Based on research that describes Alexander's disease as ... BMT for Alexander's disease .... Special thanks to Dr Ruth Ramsey, Dr Robert Wollmann, Laurel.
Bone Marrow Transplantation, (1997) 20, 247–249 1997 Stockton Press All rights reserved 0268–3369/97 $12.00
Case report Allogeneic bone marrow transplantation for Alexander’s disease M-J Staba1, S Goldman1, FL Johnson 2 and PR Huttenlocher3 Departments of 1Pediatric Hematology/Oncology, 3Pediatrics, Neurology, and Pediatric Neurology, University of Chicago Children’s Hospital, University of Chicago Hospitals, Chicago, IL; and 2Pediatric Hematology/Oncology, Oregon Children’s Cancer Center, Oregon Health Sciences University, Portland, OR, USA
Summary:
Case report
In this case report, we evaluate the efficacy of allogeneic bone marrow transplantation (BMT) in a 7-month-old female with the infantile form of Alexander’s disease. Based on research that describes Alexander’s disease as a leukodystrophy which may result from an unidentified enzyme deficiency, we attempted marrow transplantation to reverse or arrest the patient’s neurological deterioration. Despite an initial return to her pretransplant neurological state, the patient’s neurological status deteriorated. Marrow transplantation was not effective in changing her prognosis with Alexander’s disease. Keywords: Alexander’s disease; leukodystrophy; alloBMT
A 4-month-old Caucasian female presented with the developmental milestones of a 1.-month-old infant and a history of ventriculoperitoneal shunt placement for hydrocephalus, megalencephaly and a generalized tonic–clonic seizure. Neurological examination revealed head lag, absent deep tendon reflexes, generalized proximal weakness, roving nystagmus and choreathetoid and ballistic movements of all four extremities. A brain auditory evoked response (BAER) was consistent with nerve deafness. An electroencephalogram (EEG) revealed generalized slow waves. A brain CT, MRI (Figure 1) and biopsy (Figure 2) were consistent with AD.
More than 30 patients with Alexander’s disease (AD) have been reported since Alexander’s description, in 1949, of an infant with megalencephaly, hydrocephalus and progressive neurological deterioration.1 All have died secondary to the effects of neurodegeneration.2 Some researchers have classified AD as a leukodystrophy, although an enzyme deficiency has not been documented.3,4 Since the etiology of the characteristic Rosenthal fiber (RF) accumulation in AD is not known, treatment is limited to supportive care alone. Patients with other leukodystrophies, particularly late infantile onset metachromatic leukodystrophies, have demonstrated slowing and sometimes arrest of neurological degeneration following BMT.5–8 Due to the degenerative and invariably fatal nature of AD and its similar clinical presentation to other leukodystrophies, we attempted to slow the neurological deterioration of an afflicted infant by allogeneic bone marrow transplantation (BMT) and report the clinical outcome.
Correspondence: Dr M-J Staba, Department of Pediatrics, Section of Hematology/Oncology, University of Chicago Children’s Hospital, 5841 South Maryland, Chicago, IL 60637, USA Received 20 November 1996; accepted 15 April 1997
Figure 1 T2 weighted magnetic resonance image reveals diffuse increased signal intensity of the white matter. This change is superimposed on diffuse cerebral atrophy with ventricular enlargement and enlarged cortal sulci.
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confirmed by EEG. A repeat brain CT showed no change in the low densities diffusely scattered throughout the white matter. A repeat BAER revealed no improvement. The patient was weaned off ventilatory support after 1 month and remained asymptomatic on room air. Her EEG showed no seizure activity nor generalized slow waves. She was discharged home 72 days following transplant on oral feeds, phenobarbital and diazepam. Three months following BMT, she developed difficulty swallowing and progressive neurological deterioration. New onset spontaneous facial jerks, a right gaze nystagmus and bilateral exotropia were noted. Her extremities were now hypertonic with decerebrate posturing. A brain CT showed an extension of the diffuse white matter abnormality throughout the cerebrum (Figure 3), spreading to the brain stem (not shown). A nasojejunal feeding tube was placed because of her loss of swallow coordination. Her neurological function progressively worsened with episodes of apnea and bradycardia, and she died of respiratory failure 131 days following BMT. A post-mortem examination was not obtained.
