Time Of Last Evaluation Research Articles

Successful Treatment Outcomes of Hematopoietic Stem Cell Transplantation with Reduced-Toxicity Conditioning Regimen Incorporating Treosulfan in Pediatric Patients with XIAP Deficiency

Background X-linked inhibitor of apoptosis (XIAP) defciency is an inherited primary immunodefciency characterized by chronic infammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and infammatory bowel disease (IBD). Although hematopoietic stem celltransplantation (HSCT) is the only curative therapy, the outcomes of HSCT for XIAP deficiency remain unsatisfactory. Methods We have performed HSCT with treosulfan based RTC regimen for pediatric patients with non-malignant disorders since January 2016, and reviewed the medical records of patients with XIAP deficiency who underwent treosulfan based HSCT to investigate outcomes of HSCT for patients with XIAP deficiency. Results Since January 2016, 4 patients with XIAP deficiency had undergone HSCT using RTC regimen consisted of fludarabine (150-180 mg/m 2), treosulfan (42 g/m 2), rabbit ATG (5-7.5 mg/kg), and thiotepa (10 mg/kg). All patients were male and received HSCT (2 from URD and 2 from HFD) at median 13.7 years old (range, 12.8-15.3), median 2 years (range, 0.5-3.9) after diagnosis of XIAP. They all achieved engraftment and complete donor chimerism at the time of last evaluation. One patient who received HFD HSCT developed acute GI GVHD grade 3 and VOD within 1 month from HSCT, which was recovered after treatment with systemic steroid and defibrotide. Except the patient, there was no fatal acute regimen related toxicity ≥ CTCAE grade 3. Two patients developed chronic GVHD: one had limited disease which was resolved after systemic steroid therapy and the other had extensive disease. During the median 43 months (range, 33.1-63.0) follow-up, all survived without disease recurrence. Conclusions HSCT with treosulfan based RTC regimen is promising treatment option for pediatric patients with XIAP deficiency, with successful engraftment and low treatment-related toxicity. However, further studies including a larger multicenter trial and measures to refine the regimen are mandate to verify efficacy and safety of this regimen.

First reports of primary ciliary dyskinesia caused by a shared DNAH11 allele in Canadian Inuit.

Primary ciliary dyskinesia (PCD) is typically an autosomal recessive disease characterized by recurrent infections of the lower respiratory tract, frequent and severe otitis media, chronic rhinosinusitis, neonatal respiratory distress, and organ laterality defects. While severe lower respiratory tract infections and bronchiectasis are common in Inuit, PCD has not been recognized in this population. We report a case series of seven Inuit patients with PCD identified by genetic testing in three Canadian PCD centers. Patients ranged from 4 to 59 years of age (at time of last evaluation) and originated in the Qikiqtaaluk region (Baffin Island, n = 5), Nunavut, or Nunavik (northern Quebec, n = 2), Canada. They had typical features of PCD, including neonatal respiratory distress (five patients), situs inversus totalis (four patients), bronchiectasis (four patients), chronic atelectasis (six patients), and chronic otitis media (six patients). Most had chronic rhinitis. Genetic evaluation demonstrated that all had homozygous pathogenic variants in DNAH11 at NM_001277115.1:c.4095+2C>A. The discovery of this homozygous DNAH11 variant in widely disparate parts of the Nunangat (Inuit homelands) suggests this is a founder mutation that may be widespread in Inuit. Thus, PCD may be an important cause of chronic lung, sinus, and middle ear disease in this population. Inuit with chronic lung disease, including bronchiectasis or laterality defects, should undergo genetic testing for PCD. Consideration of including PCD genetic analysis in routine newborn screening should be considered in Inuit regions.

