Giovanni Piccirillo

Widespread Microstructural White Matter Involvement in Amyotrophic Lateral Sclerosis: A Whole-Brain DTI Study

BACKGROUND AND PURPOSE: The extensive application of advanced MR imaging techniques to the study of ALS has undoubtedly improved our knowledge of disease pathophysiology, even if the actual spread of the neurodegenerative process throughout the central nervous system is not fully understood. The present study aimed to detect WM patterns of microstructural abnormalities to better investigate the pathologic process in ALS, within but also beyond CSTs, in a whole-brain analysis. MATERIALS AND METHODS: DTI was performed in 19 patients with ALS and 20 matched healthy controls, by using whole-brain TBSS and VOI analyses. RESULTS: We observed a significant decrease of FA in the body of CC of the ALS group (P < .05). At the VOI level, both FA decrease and RD increase in the body of CC significantly correlated with the UMN score (P = .003 and P = .02). Additionally, significant voxelwise positive correlations between FA and the ALSFRS-R were detected in the WM tracts underneath the left premotor cortex (P < .05). CONCLUSIONS: The correlations between reduction of FA and increase of RD in the body of CC with the UMN score indicate that the WM degeneration in the CC is strictly related to the ALS pyramidal impairment, while the correlation between FA and ALSFRS-R in the associative tracts underneath the left premotor cortex might reflect the progressive spread of the disease from the motor toward the extramotor areas.

Functional overlap and divergence between ALS and bvFTD.

Amyotrophic lateral sclerosis (ALS) and behavioral variant frontotemporal dementia (bvFTD) lie on a clinical, pathologic, and genetic continuum. Neuroimaging techniques have proven to be potentially useful to unravel the shared features of these syndromes. Using resting-state functional magnetic resonance imaging (RS-fMRI), we investigated functional connectivity of brain networks in 15 ALS and 15 bvFTD patients in early stages of disease and 15 healthy controls, looking expressly for connectivity pattern divergence or overlap between the 2 disorders. Compared with controls, we found decreased RS-fMRI signals within sensorimotor, right frontoparietal, salience, and executive networks in both patient groups. Within the default mode network (DMN), divergent connectivity patterns were observed, with RS-fMRI signals in the posterior cingulate cortex enhanced in bvFTD patients and suppressed in ALS patients. Our findings confirm that ALS and bvFTD not only broadly share common RS-fMRI connectivity patterns, probably representing different phenotypical expressions of the same neurodegenerative process, but also differ in the DMN, probably reflecting a different stage of neurodegeneration.

Motor and extramotor neurodegeneration in amyotrophic lateral sclerosis: A 3T high angular resolution diffusion imaging (HARDI) study

Abstract In amyotrophic lateral sclerosis (ALS), diffusion weighted magnetic resonance imaging (DW-MRI) has produced mounting evidence of a widespread white matter (WM) damage within motor and extramotor pathways. To provide novel information about the degenerative process in ALS, overcoming some of the limitations imposed by diffusion tensor imaging (DTI), we performed a high angular resolution diffusion imaging (HARDI) analysis of DW-MRI data. Generalized fractional anisotropy (GFA) was evaluated in 19 patients with ALS and 19 matched control subjects, and was correlated with clinical scores of disability, pyramidal impairment by upper motor neuron (UMN) score and frontal dysfunction by the Frontal Systems Behaviour (FrSBe) scale. Results demonstrated that ALS patients showed a significant decrease of GFA in the WM tracts underneath the left and right precentral gyri and the body of the corpus callosum (p < 0.05, corrected), where GFA was significantly related to UMN scores (p < 0.001, uncorrected); and in the left superior longitudinal fasciculus (p < 0.05, corrected), where GFA was significantly related to FrSBe scale scores (p < 0.01, uncorrected). In conclusion, this study revealed a pattern of motor and extramotor frontal diffusivity abnormalities (probably related to behavioural and cognitive dysfunctions) showing a spatial distribution similar to what was previously described in ALS − frontotemporal dementia continuum.

Microstructural changes across different clinical milestones of disease in amyotrophic lateral sclerosis.

