MRI cortical feature of bulbar impairment in patients with amyotrophic lateral sclerosis

The decline of voluntary bulbar functions such as speech and swallowing are among the clinical manifestations of amyotrophic lateral sclerosis (ALS) influencing a worst prognosis. Differential diagnosis between the contribution of upper motor neuron (UMN) and lower motor neuron degeneration to the bulbar impairment is often hard. Thinning and T2* hypointensity of the primary motor cortex have been recently suggested as possible MRI markers of UMN impairment in ALS patients, but little research has purposely targeted the orofacial region of the primary motor cortex (fM1). With the aim of finding an MRI marker of UMN impairment responsible for bulbar dysfunction, we investigated the T2* signal intensity of fM1 and the relationship with bulbar impairment in ALS patients. Fifty-five ALS patients were examined with 3 T MRI. Their fM1 was evaluated both qualitatively in terms of T2* signal intensity and quantitatively by measuring its magnetic susceptibility with Quantitative Susceptibility Mapping (QSM). Bulbar functions were assessed clinically, by neurological examination and using the items 1–3 of the ALSFRS-R, and with neurophysiological tests. The marked hypointensity of fM1 was detected in 25% of ALS patients, including all patients with bulbar onset, and was 74% sensitive, 100% specific and 91% accurate in diagnosing functional bulbar impairment. Such hypointensity involved the middle and ventral part of fM1 and was usually visible in both hemispheres. The magnetic susceptibility was significantly higher in patients with marked fM1 hypointensity than in the other patients (p ≤ .001). The relationship with clinical and neurophysiological data suggests that such feature could be a marker of UMN degeneration for voluntary bulbar functions

Pes cavus and hereditary neuropathies: when a relationship should be suspected

The hereditary peripheral neuropathies are a clinically and genetically heterogeneous group of diseases of the peripheral nervous system. Foot deformities, including the common pes cavus, but also hammer toes and twisting of the ankle, are frequently present in patients with hereditary peripheral neuropathy, and often represent one of the first signs of the disease. Pes cavus in hereditary peripheral neuropathies is caused by imbalance between the intrinsic muscles of the foot and the muscles of the leg. Accurate clinical evaluation in patients with pes cavus is necessary to exclude or confirm the presence of peripheral neuropathy. Hereditary peripheral neuropathies should be suspected in those cases with bilateral foot deformities, in the presence of family history for pes cavus and/or gait impairment, and in the presence of neurological symptoms or signs, such as distal muscle hypotrophy of limbs. Herein, we review the hereditary peripheral neuropathies in which pes cavus plays a key role as a “spy sign,” discussing the clinical and molecular features of these disorders to highlight the importance of pes cavus as a helpful clinical sign in these rare diseases

Semiautomated evaluation of the primary motor cortex in patients with amyotrophic lateral sclerosis at 3t

Amyotrophic lateral sclerosis is a neurodegenerative disease involving the upper and lower motor neurons. In amyotrophic lateral sclerosis, pathologic changes in the primary motor cortex include Betz cell depletion and the presence of reactive iron-loaded microglia, detectable on 7T MR images as atrophy and T2*-hypointensity. Our purposes were the following: 1) to investigate the signal hypointensity-to-thickness ratio of the primary motor cortex as a radiologic marker of upper motor neuron involvement in amyotrophic lateral sclerosis with a semiautomated method at 3T, 2) to compare 3T and 7T results, and 3) to evaluate whether semiautomated measurement outperforms visual image assessment

Semiautomated Evaluation of the Primary Motor Cortex in Patients with Amyotrophic Lateral Sclerosis at 3T

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Erythropoietin in amyotrophic lateral sclerosis: a multicentre, randomised, double blind, placebo controlled, phase III study

