Diagnostic delay and outcome in immunocompetent patients with primary central nervous system lymphoma in Spain: a multicentric study.

INTRODUCTION: To assess the management of immunocompetent patients with primary central nervous system lymphomas (PCNSL) in Spain. METHODS: Retrospective analysis of 327 immunocompetent patients with histologically confirmed PCNSL diagnosed between 2005 and 2014 in 27 Spanish hospitals. RESULTS: Median age was 64 years (range: 19-84; 33% ≥ 70 years), 54% were men, and 59% had a performance status (PS) ≥ 2 at diagnosis. Median delay to diagnosis was 47 days (IQR 24-81). Diagnostic delay > 47 days was associated with PS ≥ 2 (OR 1.99; 95% CI 1.13-3.50; p = 0.016) and treatment with corticosteroids (OR 2.47; 95% CI 1.14-5.40; p = 0.023), and it did not improve over the years. Patients treated with corticosteroids (62%) had a higher risk of additional biopsies (11.7% vs 4.0%, p = 0.04) but corticosteroids withdrawal before surgery did not reduce this risk and increased the diagnostic delay (64 vs 40 days, p = 0.04). Median overall survival (OS) was 8.9 months [95% CI 5.9-11.7] for the whole series, including 52 (16%) patients that were not treated, and 14.1 months (95%CI 7.7-20.5) for the 240 (73.4%) patients that received high-dose methotrexate (HD-MTX)-based chemotherapy. Median OS was shorter in patients ≥ 70 years (4.1 vs. 13.4 months; p < 0.0001). Multivariate analysis identified age ≥ 65 years, PS ≥ 2, no treatment, and cognitive/psychiatric symptoms at diagnosis as independent predictors of short survival. CONCLUSIONS: Corticosteroids withdrawal before surgery does not decrease the risk of a negative biopsy but delays diagnosis. In this community-based study, only 73.4% of patients could receive HD-MTX-based chemotherapy and OS remains poor, particularly in elderly patients ≥ 70 years.

Prognostic biomarkers of Parkinson's disease in the Spanish EPIC cohort: a multiplatform metabolomics approach.

The lack of knowledge about the onset and progression of Parkinson's disease (PD) hampers its early diagnosis and treatment. Metabolomics might shed light on the PD imprint seeking a broader view of the biochemical remodeling induced by this disease in an early and pre-symptomatic stage and unveiling potential biomarkers. To achieve this goal, we took advantage of the great potential of the European Prospective Study on Nutrition and Cancer (EPIC) cohort to apply metabolomics searching for early diagnostic PD markers. This cohort consisted of healthy volunteers that were followed for around 15 years until June 2011 to ascertain incident PD. For this untargeted metabolomics-based study, baseline preclinical plasma samples of 39 randomly selected individuals that developed PD (Pre-PD group) and the corresponding control group were analyzed using a multiplatform approach. Data were statistically analyzed and exposed alterations in 33 metabolites levels, including significantly lower levels of free fatty acids (FFAs) in the preclinical samples from PD subjects. These results were then validated by adopting a targeted HPLC-QqQ-MS approach. After integrating all the metabolites affected, our finding revealed alterations in FFAs metabolism, mitochondrial dysfunction, oxidative stress, and gut-brain axis dysregulation long before the development of PD hallmarks. Although the biological purpose of these events is still unknown, the remodeled metabolic pathways highlighted in this work might be considered worthy prognostic biomarkers of early prodromal PD. The findings revealed by this work are of inestimable value since this is the first study conducted with samples collected many years before the disease development.

Globular glial tauopathy caused by MAPT P301T mutation: clinical and neuropathological findings.

