Neonatal hypoglycemic brain - injury a common cause of infantile onset remote symptomatic epilepsy.

OBJECTIVES: To study the etiology of remote symptomatic epilepsy with onset in the first 3 years of life. Patients with neonatal hypoglycemic brain injury (NHBI), were further studied for risk factors and clinical features. METHODS: The study was conducted at a tertiary pediatric neurology service between May-August 2004. Consecutive patients were recruited prospectively. The probable etiological diagnoses were based primarily on cranial imaging. Two radiologists, blinded to the etiological diagnosis, reviewed the cranial imaging and suggested the likely etiology based on published imaging criteria. There were three categories i.e, (i) perinatal encephaloclastic conditions (PEC) e.g., hypoxic ischemic encephalopathy (HIE) etc, (ii) developmental (DV) e.g., tuberous sclerosis, etc and (iii) postnatal (PN) e.g., trauma, etc. Three risk factors (birth weight, type of delivery, feeding difficulty) were compared between NHBI and developmental etiology (DV) groups. Neurological findings were compared between the NHBI vs the other perinatal groups. Seizure details were studied only in the NHBI group. RESULTS: 63 boys and 37 girls were recruited. Mean age of seizure onset was 13.9 months. PEC were seen in 50 patients, DV in 28 patients and PN in 5. NHBI was seen in 23 patients and was the most frequent cause of epilepsy. Low birth weight (LBW), neonatal feeding difficulties and cesarean delivery were significant risk factors for NHBI vis a vis the DV group. Microcephaly, autism, visual impairment and apraxia of hand use were common while spasticity or dystronia were rare in NHBI. Spasms were the commonest seizure type. CONCLUSION: Neonatal hypoglycemia is the most common etiology of remote symptomatic infantile onset epilepsy. LBW, poor neonatal feeding and cesarean delivery are significant clinical correlates.

The continuum of stem cell transdifferentiation: possibility of hematopoietic stem cell plasticity with concurrent CD45 expression.

Recent years have seen a surge of scientific research examining adult stem cell plasticity. For example, the hematopoietic stem cell has been shown to give rise to skin, respiratory epithelium, intestinal epithelium, renal epithelium, liver parenchyma, pancreas, skeletal muscle, vascular endothelium, myocardium, and central nervous system (CNS) neurons. The potential for such stem cell plasticity seems to be enhanced by stressors such as injury and neoplasia. Interestingly, recent studies have demonstrated that hematopoietic stem cells may be able to adopt certain nonhematopoietic phenotypes, such as endothelial, neural, or skeletal muscle phenotypes, without entirely losing their initial hematopoietic identity. We propose that transdifferentiation can, in certain conditions, be a partial rather than a complete event, and we encourage further investigation into the phenomenon of a stem cell simultaneously expressing phenotypic features of two distinct cell fates.

Differential expression of angiopoietin-1 and angiopoietin-2 may enhance recruitment of bone-marrow-derived endothelial precursor cells into brain tumors.

OBJECTIVES: Angiogenesis is necessary for sustained neoplastic development. The angiopoietins Ang-1 and Ang-2 have been implicated in the regulation of this process; recent reports have suggested that a net gain in Ang-2 activity may be an initiating factor for tumor angiogenesis. We examined the recruitment of bone marrow-derived endothelial precursor cells into developing tumor neovasculature, and the spatial relationship between these cells and angiopoietin (Ang-1 and Ang-2) expression. METHODS: For this study T-cell depleted knockout mice (RAG-2/KO-5.2) were lethally irradiated and their bone marrow was reconstituted by bone marrow cells (BMCs) from transgenic mice (C57BL/Ka-Thy1.1) expressing green fluorescent protein (GFP). Rat glioma cells (RT-2/RAG) were then injected into the transplanted animals to form solid brain tumors. The animals were killed and their brains were analysed using immunohistochemistry and fluorescence-activated cell sorting. RESULTS: We found that BMCs migrated preferentially into the tumor when compared to adjacent healthy brain parenchyma. Furthermore, GFP+/CD34+ cells represented up to 8% of endothelial-like cells within the walls of tumor blood vessels. In the tumor, significant colocalization of Ang-2 with GFP+/CD34+ cells was noted (>80%), but colocalization with Ang-1 never exceeded 20%. In normal tissue directly surrounding the tumor, GFP+/CD34+ cells colocalized strongly with both angiopoietins (>75% and >70% for Ang-1 and Ang-2, respectively). DISCUSSION: The relative increase in angiopoietin-2 activity in brain tumors may result in the creation of a pro-angiogenic environment that enhances the recruitment of putative bone marrow-derived endothelial precursor cells into the tumor's developing vascular tree.