OBJECTIVE: To assess the efficacy of recombinant human erythropoietin (rhEPO) in amyotrophic lateral sclerosis (ALS). METHODS: Patients with probable laboratory-supported, probable or definite ALS were enrolled by 25 Italian centres and randomly assigned (1:1) to receive intravenous rhEPO 40,000 IU or placebo fortnightly as add-on treatment to riluzole 100 mg daily for 12 months. The primary composite outcome was survival, tracheotomy or >23 h non-invasive ventilation (NIV). Secondary outcomes were ALSFRS-R, slow vital capacity (sVC) and quality of life (ALSAQ-40) decline. Tolerability was evaluated analysing adverse events (AEs) causing withdrawal. The randomisation sequence was computer-generated by blocks, stratified by centre, disease severity (ALSFRS-R cut-off score of 33) and onset (spinal or bulbar). The main outcome analysis was performed in all randomised patients and by intention-to-treat for the entire population and patients stratified by severity and onset. The study is registered, EudraCT 2009-016066-91. RESULTS: We randomly assigned 208 patients, of whom 5 (1 rhEPO and 4 placebo) withdrew consent and 3 (placebo) became ineligible (retinal thrombosis, respiratory insufficiency, SOD1 mutation) before receiving treatment; 103 receiving rhEPO and 97 placebo were eligible for analysis. At 12 months, the annualised rate of death (rhEPO 0.11, 95% CI 0.06 to 0.20; placebo: 0.08, CI 0.04 to 0.17), tracheotomy or >23 h NIV (rhEPO 0.16, CI 0.10 to 0.27; placebo 0.18, CI 0.11 to 0.30) did not differ between groups, also after stratification by onset and ALSFRS-R at baseline. Withdrawal due to AE was 16.5% in rhEPO and 8.3% in placebo. No differences were found for secondary outcomes. CONCLUSIONS: RhEPO 40,000 IU fortnightly did not change the course of ALS

POLG1-related and other "mitochondrial Parkinsonisms": an overview.

Mitochondrial dysfunction has been implicated in the pathogenesis of sporadic, idiopathic Parkinson disease. In some cases, mitochondrial DNA primary genetic abnormalities, or more commonly, secondary rearrangements due to polymerase gamma (POLG1) gene mutation, can directly cause parkinsonism. The case of a Parkinson disease patient with some signs or symptoms suggestive of mitochondrial disease (i.e., ptosis, myopathy, neuropathy) is a relatively common event in the neurological practice. Mitochondrial parkinsonisms do not have distinctive features allowing an immediate diagnosis, and a negative family history does not rule out a possible diagnosis of mitochondrial disorder. In this article, we do not revise the mitochondrial hypothesis of sporadic, idiopathic Parkinson disease, extensively discussed elsewhere, but we review POLG1-related parkinsonism and other well-defined forms of "mitochondrial parkinsonisms", with mtDNA mutations or rearrangements. Lastly, we try to introduce a possible diagnostic approach for patients with parkinsonism and suspected mitochondrial disorder

Anti-Ri-associated paraneoplastic cerebellar degeneration. Report of a case and revision of the literature.

Paraneoplastic cerebellar degeneration associated with anti-Ri antibodies mainly presents with opsoclonus-myoclonus-ataxia. We report here the case of a patient with anti-Ri-antibody paraneoplastic syndrome, who presented four years after treatment for small-cell lung cancer (SCLC) with oscillopsia and gait disorder. On neurological examination vertical nystagmus, ataxic gait and postural tremor of all four limbs was detected. He died one year after the onset of the symptoms because of a acute exacerbation of his severe chronic obstructive pulmonary disease. No SCLC relapse or new cancer has been detected during the one-year follow-up period.To our knowledge, our patient is the first case of anti-Ri associated disorder with oscillopsia and vertical nystagmus as the initially prominent clinical features. The findings of this case study support the variability of anti-Ri-antibody-associated paraneoplastic syndrome. Further studies must be directed to better characterize the mechanisms underlying this syndrome. Finally, paraneoplastic neurological syndromes should be kept in mind also when a neoplastic disease is not demonstrated

Magnetic susceptibility in the deep layers of the primary motor cortex in Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurological disorder that entails degeneration of both upper and lower motor neurons. The primary motor cortex (M1) in patients with upper motor neuron (UMN) impairment is pronouncedly hypointense in Magnetic Resonance (MR) T2* contrast. In the present study, 3D gradient-recalled multi-echo sequences were used on a 7 Tesla MR system to acquire T2*-weighted images targeting M1 at high spatial resolution. MR raw data were used for Quantitative Susceptibility Mapping (QSM). Measures of magnetic susceptibility correlated with the expected concentration of non-heme iron in different regions of the cerebral cortex in healthy subjects. In ALS patients, significant increases in magnetic susceptibility co-localized with the T2* hypointensity observed in the middle and deep layers of M1. The magnetic susceptibility, hence iron concentration, of the deep cortical layers of patients' M1 subregions corresponding to Penfield's areas of the hand and foot in both hemispheres significantly correlated with the clinical scores of UMN impairment of the corresponding limbs. QSM therefore reflects the presence of iron deposits related to neuroinflammatory reaction and cortical microgliosis, and might prove useful in estimating M1 iron concentration, as a possible radiological sign of severe UMN burden in ALS patients