Progressive Neurological Symptoms Research Articles

Abstract P2-16-02: Bevacizumab, etoposide, and cisplatin (BEEP) is highly effective in brain metastases of HER2 positive breast cancer progressing from whole brain radiotherapy - Subgroup analysis of a multi-center phase II study

Abstract Background: We have recently reported that starting bevacizumab (BE) 1 day before chemotherapy could further induce tumor vascular normalization, thereby significantly enhanced the activity of etoposide (E) and cisplatin (P) in breast cancer patients (pts) with progressing brain metastases after whole brain radiotherapy (WBRT) (ESMO 2013). Lapatinib plus capecitabine is the only proven active regimen for the treatment of brain metastases of HER2 positive breast cancer, with a central nerve system (CNS) objective response rate (ORR) of 18-38% and median time to progression (TTP) of 3.6-5.1 months (mo) in those who had had prior WBRT. Material and methods: Twenty-three HER2 positive breast cancer pts with progressing brain metastases after WBRT were enrolled from Jan 2011 to Jan 2013. Protocol treatment was given in 21 day cycles: BE 15 mg/kg on day 1, E 70 mg/m2/day from day 2 to day 4, and P 70 mg/m2 on day 2 (BEEP regimen), for a maximum of 6 cycles. The primary endpoint was a centrally assessed CNS ORR. A CNS objective response was defined as a ≥50% reduction in the volumetric sum of all measurable CNS lesions in the absence of increasing steroid use, development of new CNS lesion, or progressive neurologic symptoms. This trial is registered with ClinicalTrials.gov (NCT01281696). Results: Median age was 55.1 (range 33-75); 9 pts were ER+, 14 pts were ER-; 15 pts were ECOG 0-2 (65.2%), and 8 pts were ECOG 3 (34.8%). All of them had previous exposure to trastuzumab, and 20 (87.0%) of them had received trastuzumab containing regimen for the treatment of metastatic disease. Eleven pts (47.8%) received lapatinib treatment before enrollment into this trial. The median lines of chemotherapy for the treatment of metastatic disease were 3 (range 1-8). The median BEEP treatment cycles were 6 (range 1-6). Sixteen of 23 pts (69.6%; 95%CI 47.1-86.8) achieved CNS objective response, including 6 pts (26.1%) with ≥80% and 10 pts (43.5%) with 50-80% CNS volumetric reduction, respectively. Five pts (21.7%) had 20-50% CNS volumetric reduction. Seven of 11 (63.6%) who were refractory to lapatinib treatment had CNS tumor response, and 9 of 12 (75.0%) who were lapatinib naive had CNS ORR. With median follow-up of 12.1 months (mo), the median time to progression was 7.7 mo (95% CI 6.6-8.8), and overall survival was 11.8 mo (95% CI 7.0-16.6) among the 23 pts. Only 3 pts (13.0%) had disease progression during protocol treatment. Grade 3/4 toxicities (≥1%) included neutropenia, leukopenia, thrombocytopenia, infection, anemia, and in 32.7%, 14.0%, 8.4%, 8.4%, and 5.6% per cycles, respectively. Ten pts (43.5%) needed dose reduction of E to 60 mg/m2 and P to 60 mg/m2, and 2 pts discontinued from treatment due to toxicity. Conclusions: BEEP regimen has a significant anti-tumor effect for HER2 positive breast cancer with brain metastasis which progresses after WBRT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-16-02.

Miglustat: A Review of Its Use in Niemann-Pick Disease Type C

Miglustat (Zavesca®, Brazaves®), a small iminosugar molecule that reversibly inhibits glycosphingolipid synthesis, is the only disease-specific drug approved for the treatment of progressive neurological manifestations of Niemann-Pick disease type C (NP-C) in adult and paediatric patients. NP-C is a rare, autosomal-recessive lipid storage disorder characterized by impaired intracellular lipid trafficking and progressive neurological symptoms leading to premature death. In a randomized clinical trial, long-term extension studies and a retrospective observational cohort study, treatment with oral miglustat stabilized key neurological manifestations of NP-C (including horizontal saccadic eye movement peak velocity, ambulation, manipulation, language and swallowing) in paediatric and adult patients with the disease. The therapeutic effects of miglustat in stabilizing or slowing disease progression have been confirmed in other reports in the clinical experience setting. The primary tolerability issues associated with miglustat are mild to moderate gastrointestinal effects (e.g. diarrhoea, flatulence and abdominal pain/discomfort) and weight loss, which usually occur during initial therapy and are generally manageable. In the absence of a cure, miglustat is a valuable agent to reduce the progression of clinically relevant neurological symptoms in paediatric and adult patients with NP-C, which is considered a significant achievement in the treatment of this disease.