Hematopoietic stem cells give rise to perivascular endothelial-like cells during brain tumor angiogenesis.

Bone marrow (BM) cells have recently been shown to give rise to skeletal, hepatic, cardiac, neural, and vascular endothelial tissues. However, it has been shown that this is the result of cell fusion rather than transdifferentiation of hematopoietic stem cells (HSC). For this study, we established a mouse model of brain tumor growth to investigate the differentiation potential of HSC into endothelial cells during brain tumor-induced angiogenesis. Nontransgenic (GFP(neg)) recipient mice were lethally irradiated, and their hematopoietic cells were subsequently repopulated by transplantation of a single green fluorescent protein (GFP)-expressing HSC. Rat glioma (RT-2/RAG) cells were then injected into the striatum of the chimeric mice 6-8 weeks post-transplantation. The animals were sacrificed 3-9 days after tumor implantation, and the mobilization, temporal-spatial distribution, and lineage-specific marker expression profile of the GFP(+) cells within the growing tumor were analyzed. We saw that GFP(+) cells gave rise to elongated, CD34(+)/Flk-1(+) cells that incorporated into the endothelium of tumor blood vessels. However, all GFP(+) cells were also CD45(+), and the presence of CD45 on the HSC-derived endothelial-like cells supports the hypothesis that the hematopoietic cells were recruited into the tumor milieu. The fact that we failed to demonstrate the expression of von Willebrand factor in these cells argues against a true endothelial identity. Nevertheless, the recruitment of HSC-derived endothelial-like cells was an extremely rare event in normal brain parenchyma, and, thus, the permissive influence afforded by the growing tumor appeared to enhance the perivascular tropism and acquisition of an endothelial phenotypes by a population of HSC-derived cells.

Initial nonoperative management for periappendiceal abscess.

PURPOSE: Our goal was to compare initial operative and nonoperative management for periappendiceal abscess complicating appendicitis. METHODS: This study is a retrospective review of 155 consecutive patients with appendicitis complicated by periappendiceal abscess treated between 1992 and 1998. Eighty-eight patients were treated initially nonoperatively, and 67 patients were treated operatively. All patients had localized abdominal tenderness and either computed tomography or intraoperative documentation of an abscess. RESULTS: Our patient population consisted of 107 males and 48 females, with an average age of 33 (range, 16-75) years. Age, gender, comorbidity, white blood cell count, temperature, and heart rate did not differ significantly between groups. For the initial nonoperative management group, the failure rate was 5.8 percent and the appendicitis recurrence rate was 8 percent after a mean follow-up of 36 weeks. The response to treatment of the initial nonoperative group and the initial operative group was compared by length of stay (9 +/- 5 days vs. 9 +/- 3 days; P = not significant), days until white blood cell count normalized (3.8 +/- 4 days vs. 3.1 +/- 3 days; P = not significant), days until temperature normalized (3.2 +/- 3 days vs. 3.1 +/- 2 days; P = not significant), and days until a regular diet was tolerated (4.7 +/- 4 days vs. 4.6 +/- 3 days; P = not significant). Complication rate was significantly lower in the nonoperative group (17 vs. 36 percent; P = 0.008). CONCLUSIONS: Initial nonoperative management of appendicitis complicated by periappendiceal abscess is safe and effective. Patients undergoing initial nonoperative management have a lower rate of complications, but they are at risk for recurrent appendicitis.

Evaluation and management of intractable epilepsy.