Multiple failing maxillary implants in full arch rehabilitation‐ results of retreatment

Background Current implant research is shifting from survival to success, but failure is still an important topic to consider. When implants fail, there is often no fixed prosthetic alternative and retreatment is proposed. Current research on retreatment is predominantly based on single, early failures with survival rates varying between 71.0 and 94.6%. Retreatment of late and multiple failure is rarely described, despite the increasing incidence of failure due to peri-implantitis. Aim/Hypothesis The aim of this study was to assess implant retreatment in a group of patients with multiple failing implants after full maxillary rehabilitation, by implant removal, maxillary augmentation and placement of an overdenture supported by four to six implants. Material and Methods All consecutive patients (n = 16) referred for multiple late implant failures in rehabilitated maxillae between 2008 and 2018 were included in the study. The study was approved by the Medical Ethical Committee of UMCG. All patients were treated by removal of the failing implants combined with vertical and horizontal augmentation of the maxilla using the iliac, calvarial or maxillary tuberosity bone grafts. After four months of healing, four to six implants were placed in the maxilla. Four months later, a bar-retained overdenture was made. At time of last evaluation implant survival, complications, clinical parameters, change in peri-implant bone and patient-related outcome measures were recorded. Results 76 implants were placed in 16 patients. One patient with six implants was lost to follow-up due to severe illness. Therefore, 70 implants in 15 patients were evaluated at 3.3 ± 2.5 years (range 1.1–8.6 years) after loading. Common complications were antrum perforation after implant removal (n = 4; 26.6%) and wound dehiscence after augmentation (n = 4; 26.6%). Complications did not interfere with successive implant placement. In all cases, enough bone volume was present to insert the implants. Overall implant survival was 95.7%. Three implant failures occurred within the first year of function. Peri-implant bone loss was 0.32 ± 0.46 mm, pocket probing depth was 4.55 ± 1.59 mm. Plaque, calculus, inflammation and bleeding were hardly seen (median 0). Patients scored high on satisfaction of their overdentures (mean overall score 8.7 ± 1.2, max. 10). Chewing soft and tough foods were scored as ëgoodí, hard foods were scored as ëmoderateí. Oral Health Impact Profile Score was 29.5 ± 33.3. Conclusion and Clinical Implications Removing multiple failing implants and immediate reconstruction of the maxilla with bone grafts is a safe and predictable treatment procedure when applied for an implant supported overdenture. Complications did not interfere with retreatment.

Type 1 Gaucher Disease Severity and Risk for Liver Fibrosis in Untreated Patients and in Patients Treated Primarily with Enzyme Replacement Therapy for a Median of 20 Years

Type 1 Gaucher disease (GD1) is a rare, autosomal recessive disorder. Deficient lysosomal glucocerebrosidase activity causes accumulation of glucosylceramide in macrophages that infiltrate bone marrow, spleen and liver. Common clinical manifestations include hematologic cytopenias, hepatosplenomegaly and bone lesions. Since 1991, GD1 has been treated primarily with pharmacological enzyme replacement therapy (ERT). In the pre-ERT era, sequelae of fibrotic liver disease were a common cause of early death. Ultrasonic and MR elastography (MRE) suggest that increased liver stiffness attributed to fibrosis correlates with GD1 disease severity scores. Here, we evaluate the impact of initial and post-ERT (median 20 y, percentiles5-95: 5.2-27.5 y) GD1 severity on probability for liver fibrosis (LF) in 30 patients (pts) using 4 well-established LF prediction scores. We also studied 9 never-treated pts and 7 pts treated for < 18 m and examined the relationship between LF, disease severity scores and D-dimer, ferritin, chitotriosidase and GBA1 genotype.METHODS: 46 adult GD1 pts were evaluated in 2017-18. Pts with known liver disease or on anticoagulation were ineligible. Disease severity was scored with a validated assessment tool GD1-DS3: marked (DS3 6.0-19.0), moderate (DS3 3.0-5.99), mild (DS3 < 3.0). LF probability was assessed with AST/Platelet Ratio Index, Fibrosis-4 Index, Lok Score and NAFLD Fibrosis Score. Scores were classified positive, indeterminate or negative per published standards. Probabilities were stratified as: high (≥ 2 parameters positive), low (≥ 2 parameters negative), or indeterminate (any other score combination).RESULTS: 26/30 pts (86.7%) treated for at least 3 y had low probability of LF at last evaluation. 4/9 (44.4%) ERT-naïve pts and 3/7 (42.9%) pts treated for ≤ 18 m had high probability for LF. 5/7 (71.4%) pts with marked DS3 severity had high LF probability compared to 2/14 (14.3%) with moderate DS3 severity and 3/25 (12.0%) with mild DS3 severity (Table). Of 30 pts treated for ≥ 3 y, 13 had marked DS3 severity scores before starting treatment. Only 1 pt had DS3≥6.00 at the time of last evaluation along with high probability for LF. She had a history of frequent and prolonged treatment interruptions as well as morbid obesity. Of 9 treated pts with moderate baseline severity scores, 4 remained so at last evaluation. One had high probability for LF but also had developed myelodysplasia and severe hemolytic anemia that likely confounded both GD1 severity and LF scores. The third treated pt with high probability for LF had a mild DS3 score but also insulin dependent diabetes mellitus and marked obesity. Chitotriosidase activity was >1000 nMol/mL/h in proportionately more pts with marked disease (5/7, 71.4%), compared to those with moderate (4/14, 28.6%) or mild disease (5/25, 20.0%) and among those pts who were never treated (8/9, 88.9%) or treated for <18 m (4/6, 66.7%), compared to those patients treated for ≥ 3 y. (11/31, 35.5%). All patients who were either untreated or treated for ≤ 18 m had ferritin levels >150 ng/mL, whereas ferritin was increased in less than half the patients treated ≥ 3 y. There was no correlation between these biomarkers and a high probability for LF. No patients had INR> 1.5 or abnormal AST or ALT. D-dimer levels did not correlate with disease severity or probability for LF. Of 10 patients with high probability for LF, 7 had platelet counts < 120x 103/µL. 8/17 (47.1%) with pre-treatment DS3> 6.0 were N370S homozygous compared to 23/28 (82.1%) with baseline moderate or mild severity scores. 7/10 patients with high probability for LF were N370S homozygous.CONCLUSIONS: Per MRE studies reported by others, we find that LF probability based on non-invasive laboratory risk stratification is often increased parallel to GD1-DS3 score. However, in contrast to the pre-ERT era, most adult GD1 patients treated with ERT for a median 20 y, including those with initial marked disease severity, appear unlikely to develop LF. Exceptions may be attributed to confounding concurrent illnesses or to poor treatment compliance. Unlike DS3 score, we found no consistency between traditional GD1 biomarkers and probability for LF. We emphasize that N370S homozygosity can be associated with severe GD1 manifestations including LF and such pts should be treated accordingly. Our assessments of LF probability require verification with elastography especially in pts with thrombocytopenia. [Display omitted] DisclosuresWeinreb:Shire HGT: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme, a Sanofi Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Visual outcome in cats with hypertensive chorioretinopathy.