OBJECTIVE: To describe the clinical, biochemical, and neuropathological findings of an autosomal dominant globular glial tauopathy caused by the P301T mutation at the MAPT gene. METHODS: Five patients from two unrelated pedigrees underwent clinical evaluation. Genetic analysis, brain pathological examination, and biochemical analysis of tau were performed. RESULTS: The patients studied were 3 men and 2 women with a mean age at onset of 52.2 years and mean disease duration of 5.2 years. Three patients presented a corticobasal syndrome, one patient an asymmetric pyramidal syndrome compatible with primary lateral sclerosis, and one patient a frontotemporal dementia. In both pedigrees (4 patients) Sanger sequencing showed the p.P301T mutation in exon 10 of the MAPT gene. Neuropathological findings consisted of atrophy of frontal and temporal lobes with marked spongiosis and astrogliosis, and abundant phosphorylated tau protein deposits in the frontal and temporal cortex, limbic area, basal ganglia, and brain stem. The most striking finding was the presence of oligodendroglial 4R phospho-tau globular positive inclusions in the white matter and cortex. Globose-type neurofibrillary neuronal tangles, and in particular astrocytic globular inclusions and coarse tufts, were present in the grey matter. Biochemical analysis of sarkosyl-insoluble fractions revealed two tau bands of 64 and 68 kDa and case-dependent bands of lower molecular weight. CONCLUSION: This is the first pathological and biochemical study of the MAPT p.P301T mutation showing variable clinical manifestation and neuropathological phenotype of globular glial tauopathy not only among different families but also within families.

[Movement disorders in the emergency department]. / Los trastornos del movimiento en urgencias.

Acute or sub-acute movement disorders represent a small percentage of neurological emergencies but it is necessary to be aware of their existence because a failure in their diagnosis or treatment can result in significant morbidity and mortality. Clinical presentation of acute movement disorders can be diverse. In some cases acinesia or rigidity predominates, while others are characterized by dystonia, chorea o balism. The type of movement disorder suggest a specific aetiology. Drugs represent the most frequent etiologic factor and are the cause of neuroleptic malignant syndrome and serotoninergic syndrome. Emergencies secondary to Parkinson's disease are reviewed, including parkinsonism-hyperpirexia syndrome, acute psychosis and the emergencies derived from deep brain stimulators. Different aetiologies of acute dystonia and chorea are also covered and, finally, acute movement disorders due to stroke are reviewed.

[Hypersomnia: diagnosis, classification and treatment]. / Las hipersomnias: diagnóstico, clasificación y tratamiento.

Hypersomnia or excessive daytime sleepiness is common in neurological practice and may have different etiologies. Hypersomnia may be defined as sleepiness at an inappropriate time or in an inappropriate situation. It is important to consider that hypersomnia is at times referred to as tiredness or fatigue. A detailed clinical history is essential to reach an accurate diagnosis. A correct diagnosis is necessary to initiate the appropriate treatment considering the negative social and occupational consequences of hypersomnia. Excessive daytime sleepiness syndromes include primary sleep disorders like narcolepsy and hypersomnia secondary to several neurological and psychiatric disorders and also as an adverse effect of numerous drugs.

[Sleep disorders in prion diseases]. / Patología del sueño en las enfermedades priónicas.

Prion diseases are a group of encephalopathies with neurodegenerative changes caused by an altered protein named prion whose characteristic datum is transmissibility. In most cases they occur in a sporadic form although a group of them are familial associated with mutations in the gene of the prion protein. Genetic polymorphism seems to determine the different family variants. One of the most enigmatic and unusual is Fatal Familial Insomnia (FFI), a hereditary disorder characterised by loss of physiological sleep with oneiric stupor, autonomic and motor hyperactivity, and motor anomalies. The polysomnography of this entity reflects an inability to produce the physiological pattern of NREM and REM sleep, as well as hormonal and vegetative circadian fluctuations; the transition from wakefulness to sleep is markedly altered with the early disappearance sleep spindles. The hypothesis of the origin of these disorders is thalamic neuronal loss, especially in the anterior and dorsomedial nuclei, described in the neuropathology of these patients; besides PET reveals hypofunction of thalamic nuclei, centres responsible for controlling wakefulness-sleep. In Creutzfeldt-Jakob disease the wake-sleep disorders are not considered characteristic; nonetheless, frequent alterations have been found in the electroencephalographic registers of sleep. Besides thalamic neurodegeneration, there could be common etiopathogenic mechanisms in prion diseases in relation to the biological function of the prion protein.

[Sleep disorders in the elderly and in dementias]. / Trastornos del sueño en el anciano y en las demencias.

Sleep disorders are very frequent in the elderly. Bearing in mind the growth of this population group in western societies, it is of great importance to understand the sleep diseases that affect them and what their treatment should be. On the other hand, it is in this age group where we find the majority of patients with dementias. The treatment of sleep disorders in these patients is complex. An adequate control of insomnia and of the excessive nocturnal activity that usually occurs in the advanced phases of dementias has an important social repercussion. This article summarises the peculiar characteristics of sleep disorders in the elderly as well as the diagnostic and therapeutic handling of sleep disorders in patients with dementias.

