Unexplained Neurological Manifestations Research Articles

Wilson's Disease: A Prevalence Study in a Portuguese Population.

Introduction Wilson's disease (WD) is a rare and underdiagnosed genetic disorder caused by anomalous tissue copper deposition, and for which epidemiological studies, specifically in Portugal, are scarce. Objectives This study aimed to evaluate the prevalence and incidence of WD and provide a description of its main clinical and laboratory features. Methods A retrospective study was carried out, with a search between 1995 and 2015, of all patients with a minimum follow-up of three months and birth confirmed in the northern region of Portugal, with an estimated population of 3,689,682 inhabitants. Database collection was based on the Portuguese National Health Service's clinical coding system, relying on clinical data from 13 northern Portuguese hospitals, liver biopsy histology results, and hospital prescription records. Clinical and biochemical correlations were statistically assessed using chi-square, Mann-Whitney U, Friedman, and Wilcoxon tests. Results Over the 20-year period, a prevalence of 1:37.000 and an incidence of one per million person-year was found. A total of 94 patients were analyzed, with a slight male predominance (53%), the majority with the onset of clinical manifestations in pediatric age (56%), with a median age at diagnosis of 16.6 years (interquartile range of 12.3-20,.8 years). Most patients presented with predominant liver disease (54.8%), with more than a third with cirrhosis; mixed hepatic and neurological manifestations in 17.9%; and mainly neurological symptoms in 10.7% of the patients. Neurological impairment was strongly associated with delayed development of the manifestations of the disease (p = 0.001) and also a higher detection of Kayser-Fleischer rings (p < 0.001), present in 27.0% of the patients. Regarding therapy, penicillamine has been the most widely used, with adverse reactions reported in 24.8%. At six and 12 months after initiation of therapy, a significant decrease in liver enzymes was found (ALT: p = 0.002; AST: p = 0.002, respectively), but no significant reduction was observed in urinary copper excretion. Conclusion This was one of the first studies regarding WD prevalence in a Portuguese population, contributing to a better understanding of the epidemiology, diagnosis, and management of WD in the northern region of Portugal. WD should be considered in any individual with unexplained hepatic or neurological manifestations, and initial symptoms may manifest at an early age, even in children less than five years old.A high percentage of patients were identified in the early stages of the disease by asymptomatic elevation of transaminases. Following copper chelation therapy, cytolysis markers appear to be more sensitive indicators of treatment response.

Autochthonous Cases of Tick-Borne Encephalitis, Belgium, 2020.

We report 3 confirmed autochthonous tick-borne encephalitis cases in Belgium diagnosed during summer 2020. Clinicians should include this viral infection in the differential diagnosis for patients with etiologically unexplained neurologic manifestations, even for persons without recent travel history.

Toxocariasis; A Neglected Tropical Disease, Association With Asthma, Chronic Urticaria and Unexplained Neurologic Manifestations Among Children

Background: The link between parasitic infestation and allergic diseases or unexplained neurologic manifestations was hypothesized, especially in children. However, the debate continues regarding this link. Aim of the work: To determine the seroprevalence of toxocariasis in children with different allergic diseases [bronchial asthma and skin allergy], besides the unexplained neurological manifestations [epilepsy and focal neurologic deficits] in children. Patients and methods: Children with bronchial asthma [40 children], skin allergy [40 children], and unexplained neurological manifestations [epilepsy and focal neurologic deficits], [40 children] were included. All underwent a full history taking, clinical examination, lab investigations, and seropositivity determination for Toxocara canis. Results:Eosinophilia was reported in 22.5%, 30.0%, and 17.5% of asthma, skin, and unexplained neurological manifestations groups, respectively. In patients with asthma, the prevalence of toxocariasis was 15.0%; in skin disease, it was 7.5%, and in unexplained neurological manifestations, it was 12.5%. There was no significant difference between positive and negative toxocariasis regarding patient demographics. But there was a significant increase in contact with pets, chronic urticaria, lymph nodes involvement, and eosinophilia in positive when compared to negative groups. Conclusion: The association between Toxocara canis infection and allergic diseases such as bronchial asthma, chronic urticaria, and unexplained neurological manifestations [epilepsy and focal neurologic deficits] was confirmed in the present work. The contact with dogs and cats [pets] was the major determinant risk factor explaining such association. Prospective cohort studies were warranted to examine the cause-effect relationship.