Neurodegenerative process in amyotrophic lateral sclerosis (ALS) has been proven to involve several cortical and subcortical brain regions within and beyond motor areas. However, how ALS pathology spreads progressively during disease evolution is still unknown. In this cross-sectional study we investigated 54 ALS patients, divided into 3 subsets according to the clinical stage, and 18 age and sex-matched healthy controls, by using tract-based spatial statistics (TBSS) diffusion tensor imaging (DTI) and voxel-based morphometry (VBM) analyses. We aimed to identify white (WM) and gray matter (GM) patterns of disease distinctive of each clinical stage, corresponding to specific clinical milestones. ALS cases in stage 2A (i.e., at diagnosis) were characterized by GM and WM impairment of left motor and premotor cortices and brainstem at ponto-mesenchephalic junction. ALS patients in clinical stage 2B (with impairment of two functional regions) exhibited decreased fractional anisotropy (FA) (p<0.001, uncorrected) and increased mean (MD) and radial diffusivity (RD) (p<0.001, uncorrected) in the left cerebellar hemisphere and brainstem precerebellar nuclei, as well as in motor areas, while GM atrophy (p<0.001, uncorrected) was detected only in the left inferior frontal gyrus and right cuneus. Finally, ALS patients in stage 3 (with impairment of three functional regions) exhibited decreased FA and increased MD and RD (p<0.05, corrected) within WM underneath bilateral pre and postcentral gyri, corpus callosum midbody, long associative tracts and midbrain, while no significant clusters of GM atrophy were observed. Our findings reinforce the hypothesis that the neurodegenerative process propagates along the axonal pathways and develops beyond motor areas from early stages, involving progressively several frontotemporal regions and their afferents and efferents, while the detection of GM atrophy in earlier stages and its disappearance in later stages may be the result of reactive gliosis.

Amyotrophic lateral sclerosis and multiple sclerosis overlap: a case report.

The concurrence of amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS) is extremely rare. We reported the case of a 33-year-old woman with a past history of paresthesias at the right hand, who developed progressive quadriparesis with muscular atrophy of limbs and, finally, bulbar signs and dyspnea. Clinical and neurophysiologic investigations revealed upper and lower motor neuron signs in the bulbar region and extremities, suggesting the diagnosis of ALS. Moreover, magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) analysis demonstrated 3 periventricular and juxtacortical lesions, hyperintense in T2 and FLAIR sequences, and 3 liquoral immunoglobulin G (IgG) oligoclonal bands, consistent with diagnosis of primary progressive MS (PPMS). This unusual overlap of ALS and MS leads to the discussion of a hypothetical common pathological process of immunological dysfunction in these two disorders, although the role of immune response in ALS remains ambivalent and unclear.

Clinical features and lifestyle of patients with amyotrophic lateral sclerosis in Campania: brief overview of an Italian database

BACKGROUND Physical activity and occupational exposures appeared to play a relevant role in pathogenesis of amyotrophic lateral sclerosis (ALS), a neurodegenerative disease of unknown origin. MATERIALS AND METHODS We aimed to make an overview of the clinical characteristics and lifestyle (occupation and sport) of a population of 395 patients with ALS from Campania, in southern Italy. RESULTS ALS onset resulted anticipated of about 11 years in industry workers, whilst the more frequent site of onset among farmers was upper limbs. Compared to non-athletes, athletes, particularly soccer players, showed a 7 years anticipation of ALS onset, with higher mortality after 5 years. DISCUSSION AND CONCLUSIONS We suggest that subjects genetically prone to abnormal response to hypoxia during strenuous physical activity or exposed to neurotoxic agents, such as athletes, farmers or industry workers, might present increased risk to develop ALS. Future case-control and follow-up studies on our population should be implemented to deepen the present results.