To investigate factors associated with long-term visual outcome in cats with hypertensive chorioretinopathy. Eighty-eight client-owned cats diagnosed with hypertensive chorioretinopathy. Medical records from cats with systemic hypertension and associated retinal lesions were reviewed. Most cats (61%) were blind in both eyes at presentation. Presence of menace response at last follow-up evaluation was positively correlated with presence of menace response at presentation (P = .0025), time to complete retinal reattachment (P < .0001), and gender (P = .0137). Seventy-six of 132 eyes (57.6%) that were blind at presentation regained some vision following treatment. At the time of last evaluation, 101/176 eyes (60%) had a positive menace response, while 34/46 (74%) eyes with a follow-up of >6 months had a positive menace response. Eyes that had a menace response at presentation were 17 and 37 times more likely to have a menace response at last examination compared to eyes blind for less than 2 weeks and eyes blind greater than 2 weeks, respectively. Female cats were overrepresented (62.5% of cases), and male cats were 4.2 times more likely to be visual at time of last examination compared to female cats. With treatment, the prognosis for long-term vision in cats with hypertensive chorioretinopathy, even following complete retinal detachment, is good.

MRI-guided focused ultrasound thalamotomy in non-ET tremor syndromes.

To report the 6-month single-blinded results of unilateral thalamotomy with MRI-guided focused ultrasound (MRgFUS) in patients with tremors other than essential tremor. Three patients with tremor due to Parkinson disease, 2 with dystonic tremor in the context of cervicobrachial dystonia and writer's cramp, and 1 with dystonia gene-associated tremor underwent MRgFUS targeting the ventro-intermedius nucleus (Vim) of the dominant hemisphere. The primary endpoint was the reduction of lateralized items of the Tremor Rating Scale of contralateral hemibody assessed by a blinded rater. All patients achieved a statistically significant, immediate, and sustained improvement of the contralateral tremor score by 42.2%, 52.0%, 55.9%, and 52.9% at 1 week and 1, 3, and 6 months after the procedure, respectively. All patients experienced transient side effects and 2 patients experienced persistent side effects at the time of last evaluation: hemitongue numbness and hemiparesis with hemihypoesthesia. Vim MRgFUS is a promising, incision-free, but nevertheless invasive technique to effectively treat tremors other than essential tremor. Future studies on larger samples and longer follow-up will further define its effectiveness and safety. NCT02252380. This study provides Class IV evidence that for patients with tremor not caused by essential tremor, MRgFUS of the Vim improves the tremor of the contralateral hemibody at 6 months.