Discussion The rationale for treating our patient by BMT was based on the clinical and immunohistochemical similarities
Figure 2 Electron micrograph of a fibrillary astrocytic process demonstrating densely osmiophilic deposits typical of Rosenthal fibers. Bar represents 1 × 10−5 m.
Due to the poor prognosis of AD and some evidence of benefit from marrow transplantation in other leukodystrophies, the infant was treated by a BMT at 7 months of age from her 4-year-old unaffected brother, completely matched at the major histocompatibility complex, on a protocol approved by the Institutional Review Board of the University of Chicago Hospitals. The preparative regimen consisted of busulfan (16 mg/kg total dose) on days −9 to −6 and cyclophosphamide (200 mg/kg total dose) on days −5 to −2. Graft-versus-host disease prophylaxis consisted of methotrexate on days +1, +3, +6 and +11 and then weekly until day +46. Post-transplant management included transfusions with irradiated washed packed red blood cells and platelets. Treatment with mezlocillin, gentamicin, vancomycin and amphotericin was administered for 2 weeks for fever and neutropenia. Engraftment was documented by day +15 (absolute neutrophil count greater than 250/mm 3 for 2 consecutive days) and the patient became platelet transfusionindependent on day +17. She was discharged 22 days after transplant on oral feeds, dilantin and phenobarbital. She was readmitted 31 days after transplant with Pneumocystis carinii pneumonia for which she was treated with intravenous trimethoprim-sulfamethoxazole and ventilatory support. While intubated, she developed status epilepticus
Figure 3 Computed tomography brain scan taken 3 months after BMT reveals further progression of the periventricular and diffuse white matter abnormality.
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between AD and other leukodystrophies, particularly metachromatic leukodystrophy (MLD), which has been successfully treated by BMT.5–8 Our patient, who presented with the infantile form of AD characteristically had a life expectancy of between 2 months and 7 years, with the primary cause of death relating to progressive neurologic degeneration.1,9 Her brain CTs and MRI revealed progressive diffuse demyelination which were characteristic of AD and other forms of leukodystrophy.10 Microscopic analysis of her brain biopsy revealed an accumulation of intracytoplasmic RFs which was characteristic for AD.3 It is hypothesized that RFs may accumulate in AD due to dysfunctional astrocyte metabolism.11,12 Whether the massive increase of RFs is secondary to an increased synthesis or reduced degradation of proteins is currently unknown. 3,9,11 Such an abnormality in the proteolytic system of astrocytes is believed to cause the demyelination seen in patients with AD.4,9 The progressive neurodegeneration due to RF deposition and myelin loss suggest that AD is a leukodystrophy secondary to an abnormality of astrocyte protein metabolism. In similar leukodystrophies, such as MLD, reduced amounts of an enzyme have resulted in an abnormal accumulation of substrate leading to demyelination and neurodegeneration.7,10 MLD results from a deficiency of the enzyme, arylsulfatase A, which causes intralysosomal storage of cerebroside sulphate. In the hope of inducing or restoring normal levels of arylsulfatase A, transplanted marrow cells have been used as a source of the missing enzyme. A 4-year-old child with late infantile onset MLD who was treated by BMT maintained stable neurological function to 11 years of age, whereas her affected older sibling with MLD died by 8 years of age. This patient’s enzyme deficiency resolved, proving that BMT indirectly replaced the missing enzyme.5–8 We assessed our patient’s progress after BMT by correlating therapeutic response with clinical assessment, EEGs and radiographic studies. Our patient initially demonstrated a temporary increase in seizure activity after transplant. Serial neurophysiologic