Neurological Manifestations of Influenza A (H1N1): Clinical Features, Intensive Care Needs, and Outcome.

ObjectivesTo describe neurological manifestations in children with Influenza A (H1N1).MethodsThis retrospective study was conducted in the Pediatric intensive care unit (PICU) and Pediatric Neurology unit of a tertiary care teaching hospital in North India involving children with PCR confirmed Influenza A (H1N1) with neurological manifestations during 2019 outbreak.ResultsSix children (5 females, 1 male) were enrolled. All presented with neurological symptoms (seizures and altered sensorium) accompanied with fever and respiratory symptoms with duration of illness of 2–7 d. The admission Glasgow Coma Scale ranged from 4 to 12. Only 2 cases showed cerebrospinal fluid pleocytosis. Neuroimaging was suggestive of diffuse cerebral edema, acute necrotizing encephalopathy of childhood, and acute disseminated encephalomyelitis. All were treated with Oseltamivir. Four cases had clinical features of raised intracranial pressure (ICP) and were managed in PICU, 3 of them needed mechanical ventilation, 3 needed vasoactive drugs, 3 received 3% saline infusion, 1 underwent invasive ICP monitoring, and 3 (cases 4, 5 and 6) received intravenous methylprednisolone (30 mg/kg) for 5 d. Total duration of hospital stay was 10–30 d. Case 2 expired due to refractory raised ICP. Among survivors, 3 children had residual neurological deficits and the remaining 2 had achieved premorbid condition.ConclusionsInfluenza A (H1N1) can present with isolated or predominant neurological manifestations which can contribute to poor outcome. The authors suggest to rule out H1N1 in any child who presents with unexplained neurological manifestations during seasonal outbreaks of H1N1.

Pre-Transplant Use of Tyrosine Kinase Inhibitors Increases Risk of Transplant Associated Thrombotic Microangiopathy - a Single Centre Analysis of Incidence, Risk Factors and Outcomes