Cyclic mood disorder heralding adult-onset autosomal dominant leucodystrophy: A clinical masquerader

Leucodystrophies are a heterogeneous group of progressive white matter diseases which may be inherited in dominant, recessive or X-linked fashion depending on the type. Adrenoleucodystrophy (ALD) and metachromatic leucodystrophy (MLD) are rather commoner forms of leucodystrophies whereas krabbes disease, alexander disease, cannavans disease etc. are of less common type. Adult-onset autosomal dominant leucodystrophy (ADLD) is a lately described rarer form of leucodystrophy with perhaps no case report from India. Various leucodystrophies may have different clinical presentations, ranging from subtle cognitive and psychiatric manifestations to gross motor disabilities, visual impairment and seizure. Psychiatric manifestations in the form of psychoses and frank schizophrenia are commonly described in MLD. Depression though uncommonly reported in MLD, cyclic mood disorders have been rarely described in any form of leucodystrophies. We are reporting an eye opener, a case of ADLD which masqueraded as a rapid cyclic mood disorder for initial four years, later to be followed by progressive neurological signs and symptoms. To the best of our knowledge, this is perhaps the first case report of ADLD presenting as rapid cyclic mood disorder in the world literature.

Metabotropic glutamate receptor 5 knockout promotes motor and biochemical alterations in a mouse model of Huntington's disease

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder caused by a polyglutamine expansion in the amino-terminal region of the huntingtin protein, which promotes progressive neuronal cell loss, neurological symptoms and death. In the present study, we show that blockade of mGluR5 with MTEP promotes increased locomotor activity in both control (Hdh(Q20/Q20)) and mutant HD (Hdh(Q111/Q111)) mice. Although acute injection of MTEP increases locomotor activity in both control and mutant HD mice, locomotor activity is increased in only control mice, not mutant HD mice, following the genetic deletion of mGluR5. Interestingly, treatment of mGluR5 knockout mice with either D1 or D2 dopamine antagonists eliminates the increased locomotor activity of mGluR5 knockout mice. Amphetamine treatment increases locomotor activity in control mice, but not mGluR5 null mutant HD mice. However, the loss of mGluR5 expression improves rotarod performance and decreases the number of huntingtin intranuclear inclusions in mutant HD mice. These adaptations may be due to mutant huntingtin-dependent alterations in gene expression, as microarray studies have identified several genes that are altered in mutant, but not wild-type HD mice lacking mGluR5 expression. qPCR experiments confirm that the mRNA transcript levels of dynein heavy chain, dynactin 3 and dynein light chain-6 are altered following the genetic deletion of mGluR5 in mutant HD mice, as compared with wild-type mutant HD mice. Thus, our data suggest that mutant huntingtin protein and mGluR5 exhibit a functional interaction that may be important for HD-mediated alterations in locomotor behavior and the development of intranuclear inclusions.

A Case Report of Feline Pituitary Carcinoma with Hypercortisolism

ABSTRACTFeline pituitary tumors are rare. An 8-year-old male Japanese domestic cat presented with anorexia and emaciation. The cat died 17 days after admission from progressive neurological symptoms. At necropsy, a pituitary tumor measuring 25 × 18 × 15 mm was found. Microscopically, the tumor was divided into multiple lobules and had grown invasively into the adjacent brain tissue and sphenoid bone. Tumor cells had pleomorphic nuclei with prominent centrally located nucleoli and abundant amphophilic polygonal cytoplasm. Immunohistochemically, the tumor cells stained with anti-adrenocorticotropic hormone (ACTH), α-melanin-stimulating hormone (MSH) and β-endorphin antibodies. Ultrastructurally, the cytoplasm of the tumor cells contained various sized secretory granules. Based on these pathological findings, this tumor was diagnosed as pituitary carcinoma originated from pars intermedia cells.

