Rosa Cortese

Cortical Thinning and Clinical Heterogeneity in Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) has heterogeneous clinical features that could be translated into specific patterns of brain atrophy. In the current study we have evaluated the relationship between different clinical expressions of classical ALS and measurements of brain cortical thickness. Cortical thickness analysis was conducted from 3D-MRI using FreeSurfer software in 29 ALS patients and 20 healthy controls. We explored three clinical traits of the disease, subdividing the patients into two groups for each of them: the bulbar or spinal onset, the higher or lower upper motor neuron burden, the faster or slower disease progression. We used both a whole brain vertex-wise analysis and a ROI analysis on primary motor areas. ALS patients showed cortical thinning in bilateral precentral gyrus, bilateral middle frontal gyrus, right superior temporal gyrus and right occipital cortex. ALS patients with higher upper motor neuron burden showed a significant cortical thinning in the right precentral gyrus and in other frontal extra-motor areas, compared to healthy controls. ALS patients with spinal onset showed a significant cortical thinning in the right precentral gyrus and paracentral lobule, compared to healthy controls. ALS patients with faster progressive disease showed a significant cortical thinning in widespread bilateral frontal and temporal areas, including the bilateral precentral gyrus, compared to healthy controls. Focusing on the primary motor areas, the ROI analysis revealed that the mean cortical thickness values were significantly reduced in ALS patients with higher upper motor neuron burden, spinal onset and faster disease progression related to healthy controls. In conclusion, the thickness of primary motor cortex could be a useful surrogate marker of upper motor neuron involvement in ALS; also our results suggest that cortical thinning in motor and non motor areas seem to reflect the clinical heterogeneity of the disease.

Amyotrophic lateral sclerosis: a new missense mutation in the SOD1 gene

Copper-zinc superoxide dismutase-1 (SOD1) is the second most common mutated gene in amyotrophic lateral sclerosis (ALS). To date more than 150 missense mutations of SOD1 have been reported. The objective of this study was to describe a novel SOD1 mutation and its phenotypic expression. We describe a 74-year-old Caucasian man who began to complain of progressive weakness and atrophy of the right hand and over 10 months developed a severe tetraparesis, with atrophies of upper and lower limbs and neck muscles, dysphagia, and dyspnea that led to percutaneous endoscopic gastrostomy and tracheotomy. A diagnosis of ALS was made. Genetic analysis identified a heterozygous mutation in exon 4 of SOD1 that results in the amino acid substitution from arginine to cysteine at position 115 (p.R115C). We identified a novel pathogenic SOD1 mutation in a patient with a very rapid disease progression and aggressive phenotype providing additional information on the wide range of SOD1 mutations in apparently sporadic ALS and confirming the possibility of a strong genotype-phenotype correlation for distinct SOD1 mutations.

Gray matter MRI differentiates neuromyelitis optica from multiple sclerosis using random forest

Objective: We tested whether brain gray matter (GM) imaging measures can differentiate between multiple sclerosis (MS) and neuromyelitis optica (NMO) using random-forest classification. Methods: Ninety participants (25 patients with MS, 30 patients with NMO, and 35 healthy controls [HCs]) were studied in Tehran, Iran, and 54 (24 patients with MS, 20 patients with NMO, and 10 HCs) in Padua, Italy. Participants underwent brain T1 and T2/fluid-attenuated inversion recovery MRI. Volume, thickness, and surface of 50 cortical GM regions and volumes of the deep GM nuclei were calculated and used to construct 3 random-forest models to classify patients as either NMO or MS, and separate each patient group from HCs. Clinical diagnosis was the gold standard against which the accuracy was calculated. Results: The classifier distinguished patients with MS, who showed greater atrophy especially in deep GM, from those with NMO with an average accuracy of 74% (sensitivity/specificity: 77/72; p < 0.01). When we used thalamic volume (the most discriminating GM measure) together with the white matter lesion volume, the accuracy of the classification of MS vs NMO was 80%. The classifications of MS vs HCs and NMO vs HCs achieved higher accuracies (92% and 88%). Conclusions: GM imaging biomarkers, automatically obtained from clinical scans, can be used to distinguish NMO from MS, even in a 2-center setting, and may facilitate the differential diagnosis in clinical practice. Classification of evidence: This study provides Class II evidence that GM imaging biomarkers can distinguish patients with NMO from those with MS.