Introduction Transplant associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication post hematopoietic stem cell transplant (HSCT). Epidemiology, risk factors, prognosis and treatment of TA-TMA are not very clear. While type of transplant, and use of calcineurin inhibitors (CNIs) are established risk factors for TA-TMA, not much is known of other risk factors that affect TA-TMA and its outcome. We retrospectively analysed data of all patients who underwent allogeneic transplant for hematological malignancies at our centre to understand its incidence, possible risk factors and treatment outcomes. Methods All consecutive patients who underwent allogeneic HSCT for AML, ALL and CML from January 2008 to March 2019 were included. Conditioning regimens used were either myeloablative (CyTBI or BuCY) or reduced intensity (fludarabine with either melphalan, treosulfan or cyclophosphamide with or without 2 Gy TBI). Rabbit ATG was used at a dose of 2.5-5 mg/kg for patients who underwent matched unrelated donor (MUD) transplants. GVHD prophylaxis for matched sibling donor (MSD) and MUD transplants included CNIs with methotrexate or mycophenolate mofetil (MMF). Patients who underwent haploidentical (haplo) HSCT received post transplant cyclophosphamide (PTCy) on d+3 and d+4 and CNI with MMF from day+5 onwards. Definitive TA-TMA was defined using Blood and Marrow Transplant Clinical Trials Network (BMT-CTN) criteria ie schistocytes ≥2/HPF, elevated LDH, renal compromise (increase in creatinine 2 times baseline or 50 % decrease in creatinine clearance from baseline ) or unexplained neurological manifestations and negative coombs test. Probable TMA was defined as per criteria proposed by Cho et al ie schistocytes ≥2/HPF, elevated LDH, negative coombs test, no coagulopathy, drop in haemoglobin and thrombocytopenia (platelet &lt; 50 x 109/L or &gt; 50 percent decline in platelet count). Risk factors explored for development of TA-TMA were age, gender, diagnosis, type of transplant, acute and chronic GVHD, use of tyrosine kinase inhibitors (TKI) such as imatinib, dasatinib, nilotinib or sorafenib pre transplant and conditioning regimen used. Factors evaluated to affect the outcomes of TA- TMA were gender, baseline LDH, least platelet count, presence of acute GVHD, TA-TMA index (LDHx1000/platelet count per cumm), definitive vs probable TMA, and type of transplant. All categorical data was compared using Chi-square /Fisher exact test. OS probabilities were calculated using Kaplan -Meier method and were compared using log-rank test. Multivariate analysis to assess risk factors for TMA was carried out using logistic regression. Results Total 241 patients, 179 (74.2 %) male and 62 (25.7 %) female, with median age of 28.5 (3- 53) years were analysed. Donors were MSD (6/6 matched -174, and 9/10 matched-1), MUD (16) or haplo (50) donors. Diagnoses were 104(43 %) - AML, 85 (35%) - ALL (of which Ph+ patients --23) and 52 (22%) -CML patients. Conditioning regimens given were myeloablative (MAC; n= 64, 27 %) or reduced intensity (RIC; n=177, 73 %). Total 26 (10.7%) patients developed TA-TMA; 22 (85%) were males. Table 1 shows clinical features at diagnosis of TA-TMA. Median day of diagnosis of TA-TMA was d+102 (range 12- 722) post HSCT. Analysis of potential risk factors for TA-TMA is shown in table 2. Use of pre-HSCT TKI (OR 2.7, p=0.028), haplo HSCT (OR 3.16, p=0.018) and presence of acute GVHD within 30 days of diagnosis of TA-TMA (OR 4.17, p=0.003) were identified to be significant factors on multivariate analysis. CNIs were omitted as soon as TA-TMA was diagnosed. Low dose defibrotide (5mg/kg BD) was used in 4 patients. No patient received plasma exchange. Median follow up for whole cohort was 59.5 months. Median OS for whole cohort was 59.9 months (figure 1). The OS (figure 2) at 5 years was 51.1% in the patients who did not develop TA-TMA vs 29.6% in the group with TA-TMA (P=0.026).Ten (39%) patients with TA-TMA are alive at the time of analysis. No significant factors affecting outcomes of TA-TMA were identified. Conclusion Incidence of TA-TMA was 10% in our cohort. Pre-transplant TKI use, acute GVHD, and haplo HSCT are independent risk factor for TA-TMA. This is the first study in our knowledge to show pre-transplant TKI as a risk factor for development of TA-TMA. Higher index of suspicion of TA-TMA is thus warranted for those patients who receive pre transplant TKI. Disclosures No relevant conflicts of interest to declare.

Different Kinds of Paraneoplastic Syndromes in Childhood Neuroblastoma.

Background:Clinical presentations of paraneoplastic syndromes in neuroblastoma may multiply. Review of the clinical data and the literature on this syndrome may help in the diagnosis of neuroblastoma.Objectives:In order to make more accurate diagnosis, we reviewed the clinical data and the literature on this syndrome.Patients and Methods:Between April 2007 and April 2012, 68 children were diagnosed with neuroblastoma or ganglioneuroblastoma in our institution, 9 of which presented exclusively with paraneoplastic syndromes and were not treated with chemotherapy prior to diagnosis. After the diagnosis, all patients received chemotherapy and operation on NB97 protocol.Results:Among 68 pediatric patients with neuroblastoma or ganglioneuroblastoma, 4 (5.9%) patients suffered from neurological complications at diagnosis, 2 (2.9%) patients had digestive tract disorders, 2 (2.9%) patients had immune diseases, and 1 (1.5%) suffered from hematological disorder (without bone marrow involvement). All paraneoplastic syndrome patients achieved complete remission on paraneoplastic syndrome before completion of chemotherapy.Conclusions:Neuroblastoma may present with a range of non-specific neurologic symptoms in addition to the well-known opsoclonus-myoclonus syndrome and cerebellar ataxia. In any case, the presence of unexplained neurologic manifestations and other common clinical presentations such as rash, constipation, diarrhea, and especially immune disorders in an otherwise healthy child had raised the possibility of paraneoplastic syndrome due to the presence of an undiagnosed tumor.