Dialysis disequilibrium syndrome occurring during continuous renal replacement therapy.

The dialysis disequilibrium syndrome (DDS) is characterized by progressive neurological symptoms and signs attributable to cerebral edema that occurs due to fluid shifts into the brain following a relatively rapid decrease in serum osmolality during hemodialysis (HD). Since continuous renal replacement therapy (CRRT) is less efficient at solute clearance than intermittent HD, it seems logical that this mode of therapy is less likely to cause DDS. This entity has not been previously reported to occur with this modality. Here, we report two cases of DDS associated with CRRT that provide insights into its pathophysiological mechanisms and suggest strategies for its prevention.

Pathophysiology and Treatment of Neurodegeneration With Brain Iron Accumulation in the Pediatric Population

Syndromes of neurodegeneration with brain iron accumulation (NBIA) are characterized by increased iron deposition in the basal ganglia leading to complex progressive neurological symptoms. Several genetically distinct subforms have been recognized. In addition to pantothenate kinase-associated neurodegeneration (PKAN, NBIA1) and PLA2G6-associated neurodegeneration (PLAN, NBIA2), further genetic causes continue to be identified. Most of these present in childhood and are inherited following an autosomal recessive trait. However, the clinical and pathological spectrum has broadened and new age-dependent presentations have been described and there is overlap between the different NBIA disorders and with other diseases (such as spastic paraplegias, leukodystrophies and neuronal ceroid lipofuscinosis). Thus, additional clinical information (e.g., radiological findings such as precise patters of deposition of iron or co-occurrence of white matter lesions) may be useful when prioritizing genetic screening. Neuropathological work-up demonstrated variable involvement of iron deposition, but also Lewy bodies, neurofibrillary tangles and spheroid bodies. Treatment remains symptomatic. Here we review characteristic features of NBIA syndromes with a focus on pediatric cases.

Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM).

513 Background: The anti-tumor and anti-edema effects of BEV provide a rationale for testing in BCBM. Carboplatin (C) is associated with CNS responses across multiple tumor types. We evaluated BEV + C in pts with BCBM. Methods: Pts with progressive, measurable BCBM (>/= 1 cm in longest dimension) were eligible. Cycle 1: BEV 15 mg/kg on Day 1, followed on Day 8 by carboplatin AUC=5 (plus trastuzumab if HER2+). In subsequent cycles, pts received BEV + C on Day 1 (plus trastuzumab if HER2+) of a 3 week (wk) cycle. Standard brain MRI was obtained at baseline (BL) and every 2 cycles. Non-CNS scans (CT or MRI) were performed after 2 cycles, 4 cycles, then every 4 cycles. Correlative brain imaging was obtained at BL, 12-96 hours after the first dose of BEV, and after 2 cycles. Circulating tumor cells and blood for VEGF polymorphisms were also collected. The primary endpoint was composite CNS objective response rate (CNS ORR). CNS partial response required all of the following: >/= 50% reduction in volumetric sum of target CNS lesions compared to BL, no progression of non-target lesions, no new lesions, stable/decreasing steroid dose, no progressive neurologic signs or symptoms, and no progression of non-CNS disease by RECIST 1.0. The study used a 2-stage design to distinguish between ORR 5% vs 20% (responses in >/= 1/12 pts to enter 2ndstage; responses in >/= 4/37 pts needed to be promising). Results: 38 pts were enrolled between 11/3/09-8/24/12 (30 HER2+; 8 HER2-negative). Most (76%) pts had received >/=2 lines of metastatic chemotherapy. 97% of pts with HER2+ disease received prior trastuzumab; 73% had prior lapatinib. All but 5 pts progressed after WBRT and/or SRS. As of 1/15/13, 3 pts remain on protocol therapy; 22 patients have died. The composite CNS ORR was 63% (95% CI 46%-78%). CNS ORR by RECIST was 45%. CNS responses were observed in both HER2+ and HER2-negative pts. Of 34 pts with >/= 24 wks potential follow-up time, median number of cycles was 8 (range 1-19). One grade 2 CNS hemorrhage event was reported; there were no cases of grade 3/4 CNS hemorrhage. Conclusions: BEV + carboplatin is associated with a high rate of durable CNS response in pts with BCBM. Updated results, including progression-free and overall survival will be presented. Clinical trial information: NCT01004172.

