Neurological abnormalities associated with celiac disease

Abstract Background Celiac disease (CD) is a gluten-sensitive enteropathy in genetically susceptible individuals. Anecdotal reports suggest that the nervous system might be affected in the disorder, but the severity and prevalence of such an involvement have not been systematically evaluated. Materials and methods Analysis of files of CD patients diagnosed between 1980 and 1999 for neurological abnormalities. Diagnosis of CD was based on the modified criteria of the European Society for Pediatric Gastroenterology and Nutrition. Results Of 148 CD patients, 18 (12%) had 21 neurological disorders that could not be attributed to any other condition including muscle abnormality (3), epilepsy (3), psychiatric disease (4), peripheral neuropathy (3), cerebrovascular disease (1), myelopathy (1) and Down syndrome (2). Other disorders probably unrelated to CD were present in 8 patients. Conclusion If this association is not coincidental, both the central and the peripheral nervous systems may be affected in CD by a spectrum of neurological disorders that are either the outcome of CD or share the same pathogenesis with the enteropathy.     

The spectrum of neurologic disease associated with anti-GM1 antibodies

We compared anti-GM1 IgM antibody titers in patients with various neurologic diseases and in normal subjects. We found increased titers in patients with lower motor neuron disease, sensorimotor neuropathy, or motor neuropathy with or without multifocal conduction block. In patients with other diseases, titers are similar to those in normal individuals, suggesting that anti-GM1 antibody levels are not increased nonspecifically after neural injury or inflammatory diseases. Anti-GM1 antibodies in many of the patients occur as monoclonal gammopathies, predominantly of lambda light-chain type, but the antibodies are sometimes polyclonal with normal or increased serum IgM concentrations. Most of the anti-GM1 antibodies appear to react with the Gal(beta 1-3)GalNAc epitope which is shared with asialo-GM1 and GD1b, but in some patients the antibodies are more specific for GM1 and associated with motor neuropathy. Patients with motor or sensorimotor peripheral neuropathy or lower motor neuron disease should be tested for anti-GM1 antibodies or anti-Gal(beta 1-3)GalNAc antibodies, as therapeutic reduction in antibody concentrations was reported to result in clinical improvement in some patients.     

Osteoid osteoma presenting with focal neurologic signs

Osteoid osteomas are benign bone tumors, most commonly located in the femur or tibia. In young children, these tumors can be extremely difficult to diagnose. They commonly present nonspecifically with gait disturbance and pain and characteristically respond well to mild pain relievers. We report two patients who presented with neurologic signs, including atrophy, weakness, and diminished deep tendon reflexes of the affected limb. These two patients demonstrate that osteoid osteomas of the lower extremities can present with neurologic signs, and proper diagnosis requires a detailed history and clinical awareness of this phenomenon.     

Dural sarcoidosis presenting with transient neurologic symptoms

Despite the propensity of sarcoid granulomas to be clustered around blood vessels, transient ischemic attacks and strokes are rare. A 43-year-old man had recurrent transient dysarthria and right hemiparesis; a biopsy specimen showed neurosarcoidosis. There was complete resolution of both symptomatology and the subdural sarcoid mass lesion with the administration of corticosteroid therapy.     

Cerebrovascular and neurologic disease associated with antiphospholipid antibodies: 48 cases

Lupus anticoagulants and anticardiolipin antibodies are antiphospholipid antibodies (APLAb) with related antigenic specificities and are newly recognized markers for an increased risk of thrombosis. We studied 48 patients who presented with cerebral or visual dysfunction associated with APLAb to help clarify the diagnostic, clinical, laboratory, radiologic, and pathologic features in these patients. Most patients presented with transient cerebral ischemia or cerebral infarction. Recurrent and stereotypic events were frequent. Visual disturbances resulted from amaurosis fugax, retinal arterial or venous occlusion, occipital ischemia, diplopia, and migraine-like disturbances. Three patients presented with severe atypical classic migraine. Recurrent infarcts of brain and eye were significantly associated with the presence of cigarette smoking, hyperlipidemia, and a positive antinuclear antibody. During 44.4 patient-years of prospective follow-up, the combined stroke and systemic thrombotic event rate was 0.27 events per patient-year and was 0.54 events per patient-year if TIA and death were included. Forty (83%) of the patients did not have systemic lupus erythematosus (SLE). Thrombocytopenia was present in 15 (31%) and a false-positive VDRL in 11 (23%) of the patients. Cerebral angiography was normal or revealed large-vessel occlusion or stenosis without changes suggestive of vasculitis. Patients with only transient dysfunction generally had normal radiologic studies, including angiography. Organs and arterial vessels studied pathologically revealed thrombotic occlusive disease without vasculitis. APLAb are strongly associated with an immune-mediated thrombotic tendency, generally in the absence of SLE. Other stroke risk factors may add to the risk of recurrent ischemic events in patients with APLAb.     