Seizures remain uncontrolled in 15-20% of all childhood epilepsies despite conventional therapy. This review will focus on the etiologies, effects and treatment strategies in this group of patients. Risk factors for intractable seizures include early age of onset, remote symptomatic seizures, certain seizure types and epileptic syndromes. Adverse effects of chronic epilepsy on academic performance and future employment have been documented. The mechanisms underlying cognitive and behaviour decline are outlined. Errors in diagnosis and therapy often result in pseudo-intractability. Common errors are emphasised. Medical treatment strategies should be based on a complete etiological, syndromic and seizure--type diagnosis sometimes with the help of simultaneous video-EEG and MRI. A detailed past drug use review helps in planning future therapy. New antiepileptic drugs introduced in the last two decades include clobazam, vigabatrin, lamotrigine, gabapentin and topiramate. Strategies of when and how to use these are highlighted. The ketogenic diet has been rejuvenated in severe epilepsy especially in younger, more handicapped patients. Surgical treatment for epilepsy has emerged as a powerful treatment option in selected patients. The patient selection process, types of surgeries and the long-term results are highlighted. Many of these new therapies are now available in India and may offer relief to many of these unfortunate patients.

Can perforated appendicitis Be diagnosed preoperatively based on admission factors?

The optimal initial treatment for selected patients with perforated appendicitis may be nonoperative. For this reason it is important to be able to diagnose perforated appendicitis preoperatively. The purpose of this study was to determine the accuracy of diagnosing perforated appendicitis using only admission factors. The study population was comprised of 366 adult patients who underwent appendectomy for presumed appendicitis during 1997. Admission factors associated with perforated appendicitis were determined using univariate and multivariate analyses. These variables were then used to formulate a rule for the diagnosis of perforated appendicitis. Sensitivity and specificity were calculated for this rule. The admission factors analyzed were sex, race, age, days of pain, temperature, heart rate, symptoms, physical examination findings, and laboratory findings. Multivariate regression analysis revealed days of pain, temperature, and localized tenderness outside the right lower quadrant to be significant (P <0.05). Using two or more days of pain, a temperature of >/=101 F (38.3 C), or localized tenderness outside the right lower quadrant as criteria to indicate perforation, we achieved a sensitivity of 86% and a specificity of 58% for distinguishing perforated from nonperforated appendicitis. We concluded that (1) perforated appendicitis cannot reliably be distinguished from nonperforated appendicitis based on admission factors, and (2) two or more days of pain, localized tenderness outside the right lower quadrant, and a temperature of >/=101 F (38.3 C) define a group of patients with appendicitis who have a high incidence of perforation.

Patterns of recurrence in anal canal carcinoma.

HYPOTHESIS: The initial modality of treatment of anal canal carcinoma (ACC) influences the pattern of recurrence of disease. DESIGN: A retrospective analysis comparing patterns of recurrence in patients with ACC undergoing either surgery or chemoradiotherapy as their initial therapeutic intervention. Anal margin cancers and adenocarcinomas were excluded. SETTING: A university-affiliated urban medical center. PATIENTS: Eighty-one patients were given a diagnosis of ACC between February 1, 1952, and December 31, 1998. Fifty-one (63%) of the patients initially underwent surgery: abdominoperineal resection in 38 patients (75%) and local excision in 13 patients (25%). Chemoradiotherapy was the initial therapeutic intervention in 30 patients (37%). MAIN OUTCOME MEASURES: The patterns of recurrence (local vs distant disease) and survival were compared between the group that underwent palliative surgery (hereafter referred to as the surgical group) and the group that received chemoradiotherapy (hereafter referred to as the chemoradiotherapy group). RESULTS: The mean follow-up was 40 months. Local recurrence occurred in 7 patients (14%) in the surgical group vs 7 patients (23%) in the chemoradiotherapy group (P =.46). Using Kaplan-Meier actuarial analysis, local recurrence rates for the surgical and chemoradiotherapy groups at 1 year were 0% and 6%, respectively (P =.32), and at 5 years were 17% and 36%, respectively (P =.02). The average (+/-SD) time to local recurrence in the surgical group was 23 +/- 0.7 months and for the chemoradiotherapy group 16 +/- 2.9 months (P =.27). Five (71%) of the 7 patients with local recurrences in the chemoradiotherapy group underwent salvage abdominoperineal resection with 100% disease-free survival at a mean follow-up of 35 months. When patients presenting with metastatic disease were excluded, distant recurrences developed in 7 patients (16%) in the surgical group and 2 (7%) in the chemoradiotherapy group (P =.31). Actuarial 5-year distant recurrence rates for the surgical and chemoradiotherapy groups were 26% and 19%, respectively (P =.65). Five-year survival was 42% in the surgical group and 74% in the chemoradiotherapy group (P =.01). CONCLUSION: There was a higher rate of local recurrence in patients with ACC treated with chemoradiotherapy vs surgical resection as the initial therapeutic intervention. However, when this occurred, abdominoperineal resection was effective salvage therapy and was associated with a 100% disease-free survival at 3 years. Therefore, chemoradiotherapy is justified as the initial treatment for ACC and has an overall 5-year survival that is significantly higher than that attained with initial surgical treatment.