Stereotactic laser induced thermotherapy (LITT): a novel treatment for brain lesions regrowing after radiosurgery

Since the inception of radiosurgery, the management of brain metastases has become a common problem for neurosurgeons. Although the use of stereotactic radiosurgery and/or whole brain radiation therapy serves to control the majority of disease burden, patients who survive longer than 6-8 months sometimes face the problem of symptomatic radiographically regrowing lesions with few treatment options. Here we investigate the feasibility of use of MRI-guided stereotactic laser induced thermotherapy (LITT) as a novel treatment option for these lesions. Six patients who had previously undergone gamma knife stereotactic radiosurgery for brain metastases were selected. All patients had an initial favorable response to radiosurgery but subsequently developed regrowth of at least one lesion associated with recurrent edema and progressive neurological symptoms requiring ongoing steroids for symptom control. All lesions were evaluated for craniotomy, but were deemed unresectable due to deep location or patient's comorbidities. Stereotactic biopsies were performed prior to the thermotherapy procedure in all cases. LITT was performed using the Visualase system and follow-up MRI imaging was used to determine treatment response. In all six patients biopsy results were negative for tumor and consistent with adverse radiation effects also known as radiation necrosis. Patients tolerated the procedure well and were discharged from the hospital within 48 h of the procedure. In 4/6 cases there was durable improvement of neurological symptoms until death. In all cases steroids were weaned off within 2 months. One patient died from systemic causes related to his cancer a month after the procedure. One patient had regrowth of the lesion 3 months after the procedure and required re-initiation of steroids and standard craniotomy for surgical resection. There were no complications directly related to the thermocoagulation procedure. Stereotactic laser induced thermotherapy is a feasible alternative for the treatment of symptomatic regrowing metastatic lesions after radiosurgery. The procedure carries minimal morbidity and, in this small series, shows some effectiveness in the symptomatic relief of edema and neurological symptoms paralleled by radiographic lesional control. Further studies are necessary to elucidate the safety of this technology.

Spinal Cord Stimulation for Radicular Pain Following Retained Bullet in the Spinal Canal

We are reporting on the implantation of a spinal cord stimulator to treat intractable radicular pain following a retained bullet fragment in the spinal canal. Such retained fragments are associated with risks including pain, neurological deficit, infection, toxic effects, and migration. Our patient was a young man with radicular pain and history of a gunshot entering the abdomen. Computed tomography of the spine had revealed a nearly complete bullet in the right paracentral canal at L4, partially extending into the lateral recess. He presented 17 months after his injury with gradually worsening pain and parasthesias radiating from the back to the whole right leg and foot. There was no weakness. As the patient had failed conservative therapy, procedural options were considered. In this case, the potential benefits of epidural steroid injection by any approach might not have outweighed risks of infection, related to foreign body and local steroid, or possible migration due to mechanical forces during injection. As he may well need repeated epidural steroid injections to manage his pain, this increases his risk for infection. A percutaneous trial spinal cord stimulation lead was placed, with epidural entry well away from the bullet. After good results, a permanent system was implanted. There was no evidence of infection or migration, and excellent pain relief was achieved. Bullets and other foreign bodies retained in the spinal canal can cause progressive neurologic symptoms through reactive tissue formation and compression. Spinal cord stimulation can relieve radicular pain while avoiding risks associated with altering the location of the offending foreign body. Key words: Spinal cord stimulation, radicular pain, retained bullet, gunshot wound, spinal canal, spinal injury, lumbar spine

