Single institution outcomes of treatment of severe aplastic anaemia

Background: In severe aplastic anaemia, the treatment of choice for young patients with a human leucocyte antigen-matched sibling is now established as allogeneic bone marrow transplantation (BMT). In older patients and in those without a matched sibling donor, immunosuppressive therapy is the usual first option. 'Alternative' marrow donors are emerging as an option for those without a matched sibling donor. Aims: To review 10 years of local experience in treating severe aplastic anaemia with BMT and immunosuppressive therapy with emphasis on long-term outcomes. Methods: A retrospective analysis was performed of all patients with severe aplastic anaemia presenting to the Royal Brisbane and Royal Children's Hos- pitals between 1989 and 1999. Data were abstracted regarding patient demographics, pretreatment characteristics and outcome measures, including response rates, overall survival and long-term complications. Results: Twenty-seven consecutive patients were identified, 12 treated with immunosuppression alone and 15 with BMT. In these two groups, transfusion independence was attained in 25% and 100%, respectively, with overall survival being 36% and 100%, respectively. Those treated with immunosuppression were significantly older (median 41.5 versus 22 years, P = 0.008). Long-term survivors of either treatment had extremely low morbidity. Three patients carried pregnancies to term post-transplant. Three patients received alternative donor BMT with correspondingly excellent survival. Conclusions: Patients treated with allogeneic BMT for severe aplastic anaemia enjoyed extremely good long-term survival and minimal morbidity. Patients treated with immunosuppressive therapy had a poorer outcome reflecting their older age and different usage of therapies over the past decade. Optimal treatment strategies for severe aplastic anaemia remain to be determined.

Granulocyte-colony-stimulating factor (G-CSF)-primed allogeneic bone marrow: significantly less graft-versus-host disease and comparable engraftment to G-CSF-mobilized peripheral blood stem cells

Prospective studies have shown rapid engraftment using granulocyte-colony-stimulating factor-mobilized peripheral blood stem cells (G-PBSCs) for allogeneic transplantation, though the risks for graft-versus-host disease (GVHD) may be increased. It was hypothesized that the use of G-CSF to prime bone marrow (GBM) would allow rapid engraftment without increased risk for GVHD compared with G-PBSC. Patients were randomized to receive G-BM or G-PBSCs for allogeneic stem cell transplantation. The study was designed (beta < .8) to detect a difference in the incidence of chronic GVHD of 33% ( < .05). The plan was to recruit 100 patients and to conduct an interim analysis when the 6-month follow-up point was reached for the first 50 patients. Fifty-seven consecutive patients were recruited (G-BM, n = 28; G-PBSC, n = 29). Patients in the G-PBSC group received 3-fold more CD34(+) and 9-fold more CD3(+) cells. Median times to neutrophil (G-BM, 16 days; G-PBSC, 14 days; P < .1) and platelet engraftment (G-BM, 14 days; G-PBSC, 12 days; P < .1) were similar. The use of G-PBSC was associated with steroid refractory acute GVHD (G-BM, 0%; G-PBSC, 32%; P < .001), chronic GVHD (G-BM, 22%; G-PBSC, 80%; P < .02), and prolonged requirement for immunosuppressive therapy (G-BM, 173 days; G-PBSC, 680 days; P < .009). Survival was similar for the 2 groups. Compared with G-PBSC the use of G-BM resulted in comparable engraftment, reduced severity of acute GVHD, and less subsequent chronic GVHD. (Blood. 2001;98:3186-3191) (C) 2001 by The American Society of Hematology.

