Luca Sebastianelli

Effectiveness of a very early stepping verticalization protocol in severe acquired Brain injured Patients: A randomized pilot study in ICU

Background and Objective Verticalization was reported to improve the level of arousal and awareness in patients with severe acquired brain injury (ABI) and to be safe in ICU. We evaluated the effectiveness of a very early stepping verticalization protocol on their functional and neurological outcome. Methods Consecutive patients with Vegetative State or Minimally Conscious State were enrolled in ICU on the third day after an ABI. They were randomized to undergo conventional physiotherapy alone or associated to fifteen 30-minute sessions of verticalization, using a tilt table with robotic stepping device. Once stabilized, patients were transferred to our Neurorehabilitation unit for an individualized treatment. Outcome measures (Glasgow Coma Scale, Coma Recovery Scale revised -CRSr-, Disability Rating Scale–DRS- and Levels of Cognitive Functioning) were assessed on the third day from the injury (T0), at ICU discharge (T1) and at Rehab discharge (T2). Between- and within-group comparisons were performed by the Mann-Whitney U test and Wilcoxon signed-rank test, respectively. Results Of the 40 patients enrolled, 31 completed the study without adverse events (15 in the verticalization group and 16 in the conventional physiotherapy). Early verticalization started 12.4±7.3 (mean±SD) days after ABI. The length of stay in ICU was longer for the verticalization group (38.8 ± 15.7 vs 25.1 ± 11.2 days, p = 0.01), while the total length of stay (ICU+Neurorehabilitation) was not significantly different (153.2 ± 59.6 vs 134.0 ± 61.0 days, p = 0.41). All outcome measures significantly improved in both groups after the overall period (T2 vs T0, p<0.001 all), as well as after ICU stay (T1 vs T0, p<0.004 all) and after Neurorehabilitation (T2 vs T1, p<0.004 all). The improvement was significantly better in the experimental group for CRSr (T2-T0 p = 0.033, T1-T0 p = 0.006) and (borderline) for DRS (T2-T0 p = 0.040, T1-T0 p = 0.058). Conclusions A stepping verticalization protocol, started since the acute stages, improves the short-term and long-term functional and neurological outcome of ABI patients. Trial Registration clinicaltrials.gov NCT02828371

Impaired cholinergic transmission in patients with Parkinson's disease and olfactory dysfunction

Olfactory dysfunction represents a frequent and disturbing non-motor manifestation of Parkinsons disease (PD). The pathophysiology of olfactory dysfunction in PD is still poorly understood. Experimental evidence suggests that olfactory impairment could be related to central cholinergic dysfunction. Short latency afferent inhibition (SAI) technique gives the opportunity to test an inhibitory cholinergic circuit in the human cerebral motor cortex. The objective of the study was to assess the cholinergic function, as measured by SAI, in PD patients with different degrees of olfactory dysfunction. We applied SAI technique in 31 patients with PD. These patients also underwent Olfactory Event-Related Potentials (OERPs) studies to objectively evaluate the olfactory system and a battery of neuropsychological tests to assess the cognitive functions. Absent OERPs indicated a severe olfactory dysfunction in 13 subjects. The presence of OERPs with an alteration in latency and/or amplitude can be considered as a borderline condition of slight alteration of smell and was found in other 15 patients. Only 3 patients showed normal OERPs. SAI was significantly reduced in the PD patients with absent OERPs compared with those with present but abnormal OERPs. Neuropsychological examination showed a mild cognitive impairment in 12 out of 13 PD patients with severe olfactory dysfunction, and in 3 out of the 15 patients with borderline olfactory dysfunction. SAI abnormalities and presence of severe olfactory impairment strongly support the hypothesis of cholinergic dysfunction in some patients with PD, who will probably develop a dementia. Longitudinal studies are required to verify whether SAI abnormalities in PD patients with olfactory dysfunction can predict a future severe cognitive decline.

Tick-borne viral encephalomyeloradiculitis complicated by severe autonomic myenteric involvement resulting in irreversible adynamic ileus