Time to generalisation as a predictor of prognosis in amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS), prognosis is usually based on death or tracheostomy as outcomes. Nevertheless, the early course is known to be a reliable indicator of the whole course of the disease.1 The identification of outcomes in early stages would determine better planning of interventions and more appropriate stratification of newly diagnosed patients for randomised clinical trials (RCTs). The time of disease spread is probably linked to the rate of progression and the intensity of neuro-axonal degeneration,2 and it has already been related to survival in ALS.3 The aim of the present study was to evaluate if time to generalisation (TTG) may predict survival in ALS. All patients with a diagnosis of possible, probable or definite ALS, according to El Escorial criteria,4 and an onset of the disease between January 2004 and December 2007, referred to the Centre of Motor Neuron Disease, University of Bari, were enrolled in the current study. The study was terminated in April 2012. Death or tracheostomy was used as outcome measure to study the 4-year and 5-year mortality. Considered clinical variables were: (1) age at symptom onset (AAO); (2) site of symptom onset (bulbar region or spinal region); (3) time of diagnosis; (4) onset-diagnosis interval (ODI), defined as the time from the onset of the first symptom to diagnosis of ALS; (5) score of the revised ALS Functional Rating Scale (ALSFRS-r) at baseline;5 (6) TTG, considered as the time of spreading of the clinical signs from spinal (cervical, thoracic, or lumbosacral regions), or bulbar localisation or both. To detect generalisation, all the lower and upper motor neuron signs listed in the El Escorial criteria for the four body regions were investigated;4 TTG was censored at the time of the last follow-up visit; (7) overall survival (OS), defined as …

Hirayama disease: the importance of an early diagnosis

We report the favourable outcome of a patient affected by Hirayama disease (HD) who was treated with conservative therapy. Hirayama disease (HD) is a relatively rare myelopathy, a self-limiting juvenile spinal muscular atrophy of the distal upper limbs, which occurs more frequently in young men of Asian origin [1]. Only a few cases have been reported in Italy [2]. The condition is thought to stem from the disproportionate development of the vertebral column compared to the spinal cord in growth spurt. Additionally, the repetitive displacement of the posterior dural sac in neck flexion is thought to contribute to microvascular damage of the cervical spinal cord [1, 2]. The clinical features typically consist of unilateral or asymmetric progressive weakness and atrophy of the hand and forearm muscles, without sensory or pyramidal tract impairment. The careful integration of clinical, radiological and neurophysiological findings is required to establish the diagnosis of HD [1, 3]. Although likely to mimic amyotrophic lateral sclerosis (ALS), HD may have a benign course, with an initial progressive course followed by spontaneous stabilization within several years after the onset [1, 2]. Conservative treatment, consisting in the early use of a cervical collar, has been reported as stopping clinical progression. Surgical intervention, such as decompression, is only indicated in selective cases where progressive deterioration occurs despite conservative management [4]. A 20-year-old right-handed man was referred to our service in September 2011. He referred he had had a slow progressive weakness and atrophy of the right hand for 1 year. No systemic diseases or family history of neurological diseases were reported. Neurological examination revealed atrophy of thenar and interosseous muscles and weakness of fingers and forearm extension (grade 4 on Medical Research Council scale) of the right upper limb. Deep tendon reflexes were normal and symmetrical. There were no fasciculations, cramps, sensory disturbances, extrapyramidal signs or sphincter dysfunction. Routine blood, anti-GM1 antibodies and cerebrospinal fluid parameters were all within normal range. Electromyography showed increased polyphasic waves of large amplitude and long duration in C7–T1 innervated muscles on the right upper limb. Nerve conduction studies showed normal sensory and motor velocities of the median and ulnar nerves; no conduction blocks were identified. Motor and somatosensory evoked potentials were normal. Genetic analysis of ALS-related genes (SOD1, FUS, TARDBP and C9 or f72) and SMN1 and SMN2 did not show any mutations. Muscle biopsy was normal. Magnetic resonance imaging (MRI) brain was normal, whereas standard axial and sagittal MRI cervical spine showed a focal signal alteration with T2 hyperintensity at C5–C6 level, R. Cortese F. Dicuonzo S. Zoccolella I. L. Simone (&) Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Bari, Italy e-mail: isabellalaura.simone@uniba.it