Neuropsychological assessment in different King's clinical stages of amyotrophic lateral sclerosis

Abstract Emerging evidence shows that cognitive deficits associated with frontal lobe dysfunction occur from early stages of amyotrophic lateral sclerosis (ALS). We aimed to assess neuropsychological functioning at different stages of ALS to further delineate the occurrence of cognitive impairment alongside the trajectory of ALS as defined by standard assessment procedures. We investigated several cognitive domains in 74 ALS patients classified into four different clinical stages of disease, according to a recently validated staging system for ALS (known as ‘Kings’ system), and evaluated and compared the corresponding cognitive profiles. We found that data derived from global cognitive assessment and several executive (i.e. Frontal Assessment Battery and Trail Making Test B-A) and long-term memory (i.e. memory prose) tests were significantly different among the subsets of ALS patients, showing poorer performances with increasing clinical disability. In conclusion, our preliminary results support the notion that mainly frontotemporal abilities may be impaired during the ALS course and suggest that neuropsychological information could supplement the current clinical staging of patients. However, ALS-specific multi-domain screening instruments, which allow to correct neuropsychological scores for physical disability, should be validated in larger populations worldwide and routinely introduced in clinical practice.

Intravenous Immunoglobulins Efficacy in a Case of ALS with Myasthenic Symptoms

Myasthenia Gravis (MG) is a neuromuscular junction disease, for which the most specific test is an increase in anti-acetylcholine receptor antibodies (anti-ACHR-Abs) titer. Myasthenic symptoms are rarely detected in patients with Amyotrophic Lateral Sclerosis (ALS). We report the case of a patient with sporadic ALS who presented at onset clinical and instrumental features suggestive of a disorder of the neuromuscular junction. She was treated with intravenous immunoglobulins for two years, with sensitive improvement in strength and delay of disease progression. The efficacy of such immunomodulating treatment in our unusual case leads to rethink the role of immune response in ALS.

Isolated unilateral ptosis due to neurovascular conflict

Isolated ptosis due to partial oculomotor nerve palsy (ONP) is unusual with only few cases reported in the literature to date. In case of unilateral ptosis, systemic diseases, such as myasthenia gravis or other autoimmune diseases, are mainly screened, although other conditions to be considered are vascular lesions and, in particular, neurovascular conflicts. In this letter, we point out the relevance of early recognition of clinical and neuroradiological signs of this rare condition. A 50-year-old woman came to our attention exhibiting a right eye ptosis increasingly developed in recent years (Fig. 1), without reporting diplopia or fluctuating weakness of the ocular or limb muscles throughout the day. She denied head trauma. Upon neurologic examination, she had right ptosis with an intact lower lid. Eye movements were spared and pupils were equal. The remaining motor, sensory, and coordination testing was normal. Routine laboratory exams were unremarkable. In particular, acetylcholine receptor antibody test and anti-musclespecific kinase antibodies levels were normal. Repetitive nerve stimulation test at 3 Hz on the trapezius and orbicularis oculi muscles and single-fiber electromyography examination on the orbicularis oculi muscles did not suggest a neuromuscular junction disorder. Neurophysiological study included nerve conduction studies at four limbs to exclude any unusual form of chronic inflammatory demyelinating polyneuropathy [1]. Furthermore, in order to explore potential compressive etiologies of the observed partial ONP, we performed a brain magnetic resonance imaging with angiography (magnetic resonance angiography, MRA) of intracranial vessels. Specifically, the coronal reconstruction of three-dimensional constructive interference in steady-state (3D-CISS) MR sequences showed that the cisternal segment of the right ON was slightly pressed downwardly by the right posterior cerebral artery (PCA) and laterally by the posterior communicating artery (PCoA) (Figs. 2, 3). Thus, we argued that in this case the isolated partial ONP could be attributable to the anomalous course of the contiguous vessels causing both mechanical compression and probably nerve ischemia. Notably, although the most common cause of a partial third nerve palsy is microvascular, frequently associated with diabetes mellitus, hypertension and dyslipidemia [2], potential vascular conflicts should be investigated appropriately. This is especially when ON compression may be hypothesized at the interpeduncular cistern level, where ON is directly adjacent to PCA superiorly and superior cerebellar artery (SCA) inferiorly [3]. Notably the presence of any head injuries must be considered in the diagnostic workup of isolated unilateral third nerve palsy given the reported incidence of between 0 and 15 % [4]. To our knowledge few cases of isolated ONP due to anatomical variants of posterior intracranial circulation have been described [3, 4]. Compressive lesions, including PCoA aneurysm, more classically may involve the pupillary fibres, which are more vulnerable to compression because of their location at the periphery of the third nerve [2]. However, pupil sparing as in this case is not a reliable & Giovanni Piccirillo dr.gpiccirillo@gmail.com