Seroprevalence of Antibodies againstTaenia soliumCysticerci among Refugees Resettled in United States

Neurocysticercosis (NCC) is a disease caused by central nervous system infection by the larval stage of the pork tapeworm, Taenia solium. In developing countries, NCC is a leading cause of adult-onset epilepsy. Case reports of NCC are increasing among refugees resettled to the United States and other nations, but the underlying prevalence among refugee groups is unknown. We tested stored serum samples from the Centers for Disease Control and Prevention Migrant Serum Bank for antibodies against T. solium cysts by using the enzyme-linked immunoelectrotransfer blot. Seroprevalence was high among all 4 populations tested: refugees from Burma (23.2%), Lao People's Democratic Republic (18.3%), Bhutan (22.8%), and Burundi (25.8%). Clinicians caring for refugee populations should suspect NCC in patients with seizure, chronic headache, or unexplained neurologic manifestations. Improved understanding of the prevalence of epilepsy and other associated diseases among refugees could guide recommendations for their evaluation and treatment before, during, and after resettlement.

Clinical and histologic features of incontinentia pigmenti in adults with nuclear factor-κB essential modulator gene mutations

Incontinentia pigmenti (IP) is a multisystem disorder, in which cutaneous symptoms can be accompanied by dental, ocular, and central nervous system defects. In adults, the clinical diagnosis of IP is based principally on the late onset of stage 4 lesions and their association with dental, nail, ocular, or central nervous system anomalies. Nevertheless, these lesions are often unrecognized. Our aim was assessment of IP manifestations in adults to clarify diagnostic criteria for mild forms of the disease, to help physicians detect adult IP in the presence of subtle lesions and avoid misdiagnosis. We conducted clinical and histologic examination of 25 adults with IP and nuclear factor-κB essential modulator gene rearrangement or mutations. Linear atrophic, hypopigmented, and hairless lesions (stage 4) are constant in adults. Apoptotic keratinocytes in the epidermis or dermis and atrophic hair follicles, with absence of arrector pili muscles, are frequently observed. In contrast, nipple anomalies are rare. We were unable to determine the age of the onset of IP stage 4 lesions. Skin manifestations are constant in adult patients with IP. Histology is characteristic and could be considered as a minor diagnostic criterion of IP. Nipple anomalies also may be considered as a minor criterion. Detection of such subtle manifestations can evoke IP in patients with repeated miscarriages or unexplained neurologic manifestations.

Acute encephalopathy and multi-organ involvement with rhabdomyolysis during primary HIV infection

An adolescent male developed encephalopathy and multiple organ involvement with rhabdomyolysis during primary HIV infection (PHI). All symptoms and signs resolved within a few days. Nineteen cases of central nervous system complications (other than aseptic meningitis) have been reported in PHI. These include encephalopathy, meningoencephalitis, acute disseminated encephalomyelitis, multiple sclerosis, myelopathy, and meningoradiculitis. Half of the patients died or suffered sequelae. Except in cases of multiple sclerosis, steroids were not of benefit. Initiation of antiretrovirals during PHI remains controversial. Rhabdomyolysis was reported in eight patients with PHI. All patients recovered. Primary HIV infection should be considered when the clinician faces patients with unexplained neurologic manifestations, rhabdomyolysis, or multiple organ involvement.

Maladie de Whipple

Whipple's disease is a chronic, multisystemic, curable, bacterial infection that usually affects middle-aged men. It has a wide range of clinical manifestations. In the historical presentation, weight loss and diarrhoea are the most common symptoms and are preceded in three-quarters of cases by arthritis for a mean of six years. Long-term, unexplained, seronegative oligoarthritis or polyarthritis of large joints with a palindromic or relapsing course is typical. In most patients, periodic acid-Schiff staining of proximal small bowel biopsy specimens reveals inclusions within the macrophages, corresponding to bacterial structures. However, patients may have no gastrointestinal symptoms, negative jejunum biopsy results and even negative PCR tests. Even in the absence of gastrointestinal symptoms, Whipple's disease should be considered in case of negative blood culture endocarditis, unexplained central neurological manifestations or unexplained arthritis. Identification of the causative bacterium, Tropheryma whipplei, has led to the development of PCR as a diagnostic tool, particularly useful in patients in the early stages of the disease or with atypical disease. The recent cultivation of T. whipplei and the complete sequencing of its genome should improve our understanding and treatment of the disease. The future development of an assay for detection of specific antibodies in the serum and generalization of the immunohistochemical detection of antigenic bacterial structures may allow earlier diagnosis, thereby preventing the development of the severe late systemic and sometimes fatal forms of the disease.