Diastematomyelia

Retrospective case series study. This article describes our experience of the management of diastematomyelia. Diastematomyelia is a rare entity, which presents distinct clinical characteristics and requires different managements compared with other more common occult spinal dysraphism. A total of 156 patients with diastematomyelia were reviewed. All the patients underwent neurological and radiological examinations. Surgical excision of the lesion was performed for most patients and intradural exploration of the lumbar region was done to release tethering of conus in some patients. One patient died and autopsy was performed. Follow-up was carried out for all the patients, including surgical and nonsurgical approaches. There were 123 cases of type I diastematomyelia and 33 cases of type II diastematomyelia. The lumbar and thoracolumbar region was the most common site for diastematomyelia, and most spinal cords were split among 6 segments. The postoperative course was complicated by cerebrospinal fluid leakage in 2 patients, temporary neurological deterioration in 4 patients, and epidural hematoma in 1 patient. All cases did not have aggravation of symptoms during the follow-up of 2 to 20 years (mean of 4.5 yr). For the 123 patients with type I diastematomyelia, clinical symptoms were improved in 96 after surgical intervention and no worsening or occurrence of new clinical signs were observed during the follow-up. Those who did not receive surgery showed stabilization of neurological manifestation. Of the 33 type II cases, 9 surgical patients remained neurologically stable during the postoperative years without significant improvement in function, and 24 nonsurgical patients neither improved nor worsened in their neural deficit. Surgical treatment is the necessary management for type I diastematomyelia causing progressive neurological deterioration or with tethered filum, whereas conservative treatment is recommended to asymptomatic type I diastematomyelia and all type II diastematomyelia. 5.

Index of Suspicion

An 18-year-old girl presents with nighttime fevers to 39°C for 8 days. She complains also of headache, myalgia, and rash during the fevers. Eighteen days ago, she removed a tick from her neck after attending a festival in the northeastern United States. One week ago, she presented to her pediatrician with a sore throat and rash. She was hyponatremic (sodium, 129 mEq/dL) and was started on doxycycline for presumed Rocky Mountain spotted fever (RMSF). Her condition has not improved. She admits to multiple unprotected sexual encounters and cocaine abuse. The girl appears weak. Her vital signs include temperature of 38.7°C; heart rate, 84 beats per minute; respiratory rate, 20 breaths per minute; and blood pressure, 113/73 mm Hg. A salmon-colored macular rash is present on her trunk and proximal extremities. She also exhibits dermatographia. There are no mucosal lesions. The liver is enlarged to 2.5 cm beyond the rib margin, and she has right upper quadrant tenderness. Her muscles are tender to deep palpation in all four extremities. She is able to bear weight but refuses to ambulate due to bilateral lower extremity myalgia and arthralgia. A CBC demonstrates a normochromic, normocytic anemia, and leukocytosis with a left shift. ESR and CRP are elevated at 109 mm/hour and 19.8 mg/dL, respectively. A mild transaminitis is present. Ultrasonography reveals a mildly enlarged and echogenic liver. Small pleural and pelvic effusions are present on CT scan. A bone marrow biopsy and a glycosylated ferritin fraction are obtained. A clinical diagnosis is made. An 11-year old Hispanic boy who had poststreptococcal reactive arthritis (PSRA) and rheumatic fever (RF) diagnosed at age 6 years has been symptom-free while taking oral penicillin (PCN). Two months ago, he developed lemon-sized, reddish, painful subcutaneous nodules that were warm to touch on both lower extremities and revealed acute …

Clinical Reasoning: A 56-year-old man with progressive spasticity

A 56-year-old man presented with progressive neurologic symptoms that developed more than 14 years ago. His symptoms started with numbness in the toes, followed by slowly progressive lower extremity weakness, increase in tone, and imbalance. He also developed bladder and bowel urgency, constipation, and erectile dysfunction. He did not have any symptoms in his arms.

Subarachnoid–subarachnoid bypass: a new surgical technique for posttraumatic syringomyelia