studies in a child with late infantile onset MLD following treatment by BMT demonstrated initial continuance of deterioration also.8 Our patient returned to her pre-transplant neurological state and remained clinically stable for approximately 1 month as documented by neurological examinations, EEGs and brain CTs before and after transplant. However, in the final month of her life, she deteriorated neurologically and a brain CT revealed progression of demyelination. We suggest several possible reasons for the failure of BMT to improve the quality of life for our patient with AD. At the time of transplantation, she had advanced neurologic impairment and demonstrated rapidly progressive neurodegeneration, dying 4 months after transplantation. Other reports have documented that neurologic deterioration from metabolic disease may continue up to 6 months after BMT.8 If BMT is initiated prior to advanced neurodegeneration or is performed on a patient with a less progressive form of AD, transplantation may be as beneficial for AD as for other leukodystrophies. Secondly, we determined donor
marrow engraftment by our patient’s absolute neutrophil counts greater than 250/mm3 and transfusion independence which were later followed by a 1 month period of neurologic stabilization. (Engraftment of the donor’s bone marrow was not confirmed by chromosome or restriction fragment length polymorphism analysis.) Since quantifiable, metabolic markers for AD have not been discovered, it is possible that therapeutic levels of a deficient enzyme were not sufficiently restored within the 4 months of our patient’s life after BMT. Finally, unlike late infantile onset MLD and other leukodystrophies, infantile AD may not result from a deficient enzyme that could be replaced by BMT. This patient’s progressive neurodegeneration demonstrated that BMT did not alter the usual course of infantile AD.
Acknowledgements Special thanks to Dr Ruth Ramsey, Dr Robert Wollmann, Laurel Blewett, Laurie Druse and Evelyn Pope for their help in the preparation of this report.
References 1 Alexander WS. Progressive fibrinoid degeneration of fibrillary astrocytes associated with mental retardation in a hydrocephalic infant. Brain 1949; 72: 373–381. 2 Harding B. Rosenthal fibers in Alexander’s disease. J Child Neurol 1990; 5: 259–260. 3 Soffer D, Horoupian DS. Rosenthal fiber formation in the central nervous system: its relation to Alexander’s disease. Acta Neuropathol 1979; 47: 81–84. 4 Borrett D, Becker LE. Alexander’s disease: a disease of astrocytes. Brain 1985; 108: 367–385. 5 Bayever E, Ladisch ME, Philippart M et al. Bone marrow transplantation for metachromatic leukodystrophy. Lancet 1985; 2: 471–473. 6 Krivit W, Lipton ME, Lockman LA et al. Prevention of deterioration in metachromatic leukodystrophy by bone marrow transplantation. Am J Med Sci 1987; 294: 80–85. 7 Shapiro EG, Lipton ME, Krivit W. White matter dysfunction and its neuropsychological correlates: a longitudinal study of a case of metachromatic leukodystrophy treated with bone marrow transplant. J Clin Exp Neuropsychol 1992; 14: 610– 624. 8 Dhuna A, Toro C, Torres F et al. Longitudinal neurophysiologic studies in a patient with a metachromatic leukodystrophy following bone marrow transplantation. Arch Neurol 1992; 49: 1088–1092. 9 Herndon RM, Rubenstein L, Freeman J, Mathesio G. Light and electron microscopic observations on Rosenthal fibers in Alexander’s disease and in multiple sclerosis. J Neuropath Exp Neurol 1970; 29: 524–551. 10 Hess DC, Fischer AQ, Yaghami F et al. Comparative neuroimaging with pathologic correlates in Alexander’s Disease. J Child Neurol 1990; 5: 248–252. 11 Goldman JE, Corbin E. Isolation of a major protein component in Rosenthal fibers. Am J Pathol 1988; 130: 569–578. 12 Lowe J, Morrell K, Lennox G et al. Rosenthal fibers are based on the ubiquitination of glial filaments. Neuropathol Appl Neurobiol 1989; 15: 45–53.
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