Nonoperative management of perforated appendicitis without periappendiceal mass.

BACKGROUND: Initial nonoperative treatment for patients with periappendiceal mass has been shown to be safe and effective. Our goal was to evaluate the safety and efficacy of initial nonoperative management for perforated appendicitis not accompanied by a palpable mass. METHODS: The study population consisted of 77 patients with appendicitis treated initially nonoperatively between 1992 and 1998. All had localized abdominal tenderness and computed tomography findings of abscess or phlegmon. None had a palpable abdominal mass. Outcome parameters evaluated were rate of failure, complication, and recurrence. RESULTS: There were 49 males and 28 females with a mean age of 35 years (range 16 to 75). Initial nonoperative management was successful in 95% of patients. Complications occurred in 12% of patients. Recurrent appendicitis developed in 6.5% of patients after an average follow-up of 30 weeks. CONCLUSIONS: Perforated appendicitis patients with localized abdominal tenderness and abscess or phlegmon can safely and effectively be treated in an initial nonoperative fashion.

Computed tomography scanning for the diagnosis of perforated appendicitis.

The optimal initial treatment for perforated appendicitis may be nonoperative. For this reason it is important to be able to reliably distinguish between acute and perforated appendicitis. CT scanning has been shown to be highly accurate for the diagnosis of appendicitis, but it has not been specifically evaluated for perforated appendicitis. Our objective was to evaluate CT for the diagnosis of perforated appendicitis. Our study population comprised 84 patients who underwent appendectomy between 1993 and 1997 and who had CT scanning performed preoperatively. Medical records were reviewed retrospectively. CT scans were reviewed in a blinded fashion. CT findings were correlated with pathologic and clinical factors. Sixteen patients with acute appendicitis, 59 patients with gangrenous or perforated appendicitis, and 9 patients with normal appendices or other diagnoses were evaluated. For patients with pathologic documentation of appendicitis, CT findings that independently predict perforation or gangrene included abscess (P<0.001), phlegmon (P<0.001), extraluminal gas (P = 0.01), and terminal ileal wall thickening (P = 0.03). CT findings of an abscess, extraluminal gas, or phlegmon have a sensitivity of 92 per cent, specificity of 88 per cent, positive predictive value of 96 per cent, and negative predictive value of 74 per cent for perforated or gangrenous appendicitis. We conclude that CT can reliably distinguish between acute and perforated appendicitis.

Extra and central pontine myelinolysis in a child with adrenal insufficiency.

We report a 5-year-old patient with adrenal insufficiency (AI) who had a subacute monophasic neurologic illness and brainstem and striatal lesions on brain imaging. The prominent electrolyte abnormalities in AI indicate that extra and central pontine myelinolysis is the likely cause. An association between AI and extra pontine myelinolysis has not previously been reported in children.

Sporadic Stiffman syndrome in a young girl.

