Vasculitic Peripheral Neuropathy, Differences Between Systemic and Non-Systemic Etiologies: A Case Series and Biopsy Report.

BACKGROUND: Vasculitic peripheral neuropathy (VPN) is caused by vessel inflammation leading to peripheral nerve injury of acute-to-subacute onset. When VPN occurs in the context of systemic disease it is classified as Systemic Vasculitic Neuropathy (SVN) and as Non-Systemic Vasculitic Neuropathy (NSVN) when restricted to the nerves. OBJECTIVE: This study aimed to compare the clinical characteristics, biopsy findings and disease outcome in patients with VPN. METHODS: Clinical records of adult patients with VPN diagnosed at our institution between June-2002 and June-2019 were retrospectively reviewed. Demographic characteristics, clinical manifestations, nerve conduction studies, nerve biopsies, treatment and clinical evolution were analyzed in all patients with at least 6 months follow-up. RESULTS: Twenty-five patients with VPN were included (SVN, n = 10; NSVN, n = 15). No significant differences in demographic or clinical features were found between groups. The median delay between symptom onset and nerve biopsy was significantly longer in NSVN patients (10 vs 5.5 months, p = 0.009). Erythrocyte sedimentation rate (ESR) values over 20 mm/h were significantly more common in SVN patients (100% vs. 60%, p = 0.024). Nerve biopsies showed active lesions more frequently in treatment-naive patients compared to those who had received at least 2 weeks of corticosteroids (92% vs 38%; p = 0.03), with a higher proportion of definite VPN cases (92 vs 46%; p = 0.04). CONCLUSIONS: Although the clinical manifestations are similar, ESR is an important tool to help distinguish between both conditions. Early nerve biopsy in untreated patients increases diagnostic accuracy, avoiding misdiagnosis.

Enfermedad de Whipple: Múltiples recaídas sistémicas y neurológicas / Whipple’s disease: multiple systemic and neurological relapses

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Recessive RYR1 mutations cause unusual congenital myopathy with prominent nuclear internalization and large areas of myofibrillar disorganization.

AIMS: To report the clinical, pathological and genetic findings in a group of patients with a previously not described phenotype of congenital myopathy due to recessive mutations in the gene encoding the type 1 muscle ryanodine receptor channel (RYR1). METHODS: Seven unrelated patients shared a predominant axial and proximal weakness of varying severity, with onset during the neonatal period, associated with bilateral ptosis and ophthalmoparesis, and unusual muscle biopsy features at light and electron microscopic levels. RESULTS: Muscle biopsy histochemistry revealed a peculiar morphological pattern characterized by numerous internalized myonuclei in up to 51% of fibres and large areas of myofibrillar disorganization with undefined borders. Ultrastructurally, such areas frequently occupied the whole myofibre cross section and extended to a moderate number of sarcomeres in length. Molecular genetic investigations identified recessive mutations in the ryanodine receptor (RYR1) gene in six compound heterozygous patients and one homozygous patient. Nine mutations are novel and four have already been reported either as pathogenic recessive mutations or as changes affecting a residue associated with dominant malignant hyperthermia susceptibility. Only two mutations were located in the C-terminal transmembrane domain whereas the others were distributed throughout the cytoplasmic region of RyR1. CONCLUSION: Our data enlarge the spectrum of RYR1 mutations and highlight their clinical and morphological heterogeneity. A congenital myopathy featuring ptosis and external ophthalmoplegia, concomitant with the novel histopathological phenotype showing fibres with large, poorly delimited areas of myofibrillar disorganization and internal nuclei, is highly suggestive of an RYR1-related congenital myopathy.

Branching enzyme deficiency/glycogenosis storage disease type IV presenting as a severe congenital hypotonia: muscle biopsy and autopsy findings, biochemical and molecular genetic studies.

The fatal infantile neuromuscular presentation of branching enzyme deficiency (glycogen storage disease type IV) due to mutations in the gene encoding the glycogen branching enzyme, is a rare but probably underdiagnosed cause of congenital hypotonia. We report an infant girl with severe generalized hypotonia, born at 33 weeks gestation who required ventilatory assistance since birth. She had bilateral ptosis, mild knee and foot contractures and echocardiographic evidence of cardiomyopathy. A muscle biopsy at 1 month of age showed typical polyglucosan storage. The autopsy at 3.5 months of age showed frontal cortex polymicrogyria and polyglucosan bodies in neurons of basal ganglia, thalamus, substantia innominata, brain stem, and myenteric plexus, as well as liver involvement. Glycogen branching enzyme activity in muscle was virtually undetectable. Sequencing of the GBE1 gene revealed a homozygous 28 base pair deletion and a single base insertion at the same site in exon 5. This case confirms previous observations that GBE deficiency ought to be included in the differential diagnosis of congenital hypotonia and that the phenotype correlates with the 'molecular severity' of the mutation.

Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease.

Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans.

Alpha vs. gamma sarcoglycanopathy: DNA tests solve a case from Argentina.

Immunohistochemical and DNA results are described in a patient with sarcoglycanopathy. Immunostaining was comparatively normal for alpha-, attenuated for beta- and delta-, and markedly attenuated for gamma-sarcoglycan, thus sarcoglycanopathy was diagnosed, presumably a gamma-sarcoglycanopathy. Unexpectedly, two alpha-SGP-related pathogenic mutations were identified in compound heterozygosity in the SGCA gene: c.229C > T (p.Arg77Cys) in exon 3 and c.850C > T (p.Arg284Cys) in exon 7. These are discussed together with six additional changes detected in SGCB, SGCG and SGCD.

Characterization of brain tumors by MRS, DWI and Ki-67 labeling index.

With the advent of fast imaging hardware and specialized software, additional non-invasive magnetic resonance characterization of tumors has become available through proton magnetic resonance spectroscopy (MRS), hemodynamic imaging and diffusion-weighted imaging (DWI). Thus, patterns could be discerned to discriminate different types of tumors and even to infer their possible evolution in time. The purpose of this study was to investigate the correlation between MRS, DWI, histopathology and Ki-67 labeling index in a large number of brain tumors. Localized proton spectra were obtained in 47 patients with brain tumors who subsequently underwent surgery (biopsy or tumor removal). We performed MRS with short echo-time (30 ms) and metabolic values in spectra were measured using an external software with 25 peaks. In all patients who had DWI, we measured apparent diffusion coefficients (ADC) in the same region of interest (ROI) where the voxel in MRS was located. In most tumors the histological diagnosis and Ki-67 labeling index had been determined on our original surgical specimen. Cho/Cr, (Lip+Mm)/Cr, NAA/(Cho+Cr) and Glx/Cr indexes in MRS allowed discriminating between low- and high-grade gliomas and metastases (MTs). Likewise, absolute ADC values differentiated low- from high-grade gliomas expressed by Ki-67 labeling index. A novel finding was that high Glx/Cr in vivo MRS index (similar to other known indexes) was a good predictor of tumor grading.

[Clinical and electroencephalographic aspects of late infantile neuronal ceroid lipofuscinosis]. / Lipofuscinosis neuronal ceroidea infantil tardía: aspectos clínicos y electroencefalográficos.

AIMS: In this paper we describe the clinical characteristics, and particularly the epileptic seizures and electroencephalographic findings, in 15 patients with a pathology diagnosis of late infantile neuronal ceroid lipofuscinosis (NCL). PATIENTS AND METHODS: Nine female and six male patients were studied and their clinical records covering the period February 1990 to June 2003 were analysed. Neuroimaging, neurometabolic studies, ERG, PE and repeated EEG were carried out in all cases. RESULTS: The mean age on onset of the disease was 3 years (range: 1-5 years). The initial symptom was epilepsy in all cases. Massive myoclonias and myoclonic-atonic seizures were the most frequent kinds of attacks. Focal myoclonias were observed in six patients. Other types of epileptic seizures observed included generalised tonic-clonic, absence, motor focal and complex focal. The epileptic seizures were resistant to therapy. Progressive neurological and visual impairment, pyramidal and cerebellar signs, as well as mental retardation were present in all cases. Intercritical EEG recordings showed diffuse paroxysms with spike and polyspike waves, multifocal spikes and, less often, focal spikes that were predominant in posterior regions. Photostimulation showed high amplitude (300-450) occipital spikes during the application of light stimulation between 1 and 8 Hz. ERG, VEP and SSEP results were pathological. Images showed signs of brain and cerebellar atrophy. Seven of the patients died between 8.5 and 11 years of age. CONCLUSIONS: Late infantile NCL must be considered in the case of a child aged between 1 and 5 years who presents seizures that are predominantly generalised myoclonias and myoclonic-atonic, in association with progressive neurological deterioration including pyramidal, cerebellar and visual signs and an EEG trace showing occipital paroxysms triggered by low frequency photostimulation.