Déficit en cystathionine bêta-synthase et déficit en MTHFR chez l’adulte

Homocysteine lies at an important metabolic branch point; it may be either converted to cystathionine through the transsulfuration pathway, or methylated to form methionine. Hyperhomocysteinemia may result from hereditary defects affecting one of these reactions.Cystathionine beta synthase or 5,10-methylenetetrahydrofolate deficiency can both result in homocystinuria. Current knowledge about biochemical mechanisms leading to hyperhomocysteinemia, clinical and radiological features, pathogenesis and treatment are reviewed, focusing on late onset forms of these diseases which can be diagnosed in adulthood. CBS deficiency is characterized by lens dislocation, skeletal abnormalities, neurologic disturbances and thromboembolism. MTHFR deficiency leads to various neurological symptoms, ranging from developmental delay to encephalopathy, including motor and gait abnormalities, seizures, psychiatric manifestations and rarely strokes. The treatment of CBS deficiency depends on vitamin B6, whereas MTHFR deficiency can be efficiently treated by vitamin B12, folic acid, and betaine.Homocysteinemia should be measured in patients with unexplained neurological manifestations or thromboembolism.

Troubles du métabolisme des cobalamines chez l’adulte

Disorders of cobalamin metabolism include defects of absorption, transport and intracellular metabolism of cobalamin. Most of the patients present in the first years of life with haematological abnormalities and feeding difficulties but some of them have later onset form and can present with pure neurological manifestations. The suggestive clinical picture is a subacute neurological disorder similar to those observed in case of insufficient B12 intake or Biermer disease. In this frame, additional diagnosis clues could be associated megaloblastic anemia, previous history of venous thrombosis, association with psychiatric disturbances, involvement of both central and peripheral nervous system. The key investigations are measurement of plasma amino acid levels and urinary organic acid, which allow to detect abnormalities consistent with intracellular cobalamin deficiency. Treatment depends on the metabolic defect but usually consist in intramuscular cobalamin supplementation. It results in stabilization or improvement in most cases. Because this treatable condition can lead to death or irreversible neurological damage, we recommend that disorder of the cobalamin metabolism should be consider in all young adults with unexplained consistent neurological manifestations.

Hyperhomocysteinämie und B-Vitaminmangel bei neurologischen und psychiatrischen Erkrankungen

Elevated concentration of total homocysteine (Hcy) in plasma (> 12 micromol/l) is a risk factor for several diseases of the central nervous system. Epidemiological studies have shown a dose-dependent relationship between concentrations of Hcy and the risk for neurodegenerative diseases. Hcy is a marker for B-vitamin deficiency (folate, B12, B6). Hyperhomocysteinemia (HHcy) causes hypomethylation which is an important mechanism that links Hcy to dementia. Supplementation with vitamins B aims at reducing the risk of neurodegenerative diseases. Current evidence suggests that Hcy-lowering treatment has a positive effect for the secondary and primary prevention of stroke. HHcy is very common in patients with Parkinson disease particularly those who receive L-dopa treatment. Furthermore, a positive association has been reported between HHcy and multiple sclerosis. Moreover, HHcy and vitamin B deficiency are reported to have a causal role in depression, and epilepsy. In addition several anti-epileptic drugs cause secondary HHcy. Therefore, sufficient intakes of the vitamins are recommended for patients who have already developed neuropsychiatric diseases. Vitamin B deficiency should be suspected in children with development disorders, failure to thrive and unexplained neurological manifestations. Elderly people are also an important at-risk group where vitamin B deficiency and HHcy have been linked to neurodegenerative diseases. Treatment with folate, B12, and B6 can improve cerebral function. Preventive vitamin B supplementation and sufficient intake seem very important for secondary and primary prevention of neuropsychiatric disorders, especially in subjects with a low intake or status of the vitamins.