Clinical and molecular genetics of myoclonic-astatic epilepsy and severe myoclonic epilepsy in infancy (Dravet syndrome)

The majority of severe epileptic encephalopathies of early childhood are symptomatic where a clear etiology is apparent. There is a small subgroup, however, where no etiology is found on imaging and metabolic studies, and genetic factors are important. Myoclonic-astatic epilepsy (MAE) and severe myoclonic epilepsy in infancy (SMEI), also known as Dravet syndrome, are epileptic encephalopathies where multiple seizure types begin in the first few years of life associated with developmental slowing. Clinical and molecular genetic studies of the families of probands with MAE and SMEI suggest a genetic basis. MAE was originally identified as part of the genetic epilepsy syndrome generalized epilepsy with febrile seizures plus (GEFS(+)). Recent clinical genetic studies suggest that SMEI forms the most severe end of the spectrum of the GEFS(+). GEF(+) has now been associated with molecular defects in three sodium channel subunit genes and a GABA subunit gene. Molecular defects of these genes have been identified in patients with MAE and SMEI. Interestingly, the molecular defects in MAE have been found in the setting of large GEFS(+) pedigrees, whereas, more severe truncation mutations arising de novo have been identified in patients with SMEI. It is likely that future molecular studies will shed light on the interaction of a number of genes, possibly related to the same or different ion channels, which result in a severe phenotype such as MAE and SMEI. (C) 2001 Elsevier Science B.V. All rights reserved.

Sodium channel alpha 1-subunit mutations in severe myoclonic epilepsy of infancy and infantile spasms

Background: Mutations in SCN1A, the gene encoding the alpha1 subunit of the sodium channel, have been found in severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS(+)). Mutations in SMEI include missense, nonsense, and frameshift mutations more commonly arising de novo in affected patients. This finding is difficult to reconcile with the family history of GEFS(+) in a significant proportion of patients with SMEI Infantile spasms (IS), or West syndrome, is a severe epileptic encephalopathy that is usually symptomatic. In some cases, no etiology is found and there is a family history of epilepsy. Method: The authors screened SCN1A in 24 patients with SMEI and 23 with IS. Results: Mutations were found in 8 of 24 (33%) SMEI patients, a frequency much lower than initial reports from Europe and Japan. One mutation near the carboxy terminus was identified in an IS patient. A family history of seizures was found in 17 of 24 patients with SMEI. Conclusions: The rate of SCN1A mutations in this cohort of SMEI patients suggests that other factors may be important in SMEI. Less severe mutations associated with GEFS(+) could interact with other loci to cause SMEI in cases with a family history of GEFS(+). This study extends the phenotypic heterogeneity of mutations in SCN1A to include IS.

A 1-year longitudinal study of severe traumatic brain injury in Australia using the Sickness Impact Profile

Objective: To document outcome and to investigate patterns of physical and psychosocial recovery in the first year following severe traumatic brain injury (TBI) in an Australian patient sample. Design: A longitudinal prospective study of a cohort of patients, with data collection at 3, 6, 9, and 12 months post injury. Setting: A head injury rehabilitation unit in a large metropolitan public hospital. Patients: A sample of 55 patients selected from 120 consecutive admissions with severe TBI. Patients who were more than 3 months post injury on admission, who remained confused, or who had severe communication deficits or a previous neurologic disorder were excluded. Interventions: All subjects participated in a multidisciplinary inpatient rehabilitation program, followed by varied participation in outpatient rehabilitation and community-based sen ices. Main Outcome Measures: The Sickness impact Profile (SIP) provided physical, psychosocial, and total dysfunction scores at each follow-up. Outcome at 1 year was measured by the Disability Rating Scale. Results: Multivariate analysis of variance indicated that the linear trend of recovery over time was less for psychosocial dysfunction than for physical dysfunction (F(1,51) = 5.87, P < .02). One rear post injury, 22% of subjects had returned to their previous level of employability, and 42% were able to live independently. Conclusions: Recovery from TBI in this Australian sample followed a pattern similar to that observed in other countries, with psychosocial dysfunction being more persistent. Self-report measures such as the SIP in TBI research are limited by problems of diminished self-awareness.

Effects of sampling opportunities on preference for adults with severe disabilities

A variable that appears to affect preference development is the exposure to a variety of options. Providing opportunities for systematically sampling different options is one procedure that can facilitate the development of preference, which is indicated by the consistency of selections. The purpose of this study was to evaluate the effects of providing sampling opportunities on the preference development for two adults with severe disabilities. Opportunities for sampling a variety of drink items were presented, followed by choice opportunities for selections at the site where sampling occurred and at a non-sampling site (a grocery store). Results show that the participants developed a definite response consistency in selections at both sites. Implications for sampling practices are discussed.