The origin of posttraumatic syringomyelia is not completely understood. With respect to posttraumatic syringomyelia, the optimum management strategy for patients with spinal cord injury has also not been established. The authors hypothesized that reconstruction of the subarachnoid channels would reestablish CSF flow, thereby addressing the underlying cause of the syrinx formation. The authors performed a new type of surgery, subarachnoid-subarachnoid bypass (S-S bypass), in which an attempt was made to reestablish normal CSF circulation around the spinal cord. The purpose of this study was to evaluate the effectiveness of S-S bypass for posttraumatic syringomyelia. Twenty consecutive patients with symptomatic posttraumatic syringomyelia who had progressive neurological symptoms and underwent S-S bypass were included in the study. The surgical procedure was as follows: a laminectomy was performed at the level of trauma, and a midline dural opening was made under a microscope. The arachnoid was exposed up to the area of normal arachnoid mater with normal CSF circulation. After dissection of the normal arachnoid mater at the cephalic and caudal sites, 1 or 2 tubes made of medical-grade silicone were inserted into the cephalic and caudal ends of the normal subarachnoid space. Bypass tubes were laid in the subdural space, and a watertight dural closure was accomplished using running sutures. The mean follow-up period was 48.2 months (range 12-93 months). The preoperative status and postoperative clinical course were assessed according to 3 grading systems: the Frankel grading system for global neurological status, the American Spinal Injury Association motor score for motor weakness, and the Klekamp system for bladder function. The major presenting symptoms or signs were assessed in terms of symptom improvement, stabilization, or deterioration. Preoperative and postoperative MRI was used to analyze the size and craniocaudal extension of the cavity. Twelve patients showed clinical improvement, 4 were stable, and 4 showed deterioration. The mean length of the syrinx observed on preoperative MRI was 9.9 spinal levels, and the mean Vaquero index was 62.3%. The mean length of the syrinx observed on postoperative MRI was 5.3 spinal levels, and the mean Vaquero index was 28.4%. These values were significantly lower than the preoperative values (p = 0.01 and p < 0.01, respectively). This study showed that interference with CSF flow was the major cause of syrinx development and that reconstruction of CSF flow is the most important treatment strategy based on the cause of the syrinx. Subarachnoid-subarachnoid bypass, which can be performed without myelotomy, was not only a safe and effective surgical technique, but may also be a more physiological way of treating posttraumatic syringomyelia.

Chiari malformation type I: a case-control association study of 58 developmental genes.

Chiari malformation type I (CMI) is a disorder characterized by hindbrain overcrowding into an underdeveloped posterior cranial fossa (PCF), often causing progressive neurological symptoms. The etiology of CMI remains unclear and is most likely multifactorial. A putative genetic contribution to CMI is suggested by familial aggregation and twin studies. Experimental models and human morphometric studies have suggested an underlying paraxial mesoderm insufficiency. We performed a case-control association study of 303 tag single nucleotide polymorphisms (SNP) across 58 candidate genes involved in early paraxial mesoderm development in a sample of 415 CMI patients and 524 sex-matched controls. A subgroup of patients diagnosed with classical, small-PCF CMI by means of MRI-based PCF morphometry (n = 186), underwent additional analysis. The genes selected are involved in signalling gradients occurring during segmental patterning of the occipital somites (FGF8, Wnt, and retinoic acid pathways and from bone morphogenetic proteins or BMP, Notch, Cdx and Hox pathways) or in placental angiogenesis, sclerotome development or CMI-associated syndromes. Single-marker analysis identified nominal associations with 18 SNPs in 14 genes (CDX1, FLT1, RARG, NKD2, MSGN1, RBPJ1, FGFR1, RDH10, NOG, RARA, LFNG, KDR, ALDH1A2, BMPR1A) considering the whole CMI sample. None of these overcame corrections for multiple comparisons, in contrast with four SNPs in CDX1, FLT1 and ALDH1A2 in the classical CMI group. Multiple marker analysis identified a risk haplotype for classical CMI in ALDH1A2 and CDX1. Furthermore, we analyzed the possible contributions of the most significantly associated SNPs to different PCF morphometric traits. These findings suggest that common variants in genes involved in somitogenesis and fetal vascular development may confer susceptibility to CMI.

The influence of Vanishing White Matter mutations on oligodendrocyte differentiation

