in mitochondrial disorders or migrational defects.² A number of different disorders have been associated with EPC in the adult population.³ Recently, an HIV-infected patient was reported with isolated chronic EPC.⁴ The etiology was unclear, but since no other viral agent was identified, focal HIV 1 encephalitis was the presumed cause. We followed an HIV-negative child with acute myelogenous leukemia who developed a strikingly similar disorder after a bone marrow transplant. It seems plausible that an unidentified infectious agent may be responsible for an encephalitis of the motor area presenting as EPC in immunocompromised patients.

Case report

A 6-year-old Peruvian boy was well until January 1998 when he noticed left ear discomfort followed by a left facial droop. A right facial palsy ensued, and 3 months later a complete blood cell count (CBC) revealed an elevated white blood cell count (WBC) with 15% atypical cells. He was referred to Memorial Sloan-Kettering Cancer Center (MSKCC) where a bone marrow aspirate revealed 36% blasts. The morphology, immunophenotype and cytogenetic studies were consistent with AML M2 FAB morphology subtype. The patient was treated with four courses of dexamethasone, daunorubicin, cytosine arabinoside (Ara-C), thioguanine and etoposide along with intrathecal cytosine arabinoside. Remission was achieved with clearing of the neurologic deficits. On 30 July 1998 he received a T-cell depleted bone marrow transplant (BMT) from his HLA-matched brother. Pre-transplant cytoreduction consisted of 1500 cGy total body irradiation preceded by 600 cGy whole brain irradiation, thiotepa and cyclophosphamide. He received 3 doses of Ara-C intrathecally at 2, 3 and 4 months post transplant for CNS prophylaxis. After successful engraftment the patient was discharged and returned to his country in the first week of December.

The child remained asymptomatic until 30 December 1998 (5 months post BMT), when he developed myoclonic jerks of the right hand, and a few days later of the left hand. MRI showed bilateral sub-cortical, non-enhancing lesions in the posterior frontal lobes, hyperintense on FLAIR images (Figure 1). A left anterior frontal lesion with the same characteristics was also present. The patient was given phenytoin and valproic acid without improvement, and was then transferred to MSKCC. On arrival at our institution he was awake and alert. Bilateral asynchronous myoclonus affecting the flexors of both hands was present. The myoclonic jerks would persist during sleep and even during anesthesia with propofol and on occasion would also involve the flexors of the arm. An EEG showed frequent pseudoperiodic, bilateral, independent and multifocal sharp and slow waves that were asynchronous with the myoclonic movements. The cerebrospinal fluid (CSF) showed 1 WBC and 1 RBC/mm³. The glucose and protein content was 61 mg/dl and 15 mg/dl, respectively. CSF cultures were negative for virus, bacteria and fungi. Polymerase chain reaction techniques were negative for EBV, toxoplasmosis, HHV6, JC virus, BK virus and mycobacterium tuberculosis. No viral particles were identified by electron microscopy. CMV, EBV, measles and Lyme disease titers were negative in the blood and CSF. Anti-neuronal antibodies including anti-Hu antibodies were not present. Serum immunoglobulin levels were normal, as were the CD3 and CD8 cell counts. The CD4 count was low (198/mm³). The PHA proliferation response (62 548) approached normal values (>69 000).

Treatment with broad-spectrum antibiotics, anti-toxoplasma therapy and the addition of clonazepan and valproic acid did not improve the myoclonus. Marked weakness of the arms developed. The MRI showed progression of the lesions (Figure 2) involving the pre- and post-central gyri while other asymptomatic white matter lesions became apparent in both hemispheres. A repeat spinal tap 3 weeks after admission showed increased IgG but negative oligoclonal bands. An open biopsy of a right temporal lesion revealed gliosis and vascular endothelial hypertrophy. There were isolated necrotic or degenerating cells, some exhibiting nuclear alterations suggestive of a viral cytopathic effect, but definite viral inclusions were not seen and electron microscopy revealed no virions or other pathogens. Immunohistochemical studies were negative for herpes simplex, varicella-zoster, CMV, adenovirus, HIV-1 and JC virus. Nevertheless, in view of the clinical and radiological progression, cidofovir, a broad-spectrum anti-viral agent, was given for a total of four doses over a period of 6 weeks. Two days later the myoclonus improved and after 1 month only occasional myoclonus of the fingers persisted. The MRI abnormalities cleared (Figure 3) and 1 year after discharge the child is asymptomatic.