Value of the central vein sign at 3T to differentiate MS from seropositive NMOSD

Objective To assess the value of the central vein sign (CVS) on a clinical 3T scanner to distinguish between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). Methods Eighteen aquaporin-4-antibody-positive patients with NMOSD, 18 patients with relapsing-remitting MS, and 25 healthy controls underwent 3T MRI. The presence of a central vein in white matter lesions on susceptibility-weighted imaging, defined as a thin hypointense line or a small dot, was recorded. Results The proportion of lesions with the CVS was higher in MS than NMOSD (80% vs 32%, p < 0.001). A greater proportion of lesions with the CVS predicted the diagnosis of MS, rather than NMOSD (odds ratio 1.10, 95% confidence interval [CI] 1.04 to 1.16, p = 0.001), suggesting that each percent unit increase in the proportion of lesions with the CVS in an individual patient was associated with a 10% increase in the risk of the same patient having MS. If more than 54% of the lesions on any given scan show the CVS, then the patient can be given a diagnosis of MS with an accuracy of 94% (95% CIs 81.34, 99.32, p < 0.001, sensitivity/specificity 90%/100%). Conclusion The clinical value of the CVS in the context of the differential diagnosis between MS and NMOSD, previously suggested using 7T scanners, is now extended to clinical 3T scanners, thereby making a step towards the use of CVS in clinical practice. Classification of evidence This study provides Class III evidence that the CVS on 3T MRI accurately distinguishes patients with MS from those with seropositive NMOSD.

Reversible splenial lesion and complex visual disturbances due to carbamazepine withdrawal.

Reversible, transient and often silent lesions involving the splenium of the corpus callosum (SCC) have been rarely reported in a variety of disorders, including infection, antiepileptic drugs use or withdrawal, metabolic disturbances, and other common demyelinating diseases [1]. Complex visual disturbances may be related to lesions involving the SCC since interhemispheric fibers linking the activated visual areas, pass through the SCC and integrate visual information as demonstrated by electrophysiological, neuroanatomical and functional magnetic resonance imaging findings [2, 3]. We report the case of a young patient showing a reversible, Gadolinium enhancing SCC lesion associated with visual disturbances after carbamazepine withdrawal. A 24-year-old girl was admitted to our hospital, complaining about acute balance loss and altered visual perception. She described a persistent perception of quadruple images on binocular vision. She had a history of episodic migraine without aura. One month before hospital admission, because of trigeminal neuralgia, she was treated with carbamazepine 400 mg/day, abruptly interrupted after 15 days. No other systemic diseases or family history of neurological diseases were reported. Neurological and ophthalmologic evaluations were normal except for reduced visual acuity (3/10 bilaterally). She had no cognitive deficit, nor psychiatric disturbances. Standard blood tests revealed no abnormalities. Antinuclear, antimicrosomal and antithyroglobulin antibodies were negative. Cerebrospinal fluid (CSF) showed normal cell count and protein content, as well as no IgG intrathecal synthesis. Serum and CSF test for Treponema pallidum and Lyme, PCR tests for virus and anti-AQP4 antibodies were negative. Brain MRI scans showed a single T2-hyperintense, gadolinium enhancing lesion of the splenium of the corpus callosum (Fig. 1a, b). No spinal cord MRI lesions were found. Visual, brainstem auditory and somatosensory evoked potentials were normal and no abnormalities were demonstrated by computerized visual field. After 5 gr intravenous methylprednisolone therapy visual acuity improved (8/10) bilaterally and ‘‘quadruple vision’’ resolved. One month follow-up MRI showed a quite complete remission of the SCC lesion (Fig. 2a, b). MRI was completely normal after 6 months. Clinical and MRI evaluation after 2 years showed no abnormalities. The possibility of symptomatic, reversible SCC lesions due to reversible demyelination or cytotoxic edema following sudden withdrawal of carbamazepine assumption must be taken into account in clinical practice. The transient impairment of visual acuity in spite of normal visual evoked potentials and computerized visual field suggests impairment related to patient compliance and binocular dysfunction more than to abnormalities of the visual pathways [4]. Visual acuity improvement after the resolution of the ‘‘quadruple vision’’ confirms such hypothesis R. Cortese G. Pontrelli M. P. Mogavero F. Dicuonzo C. Tortorella (&) Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari, Piazza G. Cesare, 11, 70124 Bari, Italy e-mail: carla.tortorella@gmail.com

A rare association between multiple sclerosis and Charcot-Marie-Tooth type 1B.

The association between multiple sclerosis (MS) and hereditary and sporadic demyelinating disorders of the peripheral nervous system is extremely rare. We herein report a case of Charcot‐Marie‐Tooth disease type 1B with p.Val102fs mutation in the MPZ gene that developed relapsing remitting MS.