s ingediend voor het Amsterdam Kindersymposium 2013 35 The influence of Vanishing White Matter mutations on oligodendrocyte differentiation S. Dooves (1,2), J.A. van der Kreeke (1,2), P. Leferink (1,2), J.G. Jacobs (1,2), M.S. van der Knaap (1), V.M. Heine (1,2) (1) Center for Children with White Matter Disorders, Pediatrics, VU University Medical Center, Amsterdam (2) Stem Cell Laboratory, VU University/VU University Medical Center, Amsterdam INTRODUCTION Vanishing White Matter disease (VWM) is an autosomal recessive leukoencephalopathy caused by mutations in genes encoding the eukaryotic translation initiation factor 2B (eIF2B). Children are mainly aff ected, who suff er from progressive neurological symptoms as ataxia and die at young age. Previous research indicates that the macroglial cells of the brain (astrocytes and oligodendrocytes) in VWM show a defect in maturation. Currently there is no treatment available. METHODS In order to gain more knowledge about the disease pathology we tested the diff erentiation capability of stem cells derived from VWM mice in culture. Furthermore, a co-culture system is used to test the infl uence of VWM mutated astrocytes on the diff erentiation of WT oligodendrocyte precursor cells (OPCs). RESULTS The fi rst results show that VWM mutated astrocytes have a negative eff ect on the maturation of oligodendrocytes. CONCLUSION Astrocytes with a VWM mutation have a negative infl uence on OPC maturation. Further studies will show if it is possible to rescue this maturation defect. The results will give us more information about the disease mechanisms of VWM and will help in the development of a cell replacement therapy for VWM.

Surgical Approaches in Isthmic Spondylolisthesis

Isthmic spondylolisthesis is one of the most common types of spondylolisthezis in 4-8% of general population. The changes or defects occur in the pars interarticularis of neural arch may cause the formation of isthmic spondylolisthezis.Mechanic, genetic and hormonal factors may be effective during this alternation process. Clinical signs may ocur according to the spinal deformities or compression of neurological structures. Although conservative treatment may be attempted, surgical treatment may be required in the patients with pain despite medical treatment or progression of neurological symptoms. The alternative surgical techniques include; neural decompression, bone fusion, stabilization with instrumentation-fusion.

Diffusion-Weighted Magnetic Resonance Imaging of an Intramedullary Epidermoid Cyst with Dorsal Dermal Sinus Tract in a Toddler

We report the use of diffusion-weighted magnetic resonance imaging to diagnose and manage a rare case of a symptomatic thoracic intramedullary congenital epidermoid cyst with associated dermal sinus in a girl. Congenital intramedullary epidermoid cysts with associated dermal sinuses are very rare occurrences and seldom present symptomatically in very young children. We present a case of a 32-month old with a draining dimpled skin lesion. Magnetic resonance images demonstrated an intramedullary epidermoid with a dorsal dermal sinus tract opening to the skin surface which was confirmed surgically. The patient was treated with debulking to prevent recurrent infection and progression of neurological symptoms. This case demonstrates the use of diffuse-weighted MRI to assist in the diagnosis and surgical management of an atypical presentation of a rare developmental abnormality, which is not well documented in the pediatric radiological literature. Failure to diagnosis may have significant neurological permanent debilitating consequences.

An Autopsy Case of the Marburg Variant of Multiple Sclerosis (Acute Multiple Sclerosis)

We herein report an autopsy case of the Marburg variant of multiple sclerosis (MS). A 29-year-old woman developed acute and progressive neurological symptoms. A diagnosis of MS was suspected based on the patient's clinical background and brain MRI findings and the lack of evidence of malignancy on a brain biopsy. Despite the administration of typical treatment for MS, a fatal outcome occurred three months after disease onset. The autopsy revealed multiple inflammatory demyelinating lesions in the central nervous system. In addition, two noteworthy histopathological features were observed compared with prototypical MS. We evaluate the pathogenic differences between the Marburg type and prototypical MS by discussing the neuropathology and cerebrospinal fluid (CSF) findings of our case.

Evaluation of Metastatic Cholangiocarcinoma in a Spitz Dog

A 12-year-old spitz breed dog, with progressive neurologic symptoms including seizures, ataxia, mental depression, walking aimlessly and head pressing was referred to Small Animal Hospital of Veterinary Medicine, the University of Tehran. The dog was received Diazepam prior to examination and diagnosis, whereas it died at first day eventually. In physical examination, there was a firm mass with irregular nodular surface, about 8 cm in diameter under the skin of mammary glands region. At necropsy, considerable abdominal ascites, several masses with different sizes throughout liver lobes and on intestinal serosa were observed. According to histological adjectives of biliary epithelium due to firm texture of the tumour masses and numerous mitotic figures the tumour was confirmed as cholangiocarcinoma, and immuniohistochemical results for cytokeratin marker demonstrated such diagnosis.