Familial psychosis and diverse neurologic abnormalities in adult-onset Gaucher's disease.

A family is described in which adult-onset Gaucher's disease developed, followed years later by atypical psychotic disorders with neurologic and electroencephalographic abnormalities. A biochemical investigation of primary and secondary enzyme alterations in the index case was performed in an attempt to identify a pattern that might be specific to this clinical profile. The literature pertaining to CNS involvement in adult patients with Gaucher's disease is also reviewed. An etiologic link may exist between the inherited metabolic disorder and associated neuropsychiatric impairment. The biochemical basis of this hypothesized association remains unclear, however, and further enzymatic and pathologic investigations are warranted.     

Adjunctive therapies for HIV-1 associated neurologic disease

In the past decade we have seen a milder phenotype and decreased incidence of HIV-1 associated dementia (HAD), largely due to the widespread use of combination chemotherapy to reduce viral burden. However, the prevalence of neurologic disease in people living with HIV-1 has actually increased, raising significant concerns that new therapeutic strategies, directed at restoring neuronal and glial homeostasis and signaling in the central nervous system (CNS), as opposed to directly interfering with the life cycle of HIV-1, must be developed. In this review, we focus briefly on previous Phase 1 clinical trials for adjunctive (i.e., chemotherapeutic agents that do not have a primary antiretroviral mechanism of action) therapy in patients with HAD, followed by an overview of key molecular events in the neuropathogenesis of HAD, and then discuss in more detail our rationale for investigating the effects of therapeutic agents that restore impaired mitochondrial bioenergetics in the CNS. Specifically, we focus on agents that either work in part through K-ATP channels, present in both mitochondria and plasma membranes, and agents that work to weakly uncouple the respiratory capacity of the electron transport chain in mitochondria from ATP production. We propose these agents may be complementary to currently available antiretroviral agents and may significantly improve the capacity of CNS infected with HIV-1 to meet increased bioenergetic demands involved in normal synaptic communication.     

T-cell lymphoma presenting with neurologic features in immunocompetent children

Systemic T-cell lymphoma presenting with neurologic symptoms is infrequently reported in immunocompetent children. We investigated the presenting features in all 20 immunocompetent children diagnosed with T-cell lymphoma at our institution from 1992-2004. Four children presented with neurologic features. These findings suggest that early neurologic involvement of T-cell lymphoma in immunocompetent children is underrecognized and that central nervous system involvement in these patients should be more thoroughly investigated.     

Eales' disease with neurologic disorders

Two cases of Eale's disease, with neurological involvement have been studied with magnetic resonance imaging (MRI). In the first case the ophthalmological disease had been diagnosed ten years before the onset of a cerebellar ataxia. In the second case the characteristic ocular changes were followed eight years later by a myelopathy. MRI in both cases showed multifocal white matter abnormalities. The nosological interpretation of such cases remains uncertain: association of Eale's disease with multiple sclerosis or vasculopathy involving the central nervous system and the retina?     

Redox metabolism abnormalities in autistic children associated with mitochondrial disease