[Multiple brain abscesses due to Streptococcus milleri]. / Abscesos cerebrales múltiples por Streptococcus milleri.

TITLE: Abscesos cerebrales múltiples por Streptococcus milleri.

[Paraneoplasic polyneuropathy with anti-amphiphysin antibodies]. / Polineuropatía paraneoplásica con anticuerpos anti-anfifisina.

Paraneoplastic neurological syndromes consist of a dysfunction of any part of the nervous system, in isolation or in combination, caused by a malign neoplasia, but not by the direct tissular or metastasic invasion of the tumour. Their pathogeny is explained by immunological mechanisms and they are characterised by the presence of high rates of antibodies in serum and cerebrospinal fluid. We present the case of a patient with a sensitive neuropathy that produced ataxia, and who suffered from a poorly differentiated adenocarcinoma of the lung, in whom the search for antineuronal antibodies was positive for antiamphiphysin antibodies, supporting the diagnosis of paraneoplastic polyneuropathy.

[Primary central nervous system lymphoma in a unusual site: a diagnostic challenge]. / Linfoma primario del sistema nervioso central de localizacion inhabitual: un reto diagnostico.

TITLE: Linfoma primario del sistema nervioso central de localizacion inhabitual: un reto diagnostico.

[Pathophysiological bases of the non-motor symptoms in Parkinson's disease]. / Bases fisiopatológicas de los síntomas no motores de la enfermedad de Parkinson.

INTRODUCTION: The neuro-anatomical and neurochemical substrates underlying most of the non-motor symptoms (NMS) of Parkinson's disease (PD) are not understood in depth. AIM: To review the current knowledge on the pathophysiology of the different NMS of PD based on recent studies. DEVELOPMENT: In most of the NMS the pathophysiological foundation is complex. In addition to the dopaminergic dysfunction, the degeneration of non-dopaminergic (i.e. noradrenergic, serotoninergic and cholinergic) cellular systems is thought to underlie the development of most of the NMS and can be applied in dementia, depression, sleep disorders and vegetative disorders. Dementia, moreover, is essentially caused by different alterations that take place with the cerebral cortex. Dysfunction of the ventral striatum and of the mesolimbic projections exerts a crucial influence in impulsive-compulsive spectrum disorder. Loss of the sense of smell appears to be due to the neuronal degeneration of the olfactory bulb and the pain has an extremely varied pathogenetic basis and may be musculoskeletal, dystonic, radicular or central. CONCLUSIONS: Despite the fact that a huge amount of progress has been made in research on the pathophysiology of the NMS of PD, further clinicopathological and pathobiochemical comparative studies are needed to explain the pathophysiological bases of PD and to provide a broader foundation for future therapeutic strategies to treat NMS.

[Myoclonic spasms: their clinical and neurophysiological characteristics, aetiology and treatment]. / Mioclonías: características clínicas y neurofisiológicas, etiología y tratamiento.

INTRODUCTION: Myoclonus refers to the brief, sudden, involuntary movements like jerks or twitches which produce a sudden muscular contraction. AIMS: To review the clinical and neurophysiological features of myoclonus, or myoclonic spasms, and to carry out an updated examination of their causation and treatment. DEVELOPMENT: Myoclonic spasms can be classified on the basis of different criteria. According to the underlying physiological mechanism, myoclonic spasms can be classified as cortical, subcortical, spinal or peripheral. Myoclonic spasms appear in a wide range of neurological diseases. So-called symptomatic myoclonus is the type that occurs secondary to an identifiable disorder; it is usually accompanied by other neurological signs and is the most frequent kind. Epileptic myoclonus is that which forms part of an epileptic syndrome with a genetic or idiopathic cause, or that is due to static encephalopathy. Essential myoclonus is the least frequent type and includes palatal myoclonus and dystonia-myoclonus syndrome. The main therapeutic objective consists in treating the underlying cause of the myoclonus if possible and in using symptomatic treatment when this is not the case. Antiepileptic drugs that enhance the effect of gamma-aminobutyric acid are still the most effective medication. Among the non-antiepileptic drugs, piracetam and 5-hydroxytryptophan stand out above the rest. Botulinum toxin has proved to be effective in palatal myoclonus. In dystonia-myoclonus syndrome, research has been conducted on the effectiveness of deep brain stimulation on the internal globus pallidus. In the most severe forms of myoclonus, monotherapy is not usually effective. CONCLUSIONS: Progress has been made in furthering our knowledge of the neurophysiology of myoclonus, although no very effective forms of treatment have been reported for this motor disorder, which can be extremely disabling.