AB0835 More severe expression of systemic sclerosis in men than women from an ethnic cohort followed at a single center

BackgroundWhether systemic sclerosis (SSc) is differently expressed in men versus women has been debated. This is probably due to the fact that published information mainly derives from multi-ethnic cohorts followed...

Mood disorder with mixed, psychotic features due to vitamin b12 deficiency in an adolescent: case report

Vitamin B12 is one of the essential vitamins affecting various systems of the body. Reports of psychiatric disorders due to its deficiency mostly focus on middle aged and elderly patients. Here we report a case of vitamin B 12 deficiency in a 16-year old, male adolescent who presented with mixed mood disorder symptoms with psychotic features. Chief complaints were “irritability, regressive behavior, apathy, crying and truancy” which lasted for a year. Premorbid personality was unremarkable with no substance use/exposure or infections. No stressors were present. The patient was not vegetarian. Past medical history and family history was normal. Neurological examination revealed glossitis, ataxia, rigidity in both shoulders, cog-wheel rigidity in the left elbow, bilateral problems of coordination in cerebellar examination, reduced swinging of the arms and masked face. Romberg’s sign was present. Laboratory evaluations were normal. Endoscopy and biopsy revealed atrophy of the gastric mucosa with Helicobacter Pylori colonization. Schilling test was suggestive of malabsorbtion. He was diagnosed with Mood disorder with Mixed, Psychotic Features due to Vitamin B12 Deficiency and risperidone 0.5 mg/day and intramuscular vitamin B12 500 mcg/day were started along with referral for treatment of Helicobacter pylori. A visit on the second week revealed no psychotic features. Romberg’s sign was negative and cerebellar tests were normal. Extrapyramidal symptoms were reduced while Vitamin B12 levels were elevated. Risperidone was stopped and parenteral Vitamin B12 treatment was continued with monthly injections for 3 months. Follow-up endoscopy and biopsy at the first month demonstrated eradication of H. pylori. He was followed monthly for another 6 months and psychiatric symptoms did not recur at the time of last evaluation. Despite limitations, this case may underline the observation that mood disorders with psychotic features especially with accompanying extrapyramidal symptoms lacking a clear etiology may be rare manifestation of vitamin B12 and/or folate deficiency in children and adolescents and be potentially amenable to treatment.

Reduced Intensity Conditioning In Children Undergoing Unrelated Umbilical Cord Blood Transplantation for Non-Malignant Diseases: Preliminary Results Demonstrate a High Rate of Engraftment and Low Incidence of Gvhd