Lipofuscinosis neuronal ceroidea infantil tardía: aspectos clínicos y electroencefalográficos / Clinical and electroencephalographic aspects of late infantile neuronal ceroid lipofuscinosis

Objetivo. Describimos las características clínicas, particularmente las crisis epilépticas y los hallazgos electroencefalográficos, en 15 pacientes con diagnóstico anatomopatológico de lipofuscinosis neuronal ceroidea (LNC) infantil tardía. Pacientes y métodos. Se estudiaron y se analizaron las historias clínicas de nueve pacientes del sexo femenino y seis del masculino durante el período comprendido entre febrero de 1990 y junio de 2003. En todos los casos se realizaron neuroimágenes, estudios neurometabólicos, ERG, PE y repetidos EEG . Resultados. La edad mediana de comienzo de la enfermedad fue de 3 años (intervalo: 1-5 años). La manifestación inicial fue la epilepsia en todos los casos. Las crisis más frecuentes fueron las mioclonías masivas y las crisis mioclonicoatónicas. Se observaron mioclonías focales en seis pacientes. Otros tipos de crisis epilépticas observados fueron tonicoclónicas generalizadas, ausencias, focales motoras y focales complejas. Las crisis epilépticas fueron refractarias al tratamiento. En todos los casos se presentaron deterioro neurológico y visual progresivo, signos piramidales y cerebelosos y retraso mental . Los EEG intercríticos mostraron paroxismos de punta y polipunta onda difusos, espigas multifocales y, menos frecuentemente, espigas focales predominantes en las regiones posteriores. La fotoestimulación mostró espigas occipitales de elevada amplitud (300-450) durante el estímulo lumínico entre 1 y 8 Hz. El ERG, los PE visuales y los PE somatosensoriales fueron patológicos. Las imágenes evidenciaron signos de atrofia cerebral y cerebelosa. Siete de los pacientes fallecieron entre los 8,5 y los 11 años. Conclusión. En un niño de 1-5 años que comienza con convulsiones, predominantemente mioclonías generalizadas y mioclonicoatónicas asociadas a deterioro neurológico progresivo que incluye signos piramidales, cerebelosos y visuales con un EEG con paroxismos occipitales desencadenados por la fotoestimulación a baja frecuencia, debemos pensar en una LNC infantil tardía

Aims. In this paper we describe the clinical characteristics, and particularly the epileptic seizures and electroencephalographic findings, in 15 patients with a pathology diagnosis of late infantile neuronal ceroid lipofuscinosis (NCL). Patients and methods. Nine female and six male patients were studied and their clinical records covering the period February 1990 to June 2003 were analysed. Neuroimaging, neurometabolic studies, ERG, PE and repeated EEG were carried out in all cases. Results. The mean age on onset of the disease was 3 years (range: 1-5 years). The initial symptom was epilepsy in all cases. Massive myoclonias and myoclonic-atonic seizures were the most frequent kinds of attacks. Focal myoclonias were observed in six patients. Other types of epileptic seizures observed included generalised tonic-clonic, absence, motor focal and complex focal. The epileptic seizures were resistant to therapy. Progressive neurological and visual impairment, pyramidal and cerebellar signs, as well as mental retardation were present in all cases. Intercritical EEG recordings showed diffuse paroxysms with spike and polyspike waves, multifocal spikes and, less often, focal spikes that were predominant in posterior regions. Photostimulation showed high amplitude (300-450) occipital spikes during the application of light stimulation between 1 and 8 Hz. ERG, VEP and SSEP results were pathological. Images showed signs of brain and cerebellar atrophy. Seven of the patients died between 8.5 and 11 years of age. Conclusions. Late infantile NCL must be considered in the case of a child aged between 1 and 5 years who presents seizures that are predominantly generalised myoclonias and myoclonic-atonic, in association with progressive neurological deterioration including pyramidal, cerebellar and visual signs and an EEG trace showing occipital paroxysms triggered by low frequency photostimulation

Clinical and histopathological aspects of central core disease associated and non-associated with RYR1 locus.