A 14-month-old girl had experienced sudden episodes of breath-holding and spasms of the trunk and limb muscles, leading to cyanosis and loss of consciousness since 3 months of age. Her clinical features and electromyography suggested Stiffman syndrome, and her response to high-dose diazepam and baclofen confirmed the diagnosis. Stiffman syndrome is a rare entity, rarer still in childhood. This is the youngest case of sporadic Stiffman syndrome reported in literature. Distinguishing Stiffman syndrome from similar conditions such as Schwartz-Jampel syndrome or neuromyotonia is important because administration of GABAergic agents (valproate, baclofen, diazepam) elicits a good response.

Megalencephalic leukodystrophy in an Asian Indian ethnic group.

Over a 10-year period, we reviewed 30 patients with leukodystrophy, megalencephaly, and a relatively benign course. Most of these patients (26) belonged to a distinctive ethnic group called the Agrawals. Head circumference exceeded the 95th percentile in 28 patients; 22 patients had seizures; 22 had pyramidal signs (16 more pronounced and 6 mild); and 16 had cerebellar ataxia. The median age of onset of symptoms was 1.8 years. Interictal electroencephalogram (EEG) was abnormal in 21 of 23 patients. The inheritance is possibly autosomal recessive.

Difficult to control epilepsy in childhood--a long term study of 123 cases.

One hundred and twenty three children with difficult to control epilepsy (DCE) were studied. Etiological factors which predominated included an age of onset less than 2 years (71.5%), male sex (69%), mixed, secondarily generalized, or complex partial seizures (77%), mental retardation (64%) and neurological abnormalities (52%). Static neurological disease was seen in 63%, with only 17% having idiopathic disease. Identifiable epileptic syndromes were noted in less than half the children. The surface EEG was abnormal in 84%, and correlated with the clinical seizure type in 81%. CT and MRI were helpful in diagnosis in only 38 and 48%, respectively, and even less so in therapy decisions, 7 and 16%, respectively. Prior therapy revealed the use of polytherapy in 61% and suboptimal dosages in 78%. In the 100 patients with adequate follow up, 67% showed a good response, i.e., 35% complete and 32% more than 50% reduction in seizures. Only 11% were total nonresponders, and most were severely retarded. Major treatment strategies employed included switching to monotherapy, supranormal dosages and avoidance of sedative anticonvulsants. Side effects were noted in 41% with 8 cases being life threatening. Overall mortality was 4%. We concluded that risk factors for DCE included early age of onset, mental retardation and certain seizure types. EEG was more helpful than neuroimaging. Treatment responses were favorable, especially in those with normal intellect and the use of normal or high dose monotherapy.

Detection of human T-cell lymphoma/leukemia virus type I DNA and antigen in spinal fluid and blood of patients with chronic progressive myelopathy.

The presence of antibodies to human T-cell lymphoma/leukemia virus Type I (HTLV-I) has been associated with chronic progressive myelopathy. We attempted to isolate the virus from the blood and spinal fluid of patients with chronic progressive myelopathy and to define the clinical, radiologic, and electrophysiologic features of this disease. Ten of 13 patients from tropical countries and 2 of 8 from the United States had serum antibodies to HTLV-I. The virus was detected in cultures of peripheral-blood lymphocytes from three of seven patients by means of Southern blot hybridization. Using a sensitive in vitro enzymatic gene-amplification technique, we detected HTLV-I sequences in fresh peripheral-blood mononuclear cells of all of 11 patients tested who were positive for the antibody, and in cell cultures of the spinal fluid from 3 of the 11 tested. Magnetic resonance imaging of the cranium revealed periventricular lesions in the white matter of 3 of the 12 antibody-positive patients. Five of these patients had mild axonal sensorimotor polyneuropathy, and one had bilateral lumbar radiculopathy. Visual evoked potentials were abnormal in three seropositive patients, and brain-stem evoked responses were abnormal in two. The detection of the DNA and proteins of HTLV-I strengthens the proposition that this virus is involved in the pathogenesis of a subset of cases of chronic progressive myelopathy.