AbstractAbstract 3535 Background and Objective:Reduced intensity conditioning (RIC) regimens decrease transplant related morbidity and mortality and are increasingly being utilized prior to allogeneic hematopoietic stem cell transplantation. Unrelated umbilical cord blood transplantation (UCBT) has been successful with RIC regimens for patients with various malignancies, who have undergone multiple cycles of chemotherapy, thereby reducing the likelihood of graft rejection. However, for treatment of non-malignant diseases where co-morbid conditions would warrant reduced toxicity, previously reported successful RIC regimens utilizing UCBT have failed to provide reproducible engraftment commonly resulting in graft rejection and autologous reconstitution. We designed a novel RIC regimen for this group of patients with the main objective of studying its efficacy to promote clinically significant and durable engraftment after UCBT. Methods:Between December 2008 and July 2010, eight children with non-malignant diseases lacking matched related donors enrolled on this protocol (clinicaltrials.gov NCT00744692): MPS I (1), MPS IIIB (2), Metachromatic leukodystrophy (MLD) (1), Cartilage Hair Hypoplasia (CHH) (1), Zap-70 deficiency (1), and Hemophagocytic lymphohistiocytosis (HLH) (2). Seven children, with >42 days follow-up post-UCBT are presented in this preliminary interim analysis. Immunosuppression was based on alemtuzumab (3.2mg/kg) and fludarabine (150 mg/m2), while melphalan (140 mg/m2), thiotepa (200mg/m2) and hydroxyurea (days -22 to -10) provided myelosuppression. GVHD prophylaxis consisted of tacrolimus and MMF. G-CSF support was provided to all patients by day +1. Median age and weight at the time of transplant were 3.3 years and 15.1 kg respectively. Male: Female ratio was 1.3. All patients received single UCBT with a cryopreserved median cell dose of 7.7 × 107 TNC/kg (range 5.7–29.3). HLA matching was 4/6, 5/6 and 6/6 in 1, 4 and 2 patients respectively. Results:Prior to enrollment, the MPS I patient had significant cardiomyopathy with obstructive sleep apnea and the child with ZAP-70 deficiency had severe bronchiectasis and enteroviral meningitis. Nevertheless, all patients tolerated the conditioning regimen well. None of the patients had mucositis > grade 2, although all required TPN and narcotic support. To date, no patient experienced CNS, cardiac, pulmonary or hepatorenal toxicity attributable to conditioning, and no one had VOD. One patient (CHH with 6/6–matched UCBT demonstrating no post-thaw growth in colony forming assay) experienced autologous recovery on day +30. He was successfully retransplanted with RIC conditioning. The remaining patients (6 of 7) engrafted at a median of 20 days post-transplant (range 15–28 days). At the time of last evaluation, whole blood donor chimerism in engrafted patients ranged from 63% to >98%. Acute GVHD of skin, Grade 1, was seen in 4 patients. None of the patients have had Grade 2–4 acute GVHD or chronic GVHD thus far, although follow-up for chronic GVHD is short. Platelet count > 50K, untransfused, was achieved in 5 of 6 engrafted patients at a median of 39 days. Viral reactivation and/or de novo viral infections were seen commonly, majority without appreciable end organ disease. Adenovirus infection was noted in 4 patients (2 patients had adenoviral gastroenteritis and 1 patient had detection of adenovirus in nasal wash that resolved without specific systemic therapy; 1 patient had adenoviremia that resolved with cidofovir and adoptive immunotherapy); the patient with autologous recovery had prolonged CMV viremia. Two patients with immune deficiencies had pre-existing infectious histories, but no worsening was noted after transplant.Six of 7 patients are alive with a median follow-up of 256 days (43 – 587 days). One patient with mixed chimerism died on day +170 of an acute hemolytic transfusion reaction. Five of 7 patients survive event free. Conclusion:Reduced intensity conditioning consisting of alemtuzumab, fludarabine, melphalan, thiotepa and hydroxyurea is well tolerated and results in a high rate of donor engraftment with a low risk of GVHD in children with non-malignant diseases undergoing UCBT. Despite the common occurrence of viral infections these have not caused severe end organ damage or death. Long-term follow-up will determine whether donor chimerism will be durable after this approach. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Post-surgical inflammatory neuropathy