Research studies have uncovered several metabolic abnormalities associated with autism spectrum disorder (ASD), including mitochondrial disease (MD) and abnormal redox metabolism. Despite the close connection between mitochondrial dysfunction and oxidative stress, the relation between MD and oxidative stress in children with ASD has not been studied. Plasma markers of oxidative stress and measures of cognitive and language development and ASD behavior were obtained from 18 children diagnosed with ASD who met criteria for probable or definite MD per the Morava et al. criteria (ASD/MD) and 18 age and gender-matched ASD children without any biological markers or symptoms of MD (ASD/NoMD). Plasma measures of redox metabolism included reduced free glutathione (fGSH), oxidized glutathione (GSSG), the fGSH/GSSG ratio and 3-nitrotyrosine (3NT). In addition, a plasma measure of chronic immune activation, 3-chlorotyrosine (3CT), was also measured. Language was measured using the preschool language scale or the expressive one-word vocabulary test (depending on the age), adaptive behaviour was measured using the Vineland Adaptive Behavior Scale (VABS) and core autism symptoms were measured using the Autism Symptoms Questionnaire and the Social Responsiveness Scale. Children with ASD/MD were found to have lower scores on the communication and daily living skill subscales of the VABS despite having similar language and ASD symptoms. Children with ASD/MD demonstrated significantly higher levels of fGSH/GSSG and lower levels of GSSG as compared with children with ASD/NoMD, suggesting an overall more favourable glutathione redox status in the ASD/MD group. However, compare with controls, both ASD groups demonstrated lower fGSH and fGSH/GSSG, demonstrating that both groups suffer from redox abnormalities. Younger ASD/MD children had higher levels of 3CT than younger ASD/NoMD children because of an age-related effect in the ASD/MD group. Both ASD groups demonstrated significantly higher 3CT levels than control subjects, suggesting that chronic inflammation was present in both groups of children with ASD. Interestingly, 3NT was found to correlate positively with several measures of cognitive function, development and behavior for the ASD/MD group, but not the ASD/NoMD group, such that higher 3NT concentrations were associated with more favourable adaptive behaviour, language and ASD-related behavior. To determine whether difference in receiving medications and/or supplements could account for the differences in redox and inflammatory biomarkers across ASD groups, we examined differences in medication and supplements across groups and their effect of redox and inflammatory biomarkers. Overall, significantly more participants in the ASD/MD group were receiving folate, vitamin B12, carnitine, co-enzyme Q10, B vitamins and antioxidants. We then determined whether folate, carnitine, co-enzyme Q10, B vitamins and/or antioxidants influenced redox or inflammatory biomarkers. Antioxidant supplementation was associated with a significantly lower GSSG, whereas antioxidants, co-enzyme Q10 and B vitamins were associated with a higher fGSH/GSSG ratio. There was no relation between folate, carnitine, co-enzyme Q10, B vitamins and antioxidants with 3NT, 3CT or fGSH. Overall, our findings suggest that ASD/MD children with a more chronic oxidized microenvironment have better development. We interpret this finding in light of the fact that more active mitochondrial can create a greater oxidized microenvironment especially when dysfunctional. Thus, compensatory upregulation of mitochondria which are dysfunctional may both increase activity and function at the expense of a more oxidized microenvironment. Although more ASD/MD children were receiving certain supplements, the use of such supplements were not found to be related to the redox biomarkers that were related to cognitive development or behavior in the ASD/MD group but could possibly account for the difference in glutathione metabolism noted between groups. This study suggests that different subgroups of children with ASD have different redox abnormalities, which may arise from different sources. A better understanding of the relationship between mitochondrial dysfunction in ASD and oxidative stress, along with other factors that may contribute to oxidative stress, will be critical to understanding how to guide treatment and management of ASD children. This study also suggests that it is important to identify ASD/MD children as they may respond differently to specific treatments because of their specific metabolic profile.     

以球麻痹起病的副肿瘤综合征

目的归纳总结以球麻痹起病的神经系统副肿瘤综合征(PNS)的临床特点及转归,为临床进一步认识PNS提供依据。方法回顾分析作者医院2010-2019年收治的以球麻痹起病的符合PNS诊断标准的患者,按照是否符合重症肌无力(MG)诊断标准,分为MG组及非MG组;比较两组间临床特征、实验室检查指标、治疗、预后的差别。结果收集随访PNS患者20例,其中MG组患者11例,平均发病年龄(39.0±14.0)岁,以女性为主〔8例(72.7%)〕;非MG组共9例,平均发病年龄为(60.0±15.0)岁,以男性为主〔8例(88.9%)〕;非MG组肿瘤标志物阳性率高于非MG组(18.1%比77.8%,P=0.031)。MG组均接受了外科干预治疗;两组中均有部分患者使用激素及(或)丙种球蛋白治疗,痊愈及好转患者比例差异无统计学意义(P>0.05)。MG组无死亡,非MG组死亡2例。结论在以球麻痹首发的PNS患者中,符合MG的患者女性多见,外科手术联合免疫抑制剂能显著改善患者预后,而不符合MG者以老年男性多见,肿瘤标志物阳性率更高,预后及死亡率更差。     