We analysed the clinical, histochemical, ultrastructural and genetic data of patients affected by central core disease (CCD) studied during the last 20 years. From a total series of 86 CCD-families, we have identified 46 CCD families with RYR1 mutations (16 autosomal dominant, 8 autosomal recessive, 17 sporadic cases and 5 de novo mutations). Out of the other 40 CCD families, the RyR1 gene was entirely excluded in 7 families, by cDNA sequencing or linkage analysis, indicating a genetic heterogeneity of CCD.

Mitochondrial DNA depletion: mutations in thymidine kinase gene with myopathy and SMA.

BACKGROUND: The mitochondrial DNA (mtDNA) depletion syndrome (MDS) is an autosomal recessive disorder of early childhood characterized by decreased mtDNA copy number in affected tissues. Recently, MDS has been linked to mutations in two genes involved in deoxyribonucleotide (dNTP) metabolism: thymidine kinase 2 (TK2) and deoxy-guanosine kinase (dGK). Mutations in TK2 have been associated with the myopathic form of MDS, and mutations in dGK with the hepatoencephalopathic form. OBJECTIVES: To further characterize the frequency and clinical spectrum of these mutations, the authors screened 20 patients with myopathic MDS. RESULTS: No patient had dGK gene mutations, but four patients from two families had TK2 mutations. Two siblings were compound heterozygous for a previously reported H90N mutation and a novel T77M mutation. The other siblings harbored a homozygous I22M mutation, and one of them had evidence of lower motor neuron disease. The pathogenicity of these mutations was confirmed by reduced TK2 activity in muscle (28% to 37% of controls). CONCLUSIONS: These results show that the clinical expression of TK2 mutations is not limited to myopathy and that the myopathic form of MDS is genetically heterogeneous.

Encefalitis granulomatosa amebaina causada por balamuthia mandrillaris. Presentación de cuatro casos en pediatría / Balamutia amebis granulomatous encephalitis

Las amebas de vida libre comprenden los géneros Naegleria,Acanthamoeba y Balamuthia,que se distribuyen en la naturaleza y pueden causar infeccíon en el sistema nervioso central en niños y adultos.La variedad balamuthia mandrillaris produce una encefalitis granulomatosa amebiana(EGA)de evolución crónica y que afecta a inmunosuprimidos.Se decriben 4 pacientes de edad pediátrica que presentaron esta enfermedad.Todos ellos eran inmunocompetentes.Solo dos de los cuatro niños presentaron lesiones en la cara,que se corresponde con el modo de contagio más frecuente por inmersión en aguas contaminadas.Uno de los niños inició el cuadro clínico con osteomielitis crónica.La evolución en nuestros pacientes fue aguda,con grave compromiso neurológico.No existieron datos significativos o patognomónicos en los exámenes de L.C.R e imágenes de TAC y RM.El diagnóstico se realizó por biopsia de una lesión cerebral,confirmado por inmunofluorescencia.Todos los niños fallecieron a pesar de recibir diversos esquemas terapeúticos.Conclusión:se sugiere considerar la infección por ameba de vida libre en el diagnóstico diferencial de un niño que presenta un cuadro de encefalitis aguda,independiente de si es o no inmunocomprometido

Merosin-positive congenital muscular dystrophy with mental retardation, microcephaly and central nervous system abnormalities unlinked to the Fukuyama muscular dystrophy and muscular-eye-brain loci: report of three siblings.

Classical merosin (2 laminin)-positive congenital muscular dystrophy is a heterogeneous subgroup of disorders; a few cases characterized by severe mental retardation, brain involvement and no ocular abnormalities were called Fukuyama-like congenital muscular dystrophy. We report a family of healthy non-consanguineous parents, with four affected siblings, of which one died at the age of 7 months due to an intercurrent illness, who presented congenital hypotonia, severe mental retardation, microcephaly, delayed psychomotor development, generalized muscular wasting and weakness with mild facial involvement, calf pseudohypertrophy, joint contractures and areflexia. Muscle biopsy disclosed severe muscular dystrophy. Immunostaining for laminin 2 80 kDa and clone Mer3/22B2 monoclonal antibodies, 1 and 1 chain was preserved. Magnetic resonance imaging findings were consistent with pontocerebellar hypoplasia, bilateral opercular abnormalities and focal cortical dysplasia as well as minute periventricular white matter changes. Clusters of small T2-weighted focal hyperintensities in both cerebellar hemispheres consistent with cysts were observed in two of the three siblings studied with magnetic resonance imaging. Ophthalmologic and cardiologic examination was normal. Haplotype analysis using microsatellite markers excluded the Fukuyama congenital muscular dystrophy, LAMA2 and muscle-eye-brain disease loci. Thus, a wider spectrum of phenotypes, gene defects and protein deficiencies might be involved in congenital muscular dystrophy with brain abnormalities.