[Pontine stroke due to vasospasm secondary to perimesencephalic subarachnoid hemorrhage]. / Infarto pontino por vasoespasmo secundario a hemorragia subaracnoidea perimesencefálica.

INTRODUCTION: Spontaneous non-aneurysmal subarachnoid hemorrhages generally have a good short and long term outcome, especially those with a perimesencephalic location. Vasospasm is an uncommon complication of this type of subarachnoid hemorrhage, and ischemic cerebral lesions related to vasospasm are even less frequent. CASE REPORT: A 46 year-old man was admitted with a perimesencephalic subarachnoid hemorrhage. Angiographic study performed on admission was normal. Two weeks later he developed dysarthria and right faciobrachial paresis. Transcranial doppler showed a diffuse and moderate increase of medium velocity flow at basilar artery level suggestive of moderate vasospasm. An angioresonance confirmed this finding and a paramedian pontine infarction was found on resonance images. The patient was treated with nimodipine and he was discharged from hospital with only mild residual deficit. CONCLUSION: Cerebral infarction related to vasospasm as complication of subarachnoid perimesencephalic hemorrhage is exceptional. The factors that could have been involved in the development of this complication are discussed.

[Involuntary movements in brainstem ischemic lesions]. / Movimientos involuntarios en lesiones isquémicas del tronco cerebral.

INTRODUCTION: The appearance of movement disorders in vascular disease of the brainstem has hardly been described in the literature. Its frequency is probably underestimated due to their briefness and that they are often misinterpreted as epileptic seizures. Their pathophysiological mechanism is uncertain. Several mechanisms, such as the existence of a seizure-generating brainstem center, capable of generating epileptic activity or the interruption of the corticospinal tracts due to ischemia, have been proposed. CLINICAL CASES: We present three patients with disease of the basilar artery and extensive brainstem infarction who have the presentation of sudden, involuntary movements in limbs in the initial phase, in paroxysms of short duration and of varied semiology in common. We described this in all of them. An electroencephalographic functional study during these episodes was done in one of the cases. CONCLUSIONS: Preservation of conscious level, its variability of presentation, the null response to antiepileptic drugs and normality of the electroencephalogram in one of them leads us to ratify the hypothesis of failure of the cortical inhibitory projections as subcortical centers in trunk or spinal cord as pathophysiological origin of these involuntary movements. We stress the importance of recognizing these clinical manifestations of appearance in the initial phases of the disease, that permit a rapid diagnosis with the help of the transcranial Doppler to establish an early and aggressive treatment of this disease having known seriousness and bad prognosis. Further prospective studies would be interesting to know what the real incidence of these movements is, and functional ones to clarify the pathophysiological nature of this phenomenon.

Isolated pontine infarcts: etiopathogenic mechanisms.

Although there are several clinico-topographical studies of pontine infarcts, few include vascular studies. To clarify the etiopathogenic mechanisms of pontine infarcts we analyzed the vascular findings and their association with MRI lesions. The clinical features and vascular findings on transcranial Doppler (TCD) or MR angiography (MRA) of 67 patients with acute infarcts involving the pons were studied. Functional outcome was assessed by modified Rankin Scale (mRS) scores on admission and 2 months later. Two groups of isolated pontine infarcts were found on the basis of lesion location on MRI, according to the extent or not to the anterior surface of the pons: paramedian pontine infarcts (PPI, n = 36) and lacunar pontine infarcts (LPI, n = 31). Hypertension was the most common vascular risk factor and pure motor syndrome was the most frequent clinical profile in both groups. Basilar artery stenosis found on TCD or MRA was significantly more frequent amongst the PPI group (P < 0.05). On admission and 2 months later, the mRS scores of the PPI group were significantly worse (P < 0.0001) than those of the LPI group. Patients with PPI have a significantly higher frequency of basilar artery stenosis and they have a worse prognosis than patients with LPI.