Transient neurologic deficits associated with carbamazepine-induced hypertension

Carbamazepine is a well-established, effective treatment of complex partial seizures and is well tolerated in most patients. The adverse effects of carbamazepine include aplastic anemia, agranulocytosis, pancytopenia, bone marrow depression, thrombocytopenia, cardiac conduction abnormalities, congestive heart failure, and peripheral edema. Hypertension or hypotension has also rarely been documented in patients with either therapeutic or toxic blood levels of carbamazepine. It is possible that carbamazepine-induced hypertension in those with therapeutic blood levels is rarely seen because most of the patients who begin treatment are young and do not have baseline hypertension. The authors describe a patient of African-American descent with a history of controlled essential hypertension who developed severe uncontrolled hypertension when started on carbamazepine. Treatment with additional antihypertensive medications did not reduce his blood pressure. In addition, he developed two episodes of transient neurologic deficits, the symptoms of which consisted of dysarthria, vertigo, and unstable gait. A substantial reduction of his carbamazepine dose resulted in the control of his blood pressure and no recurrence of his symptoms.     

Trends and survival for AIDS patients presenting with indicative neurologic diseases

Nervous system involvement in patients with AIDS is frequent either due to direct infection by the HIV-1 or to opportunistic infections or neoplasms. In the present study we evaluate the epidemiologic characteristics of patients in whom the first AIDS manifestation was an indicative neurologic disease (IND) and the influence of such a presenting form in the patients' survival. Out of 1250 reported cases, 252 (20.2%) presented with one of the INDs, according with the CDC AIDS definition criteria. Neither sex nor age differences were found between patients presenting with and without an IND. IVDUs were more likely to present with an IND than homosexual/bisexual men (p = 0.024). Cerebral toxoplasmosis (CT) was the only IND with a significant proportional increase over time. Although some of the IND have a specific treatment, as a whole patients presenting with an IND lived shorter than those presenting with any of the other indicative disorders (p less than 0.0001). The incidence of IND is greater than elsewhere, mainly because of CT. The increment of CT may be in part due to the introduction of the new AIDS definition criteria.     

Cardiomyopathy associated with neurologic disorders and mitochondrial phenotype

Cardiomyopathy and neuromuscular abnormalities may simultaneously coexist and present with defects in mitochondrial DNA and bioenergetic function. We sought to evaluate the relationship between clinical and mitochondrial phenotypes in 28 young patients with both cardiomyopathy and neurologic disorders including seizures, dystonia, ophthalmoplegia, Kearns-Sayre syndrome, Leigh disease, and Friedreich's ataxia. All tissues examined displayed marked defects in respiratory complex activities. Five patients had abundant large-scale mitochondrial DNA deletions and one patient displayed a pathogenic point mutation previously reported with mitochondrial cytopathy. In this cohort, patients with hypertrophic cardiomyopathy displayed a higher incidence of complex I defects, fewer DNA deletions and mitochondrial structural abnormalities and were less often associated with developmental delay phenotype compared with patients with dilated cardiomyopathy. Although structural abnormalities are present in a subset of patients, evaluation of respiratory enzyme activity appears to be most informative whether tissues examined were derived from heart or skeletal muscle. Defects in mitochondrial DNA and bioenergetics are frequently present in children with cardiomyopathy presenting with a variety of neurologic abnormalities and are amenable to biochemical and molecular analysis.     

Methanol poisoning: factors associated with neurologic complications

Hospital records of thirty patients with methanol poisoning were studied. Neurologic manifestations at presentation including coma, seizures and decreased visual acuity were seen in nineteen patients. The mean blood pH at presentation was significantly lower in the patients with these neurologic signs and symptoms than in the eleven patients without them (p less than 0.05). Methanol levels at presentation tended to be higher in patients with neurologic manifestations at presentation and these patients tended to present later after methanol ingestion than those patients without neurologic manifestations. Fifteen patients with methanol poisoning developed serious neurologic sequelae or died. The mean blood pH was significantly lower in this patient group than in those who survived without neurologic sequelae (p less than 0.05). Methanol levels at presentation were not different in the patients who developed neurologic sequelae or died as compared to those who did not. The time from ingestion of methanol to presentation at the hospital was however significantly longer in those patients who developed neurologic sequelae or died (p less than 0.05). Initiation of treatment within eight hours of ingestion of methanol was associated with a better clinical outcome.