Post-surgical neuropathies are usually attributed to mechanical factors, such as compression, stretch, contusion or transection. The role of inflammatory mechanisms in neuropathies occurring after surgeries is poorly appreciated and not well characterized, and may provide a rationale for immunotherapy. A total of 23 selected patients with post-surgical neuropathies received nerve biopsies, of which 21 demonstrated increased inflammation. Here we report the clinical features in these 21 cases of biopsy-confirmed and 12 cases of clinically suspected post-surgical inflammatory neuropathies, in whom no trauma to the nerves was documented. All neuropathies developed within 30 days of a surgical procedure. Of 33 patients, 20 were male and the median age was 65 years (range 24-83). Surgical procedures were orthopaedic (n=14), abdominal/pelvic (n=12), thoracic (n=5) and dental (n=2). Patients developed focal (n=12), multifocal (n=14) or diffuse (n=7) neuropathies. Focal and multifocal neuropathies typically presented with acute pain and weakness, and focal neuropathies often mimicked mechanical aetiologies. Detailed analyses, including clinical characteristics, electrophysiology, imaging and peripheral nerve pathology, were performed. Electrophysiology showed axonal damage. Magnetic resonance imaging of roots, plexuses and peripheral nerves was performed in 22 patients, and all patients had abnormally increased T(2) nerve signal, with 20 exhibiting mild (n=7), moderate (n=12) or severe (n=1) enlargement. A total of 21 patients had abnormal nerve biopsies that showed increased epineurial perivascular lymphocytic inflammation (nine small, five moderate and seven large), with 15 diagnostic or suggestive of microvasculitis. Evidence of ischaemic nerve injury was seen in 19 biopsies. Seventeen biopsies had increased axonal degeneration suggesting active neuropathy. Seventeen biopsied patients were treated with immunotherapy. In 13 cases with longitudinal follow-up (median 9 months, range 3-71 months), the median neuropathy impairment score improved from 30 to 24 at the time of last evaluation (P=0.001). (i) not all post-surgical neuropathies are mechanical, and inflammatory mechanisms can be causative, presenting as pain and weakness in a focal, multifocal or diffuse pattern; (ii) these inflammatory neuropathies may be recognized by their spatio-temporal separation from the site and time of surgery and by the characteristic magnetic resonance imaging features; (iii) occasionally post-surgical inflammatory and mechanical neuropathies are difficult to distinguish and nerve biopsy may be required to demonstrate an inflammatory mechanism, which in our cohort often, but not exclusively, exhibited pathological features of microvasculitis and ischaemia; and (iv) recognizing the role of inflammation in these patients' neuropathy led to rational immunotherapy, which may have resulted in the subsequent improvement of neurological symptoms and impairments.

Frontal Sinus Inverted Papilloma: Surgical Strategy Based on the Site of Attachment

The surgical management of inverted papilloma (IP) involving the frontal sinus (FS) remains a challenge given the narrow confines of the frontal recess and the close proximity to critical structures. The objective of this study was to elucidate a surgical strategy for management of frontal sinus IP based on the site of attachment. A retrospective chart review was performed on 18 patients with FS IP treated at the Pusan National University Hospital and the Cleveland Clinic Foundation between 1998 and 2008. The mean age was 53.8 years with a male/female ratio of 13:5. The sites of tumor attachment included the medial wall (MW; six cases), posterior wall (PW; five cases), diffuse (all walls involved; five cases), intersinus septal cell (three cases), lateral wall (two cases), and anterior wall (two cases). IP involvement was unifocal in 10 cases and multifocal in 8 cases. Unifocal IP attached to the MW or PW was managed strictly by endoscopic frontal sinusotomy (EFS) in five of six cases (83%). Multifocal IP required endoscopic modified Lothrop (EML) and/or open approaches (endoscopic frontal trephination [EFT], four, osteoplastic flap [OPF], one) in seven of eight cases (88%). One additional patient with bilateral anterior table involvement required OPF. Four (22%) patients developed recurrences. Two were managed by EML, one was managed by EFS, and one was managed by EFT and EFS. Two patients developed cerebrospinal fluid leaks that were managed endoscopically without untoward effects. All patients were free of disease at the time of last evaluation with a mean follow-up of 36.6 months. Frontal sinus IP with MW or PW involvement can generally be managed by standard EFS. Tumors with multifocal involvement often require EML, along with adjunct EFT in selected cases. OPF can be avoided as the primary surgical approach in most patients with sinonasal papilloma of FS.

Long-Term Outcomes of Bilateral Subthalamic Nucleus Stimulation in Patients with Advanced Parkinson’s Disease

Background: In patients with advanced Parkinson’s disease (PD), deep brain stimulation (DBS) of the subthalamic nucleus (STN) has been shown to improve motor function and decrease medication requirements in the short term. However, the long-term benefits of DBS are not yet established. Objective: It was the aim of this study to evaluate long-term outcomes of patients with PD treated with bilateral DBS of the STN. Design and Methods: Thirty-three subjects who had bilateral STN DBS were followed prospectively after surgery. We evaluated subjects, using the Unified Parkinson’s Disease Rating Scale (UPDRS), preoperatively, 12 months after surgery and at a long-term follow-up visit. Ratings were performed on and off dopaminergic medications. We compared postoperative UPDRS scores, dyskinesia ratings and medication dosages with preoperative values. Results: Twenty-seven subjects had evaluations beyond 18 months (median 33.7 months). Total UPDRS scores in the ‘medication-off’ state were improved by 37% (p < 0.001) at 12 months and 17.7% (p = 0.0051) at the long-term evaluation. Medication-off state UPDRS part III scores were significantly improved at both 1 year and at the last evaluation (37.6 and 29.3%; p < 0.001). Dopaminergic medication requirements were decreased by 35.3% (p < 0.001) during the first postoperative year and remained below preoperative levels at the long-term evaluation. Average duration of ‘off’ time remained decreased by about 40% at both 1 year and at the time of last evaluation. Subjects had a sustained reduction in dyskinesia severity (88.6% at 1 year and 68.8% at last evaluation). Conclusions: In this cohort of subjects with advanced PD, bilateral STN stimulation improved ‘off’ medication motor function, reduced time spent in the medication-off state and reduced medication requirements for up to 4 years after surgery. We conclude that STN DBS is an effective long-term therapy for selected patients with advanced PD.