Discussion

Epilepsia partialis continua is defined by the presence of clonic movements of one muscle group which are repeated at fairly regular, short intervals and persist for days or months.⁵ As described by Juul-Jensen and Denny-Brown, each twitch is brief and sudden, and although involving predominantly one muscle group, may from time to time include other muscles on the same side of the body without impairing consciousness. Although considered by some to be a form of focal status epilepticus, the absence of Jacksonian march, the poor response to anticonvulsants, and the frequent absence of synchronism between the muscular contractions and the spike activity on EEG makes EPC a distinct condition. Our patient fulfills the criteria of EPC syndrome, with the unusual additional feature of bilateral asynchronous involvement.

EPC was first described by Kojewnikoff in 1895⁶ and in 1927 Omorokow⁷ reported 52 cases during an outbreak of Russian spring-summer encephalitis. In children, EPC is frequently caused by Rasmussen encephalitis, a condition of unclear etiology that has been associated with antibodies against glutamic acid receptors and with cytomegalovirus infection.^8,9 The causes of EPC include metabolic and developmental errors, brain tumors, demyelinating disorders, trauma and strokes. Recently, Shavit and associates¹⁰ described three adults with cancer and focal sensorimotor encephalitis presenting with EPC. The presence of high titers of the antineuronal antibody anti-Hu led the authors to believe that EPC may be a manifestation of paraneoplastic encephalitis.

To our knowledge, EPC in the setting of a bone marrow transplant has not been described. The clinical and radiological evolution of the case we report was extremely unusual. At the time of presentation, the MRI showed two lesions mainly involving the white matter underlying the motor strip, but also an anterior frontal lesion that regressed spontaneously as new foci developed and the rolandic abnormalities markedly worsened. After a period of increased activity, the lesions regressed and the myoclonus nearly resolved. The cause for the improvement was unclear. Although it followed the administration of cidofovir, it may have been coincidental. The radiological picture, CSF profile and biopsy results excluded vascular, neoplastic and demyelinating disorders. Our patient did not express anti-neuronal antibodies by immunohistochemistry or Western blot. Furthermore, although limbic encephalitis has been described in adolescents, no paraneoplastic syndromes have been associated with leukemia. An extensive search for infectious agents was negative. Examination of biopsy material showed gliosis, scattered necrotic or degenerating cells, some exhibiting nuclear alterations suggestive of viral cytopathic effect, but no viral inclusions or other diagnostic abnormalities were found on immunohistochemical assessment or electron microscopy. However, the biopsies were obtained far from the motor cortex in areas where the disease could have been regressing.

An unrecognized infectious agent may yet have been responsible for this child's illness. Recently, Bartolomei et al⁴ reported a 58-year-old HIV-positive man, who presented with EPC and magnetic resonance images identical to our patient. An extensive search for an opportunistic infection was unrewarding, but the patient improved markedly after administration of prednisone combined with anti-HIV agents, which led the authors to speculate that direct central nervous system involvement by HIV-1 was responsible for the encephalitis. However, if the encephalitis was due to another infectious agent, the resolution of the lesions may simply have reflected the overall improvement in immunologic function promoted by anti-retroviral therapy.

Our case demonstrates that a focal encephalopathy, mainly affecting the motor area and expressed clinically by the development of EPC, may complicate the course of bone marrow transplantation. A similar case involving an immunocompromised patient has been described, but no infectious agent has been clearly implicated.⁴ We postulate that an unrecognized infectious pathogen may be responsible for an immunosuppression-associated rolandic encephalitis that may be reversed with measures that improve immune responsiveness.

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10 Shavit YB, Graus F, Probst A et al. Epilepsia partialis continua: a new manifestation of anti-Hu-associated paraneoplastic encephalomyelitis. Ann Neurol 1999; 45: 255-258, MEDLINE

Figure 1 Coronal FSE-FLAIR image revealing bilateral predominantly subcortical white matter lesions without associated mass effect.

Figure 2 Axial FSE-FLAIR image showing progression of the symmetric bilateral frontal-parietal lesions with mild gyral swelling.

Figure 3 Axial FSE-FLAIR image obtained after the institution of anti-viral therapy shows a normal appearing brain with complete resolution of the bifrontal-parietal lesions.