MECP2 mutations are an infrequent cause of mental retardation associated with neurological problems in male patients

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene located on Xq28, cause Rett syndrome (RTT) in female patients. Meanwhile, nonmosaic MECP2 mutations unknown in girls have been found in an increasing number of male patients with a normal 46, XY karyotype. They can cause a broad spectrum of neurodevelopmental disorders which often show a combination of mental retardation (MR) with neurological symptoms. We present the results of MECP2 analysis in a group of 72 male patients with an unexplained combination of MR and neurological features, and review the mutational reports published on male patients since the discovery of the MECP2 gene. Analysis included sequencing of exon 1 which thus far was mostly omitted from DNA screening. One pathogenic mutation has been found in a patient with Rett variant, in addition to an unclassified variant and a series of nonpathogenic changes. No changes have been found in exon 1. Criteria for testing of male patients are classic RTT, severe neonatal encephalopathy, and RTT variant which may be clinically underrecognized. Testing can also be considered in males with a combination of unexplained MR and (progressive) neurological manifestations although the yield of MECP2 analysis is probably low in this situation. Based on the literature, MECP2 testing in males with MR only is debatable.

Linfomatosis intravascular: Descripción de tres casos

Intravascular lymphomatosis (IVL) is a rare malignancy characterized by a proliferation of atypical lymphoid cells occluding small blood vessels (venules, capillaries and small arteries). The symptoms are caused by embolisms due to massive proliferation. Nervous system and skin are the most common sites of involvement but all organs may be involved, although it is typified by the absence of malignant cells in lymphoid tissues. We describe three cases of IVL: first patient was a 57 years old man with rapidly progressive dementia and neurological involvements and second case of a 69 years old man hospitalised with predominant symptoms in the lung (cough, dyspnea and fever), and a woman presenting as fever of unknown origin (FUO) with systemic inflammatory response syndrome. In all cases that we reported have been diagnosed post-mortem because of rapid progression of a multisystem disease and the absence of pathognomonic clinical manifestations. Diagnosis can be made using biopsy of one of the involved organs. In conclusion, we propose that IVL should be included in the differential diagnosis of acute confusional state, dementia or other unexplained neurological manifestations, fever of unknown origin, vasculitis, occult neoplasia or infections with signs of a systemic disease and marked elevation of serum lactate dehydrogenase (LDH).

Syndrome de Sjögren avec épilepsie et dysautonomie

Primary Sjogren syndrome is considered as the most frequent connective tissue disease. Neurological complications may affect the peripheral nervous system and to lesser extent the central nervous system. Autonomic system nervous dysfunction and epilepsy have been rarely reported. We present on case of Sjogren's syndrome with epilepsy and autonomic nervous system dysfunction. The epilepsia respond to valproate. Autoimmune investigations for Sjogren's syndrome should be initiated in any patient presenting with unexplained neurologic manifestations.

The neurological manifestations of HIV infection

Case records of HIV infected patients were analyzed for identifying neurological manifestations. Eight patients (7 males) were identified to have probable HIV encephalopathy (in a period of 24 months) as per the CDC revised classification system. Their ages ranged from one year to ten years. The neurological manifestations noted included-developmental delay (2 cases), seizures (6 cases), acute onset alteration of sensorium (4 cases), aphasia (2 cases), loss of vision (2 cases), focal neurological deficits (6 cases), brisk deep tendon reflexes (7 cases), extensor plantar responses (5 cases) and signs of cerebellar dysfunction (2 cases). Other clinical features included growth failure, microcephaly, fever, lymphadenopathy, hepatomegaly, splenomegaly, pneumonia, otorrhea and oral candidiasis. Cerebrospinal fluid studies were normal. The neuroimaging features included cerebral atrophy and ventricular dilatation, cerebral infarction, basal ganglia calcification and cerebellar atrophy. Childhood HIV infection may have a variety of neurological abnormalities. HIV infection should be suspected in children presenting with unexplained neurological manifestations and growth failure.

Les localisations rares de la sarcoïdose:f aspects cliniques et réflexions sur l'approche diagnostique

Rare localisations of sarcoidosis, mainly neurological and cardiological ones are in the most cases seriously threatening whether functional or vital prognosis. They are often responsible for a delay in diagnosis or treatment. Concerning young patients, any unexplained neurological or cardiological manifestations should lead to consider the diagnosis of sarcoidosis. When histological evidence is not obtained, in particular in presence of central nervous system localisations. Systemic explorations such as pulmonary radiography, bronchoalveolar lavage, salivary glands biopsies should be performed. In most cases, these localisations will lead to corticotherapy, which, when revealing unsuccessfully, is associated with another immunosuppressive agent.