A comparison of two treatment regimens of ceftriaxone in late Lyme disease

The optimal duration of treatment for patients with late Lyme disease is unresolved. In a prospective, open label, randomized, multi-center study, a 14 day course of ceftriaxone was compared to 28 days of therapy. Entry criteria included objective abnormalities compatible with late Lyme disease and serologic reactivity to Borrelia burgdorferi. Randomization took place prior to obtaining serologic results. Clinical response was rated as cure; improvement; failure; or not assessable. Of the 201 patients randomized, 21 patients in the 14 day group and 37 in the 28-day group were excluded from the study for failure to meet serologic criteria. Of those who met serologic criteria, 80 patients received 14 days and 63 received 28 days of ceftriaxone. At time of last evaluation, there were 5 treatment failures in the 14 day group and none in the 28 day group (p = 0.07). Clinical cure rates were 76% for the 14 day group and 70% for the 28 day group (p = NS). Therapy was discontinued due to adverse events for a significantly greater proportion of patients in the 28-day group compared to the 14-day group (p < 0.02). Ceftriaxone for 14 days eradicated the signs and symptoms of late Lyme disease in the majority of evaluable patients. Although there were more failures in the 14-day group than in the 28-day group, this study did not have the power to determine if a clinical subset of patients may benefit from 28 days of therapy.

Pulse methylprednisolone, cyclosporine, and ACE inhibitor therapy decreases proteinuria in two siblings with familial focal segmental glomerulosclerosisa

Familial focal segmental glomerulosclerosis (FSGS) is a heterogeneous renal disease characterized by proteinuria and an unremitting deterioration of renal excretory function. Previous studies showed corticosteroid unresponsiveness and a variable response to cyclophosphamide therapy. We hypothesized that treatment with pulse methylprednisolone therapy (PMT), alternate-day corticosteroids, and cyclosphosphamide or cyclosporine would decrease proteinuria in patients with familial FSGS. Two adolescent brothers, 13 and 16 years old, presented with nephrotic range proteinuria, but with normal renal excretory function. Both brothers had renal biopsies that showed FSGS with mesangial hypercellularity and tubular atrophy. Intravenous PMT, at doses of 1 g, was initiated per the Tune-Mendoza protocol. Both patients received lisinopril therapy. One brother (case 1) was treated with PMT, alternate-day corticosteroids, and cyclophosphamide (total cumulative cyclophosphamide dose was 154.3 mg/kg). Urinary protein-to-urinary creatinine (UP/UC) ratios decreased from 6.79 to 3.79. Cyclosporine therapy decreased the UP/UC further from 2.48 to 0.76 at the end of PMT. The other brother (case 2), treated with PMT, alternate-day corticosteroids, and cyclosporine, experienced a decrease in UP/UC from 7.27 to 1.14. At the time of last evaluation, approximately 7 months after the last PMT dose, the UP/UC ratios were 0.27 (case 1) and 0.37 (case 2). PMT-attributable adverse effects were not severe. Both patients continued to receive oral cyclosporine and lisinopril after completion of PMT. PMT and cyclosporine therapy may reduce proteinuria, without decreasing renal excretory function, in some patients with familial FSGS. Further evaluation of cyclosporine therapy and PMT of patients with familial FSGS is warranted.

One-stage reconstruction of bladder exstrophy.