Patología infecciosa pseudotumoral del sistema nervioso central en la infancia / Infections mimicking central nervous system(CNS)tumors in children

Las infecciones del sistema nervioso central(SNC)pueden presentarse como lesiones ocupantes seudotumorales con efecto de masa,principalmente en pacientes inmunosuprimidos,pudiendo ser la primera manifestación de la enfermedad.La mayoría de los casos publicados corresponden a adultos especialmente dentro de la población HIV.En un contexto clínico adecuado,lesiones de tipo tumoral en las neuroimágenes,deben plantear el diagnóstico diferencial con patología infecciosa.Nuestro objetivo es describir los hallazgos clínicos y de neuroimágenes de 16 pacientes con infecciones intracraneanas a forma seudotumoral que requieren cirugía con presunción diagnóstica de lesión neoplásica.En nuestra serie de 1.0005 lesiones expansivas intracraneales neuroquirúrgicas,excluyendo inmunosuprimidos,trasplantados y HIV conocidos(con riesgo potencial de absceso cerebral)se diagnosticaron en 16 biopsias cerebrales(1,6 por ciento)Infecciones por protozoarios(enfermedad de Chagas:2,toxoplasmosis:3,uno de ellos asociado a Mycobacterium avium intracellulare,amebas de via libre:2)cestodes(Cysticercus cellulosae:2,quiste hidiatídico Echinococcus granulosus:4 y tuberculomas:3.En casos clínicos estudiados y seleccionados algunas observaciones pueden ayudar a evitar procedimientos invasivos del SNC así como modificar la táctica y técnica quirúrgica

Patología infecciosa pseudotumoral del sistema nervioso central en la infancia / Infections mimicking central nervous system (CNS) tumors in children

Las infecciones del sistema nervioso central(SNC)pueden presentarse como lesiones ocupantes seudotumorales con efecto de masa,principalmente en pacientes inmunosuprimidos,pudiendo ser la primera manifestación de la enfermedad.La mayoría de los casos publicados corresponden a adultos especialmente dentro de la población HIV.En un contexto clínico adecuado,lesiones de tipo tumoral en las neuroimágenes,deben plantear el diagnóstico diferencial con patología infecciosa.Nuestro objetivo es describir los hallazgos clínicos y de neuroimágenes de 16 pacientes con infecciones intracraneanas a forma seudotumoral que requieren cirugía con presunción diagnóstica de lesión neoplásica.En nuestra serie de 1.0005 lesiones expansivas intracraneales neuroquirúrgicas,excluyendo inmunosuprimidos,trasplantados y HIV conocidos(con riesgo potencial de absceso cerebral)se diagnosticaron en 16 biopsias cerebrales(1,6 por ciento)Infecciones por protozoarios(enfermedad de Chagas:2,toxoplasmosis:3,uno de ellos asociado a Mycobacterium avium intracellulare,amebas de via libre:2)cestodes(Cysticercus cellulosae:2,quiste hidiatídico Echinococcus granulosus:4 y tuberculomas:3.En casos clínicos estudiados y seleccionados algunas observaciones pueden ayudar a evitar procedimientos invasivos del SNC así como modificar la táctica y técnica quirúrgica

Extratemporal epilepsy in children: candidate selection and surgical treatment.

From June 1988 to June 1998, 60 children with extratemporal epilepsies (EE), most of whom were symptomatic, underwent surgery. All patients were studied by means of CT scanning, MRI and scalp EEG. Video-telemetry was used in 40 cases. Intracranial electrodes were placed in 10. Intraoperative ECoG was used in the 35 children who underwent resective procedures and in the 25 in whom disconnection was performed. Surgical procedures were as follows: 24 lesionectomies, 25 disconnecting procedures, 7 polectomies and/or lobectomies, 3 corticectomies and 1 anatomical hemispherectomy. After at least 1 year's follow-up in 48 children, to date 38 are in Engel class I, 7 in class II, 1 in class III and 2 in class IV. That is to say, in 46 of the 48, surgical outcomes ranges from very good to at least worthwhile, as reflected in their classification in Engel class III.