From 1984 to 1990 a primary one-stage reconstruction of bladder exstrophy was performed at our hospital on 15 consecutive infants. Reconstruction included Cohen's ureteral reimplantation, bladder neck reconstruction according to Young-Dees, bladder closure, symphyseal bone approximation, abdominal wall closure, and repair of epispadias in females. Postoperatively, all patients were immobilized by overhead extension. Iliac osteotomy was done in 9 children, but was abandoned in recent years for infants less than one month old Follow-up examinations included an interview with the parents, clinical examinations, blood and urine analyses, uroflowmetry, and ultrasound scan of the abdomen. Nuclear renal scan, i.v. pyelography, and cystography were carried out as indicated. At the time of last evaluation the children were between 3 and 9 years of age. The cosmetic results were satisfactory in all cases. Eight of 15 children were dry day and night with micturition intervals more than 3 hours during day time (complete continence). Five children were dry during day time with micturition intervals up to 3 hours, but occasionally wet their beds (partial continence). Two children were incontinent. Eleven of 15 children had a bladder capacity of more than 100 ml. Renal function was normal in all patients. Two children showed a mild VUR, and no other abnormalities of the upper urinary tracts were found. Iliac osteotomy did not influence the functional or cosmetic results, but in two patients asymmetry of pelvic bones with consecutive lumbar scoliosis was found. Comparing these results with reports on staged reconstructive procedures, we conclude that by primary complete one-stage reconstruction a well acceptable success rate is achieved, and that by this method possibly some advantages are offered to patients with bladder exstrophy.

Role of arthroscopy in osteoarthritis of the knee

We compared arthroscopic patial meniscectomy with limited debridement versus arthroscopic abrasion arthroplasty in patients with osteoarthritis. Group I consisted of 131 knees in 131 patients treated by partial meniscectomy and debridement of loose articular cartilage or removal of loose bodies. All patients had grade 3 or 4 chondromalacia in the affected compartment. The patients were followed for a mean of 3 ± 1 years. Group II consisted of 28 knees in 28 patients treated by debridement with abrasion arthroplasty of exposed bone. The mean age of this group of patients was 63 years and they were followed for a mean of 3.8 years. The Group I patients noted 80% improvement by 1 year but this fell to 67% by 5 years after meniscectomy. Overall, 104 were improved, 16 unchanged, and 15 worse at the time of last evaluation compared to their preoperative status. In the Group II patients, 11 were improved, 8 unchanged, and 9 worse. Fifty percent of Group II subsequently underwent a total knee arthroplasty for salvage at a mean of 3 years following the abrasion procedure. Abrasion arthroplasty appears to offer little benefit over partial meniscectomy and debridement in the degenerative knee. Results of abrasion arthroplasty are unpredictable.

Inflammatory pseudotumor of the esophagus

felt that the lesion probably represented an inflammatory pseudotumor of the esophagus secondary to gastroesophageal reflux. Continued medical management was followed by repeated endoscopic evaluation 3 and 5 months after the lesion was initially observed. These examinations revealed mild to moderate esophagitis above the hiatus hernia and continued decrements in the size of the lesion. At the last examination, the lesion was approximately 8 mm in diameter (Figure 2b). Esophageal moti Iity studies at the time of last evaluation revealed an indeterminate distal high pressure zone with normal magnitude and progression of primary swallowing waves. The 24 hour pH-monitoring composite score was 150 which is grossly abnormal and consistent with clinically sigInflammatory pseudotumor of the esophagus A complication of gastroesophageal reflux

Fractures of the Shaft of the Femur in Children: Treatment and Results

Summary and Conclusion The treatment and results of 95 fractures in 93 children with fractures of the femoral shaft have been presented and the method of skeletal traction used most frequently at The Children's Hospital Medical Center in Boston has been described. The angular and linear deformities are reported for this series both after the reduction was complete and at the time of last evaluation, one to 12 years later. Residual angulation was not sufficient to influence function in any of these patients, although two did have bowing that was apparent to the examiner on close palpation of the femur. No serious complications were recorded and the desired linear relationship of the fragments was easily obtained. The only sequel of note was the relative lengthening of the fractured extremity secondary to its more rapid growth. If the initial alignment of the fracture fragments is less than 20 degrees when the femur is firm, there should be no clinical deformity after remodeling has taken place. The fracture fragments may be allowed to over-ride in children between two years and ten years of age but not in excess of 1.0 to 1.5 cm. In children under two years and in those approaching adolescence, stimulation of growth is not likely to occur and over-riding should not be allowed.