Tick-borne encephalitis (TBE) virus infection of the central nervous system may manifest as meningitis, meningoencephalitis or meningoencephalomyelitis with or without multiple radicular involvement. Among patients with acute TBE, involvement of the autonomic nervous system has been infrequently reported, and manifests mostly with cardiovascular signs and symptoms, such as alterations in heart rate variability and orthostatic hypotension [1–3]. Here, we present the case of a patient with encephalomyeloradiculitis, in whom a severe and irreversible autonomic dysfunction of the gastrointestinal tract remained as the most disabling sequela. A 75-year-old man with arterial hypertension and diabetes mellitus (DM) type 2 under good control with diet and oral antidiabetic drugs, was hospitalized in midsummer 2016 because of rapidly progressive confusion, dizziness, repeated vomiting, and weakness of the lower extremities with gait disturbance. A tick bite four weeks earlier was reported. He was not vaccinated against TBE. Diabetic polyneuropathy had not been previously diagnosed. On admission, routine laboratory blood test revealed mild leukocytosis (11,000 cells/ll with a normal differential count), fasting hyperglycemia (153 mg/dl) and normal serum level of C-reactive protein (\0.5 mg/dl). The following day, the patient was lethargic and febrile (38.1 C). He presented moderate flaccid tetra-paresis that was accentuated in the lower limbs with significant limb and trunk ataxia. Deep tendon reflexes were absent. No cranial nerve signs were detected. Cerebrospinal fluid (CSF) examination showed mild lymphocytic pleocytosis (43 cells/ll of which 30 cells/ll were mononuclear) and elevated protein concentration (80 mg/dl). Specific serum IgM to TBE virus but not IgG antibodies were demonstrated using enzyme-linked immunosorbent assay. Presence of anti-TBE virus IgG in CSF could not be investigated because of technical laboratory reasons. On the same day, cerebral magnetic resonance imaging (MRI) with gadolinium contrast demonstrated small nonspecific gliosis lesions in the periventricular white matter bilaterally (Fig. 1). On day 11, the patient developed global respiratory insufficiency and mechanical ventilation was needed for three days. On day 20, MRI of the whole spine with gadolinium showed no signal alteration or pathologic contrast enhancement in spinal cord, roots or meninges. On day 22, electroneurography (ENG) and electromyography (EMG) examination showed findings consistent with axonal polyradiculoneuropathy. Raffaele Nardone and Christian J. Wiedermann are equally contributing senior authors.

Low-frequency rTMS of the unaffected hemisphere in stroke patients: A systematic review

The aim of this review was to summarize the evidence for the effectiveness of low‐frequency (LF) repetitive transcranial magnetic stimulation (rTMS) over the unaffected hemisphere in promoting functional recovery after stroke. We performed a systematic search of the studies using LF‐rTMS over the contralesional hemisphere in stroke patients and reviewed the 67 identified articles. The studies have been gathered together according to the time interval that had elapsed between the stroke onset and the beginning of the rTMS treatment. Inhibitory rTMS of the contralesional hemisphere can induce beneficial effects on stroke patients with motor impairment, spasticity, aphasia, hemispatial neglect and dysphagia, but the therapeutic clinical significance is unclear. We observed considerable heterogeneity across studies in the stimulation protocols. The use of different patient populations, regardless of lesion site and stroke aetiology, different stimulation parameters and outcome measures means that the studies are not readily comparable, and estimating real effectiveness or reproducibility is very difficult. It seems that careful experimental design is needed and it should consider patient selection aspects, rTMS parameters and clinical assessment tools. Consecutive sessions of rTMS, as well as the combination with conventional rehabilitation therapy, may increase the magnitude and duration of the beneficial effects. In an increasing number of studies, the patients have been enrolled early after stroke. The prolonged follow‐up in these patients suggests that the effects of contralesional LF‐rTMS can be long‐lasting. However, physiological evidence indicating increased synaptic plasticity, and thus, a more favourable outcome, in the early enrolled patients, is still lacking. Carefully designed clinical trials designed are required to address this question. LF rTMS over unaffected hemisphere may have therapeutic utility, but the evidence is still preliminary and the findings need to be confirmed in further randomized controlled trials.

Transcranial magnetic stimulation studies in complex regional pain syndrome type I: A review

The sensory and motor cortical representation corresponding to the affected limb is altered in patients with complex regional pain syndrome (CRPS). Transcranial magnetic stimulation (TMS) represents a useful non‐invasive approach for studying cortical physiology. If delivered repetitively, TMS can also modulate cortical excitability and induce long‐lasting neuroplastic changes. In this review, we performed a systematic search of all studies using TMS to explore cortical excitability/plasticity and repetitive TMS (rTMS) for the treatment of CRPS. Literature searches were conducted using PubMed and EMBASE. We identified 8 articles matching the inclusion criteria. One hundred fourteen patients (76 females and 38 males) were included in these studies. Most of them have applied TMS in order to physiologically characterize CRPS type I. Changes in motor cortex excitability and brain mapping have been reported in CRPS‐I patients. Sensory and motor hyperexcitability are in the most studies bilateral and likely involve corresponding regions within the central nervous system rather than the entire hemisphere. Conversely, sensorimotor integration and plasticity were found to be normal in CRPS‐I. TMS examinations also revealed that the nature of motor dysfunction in CRPS‐I patients differs from that observed in patients with functional movement disorders, limb immobilization, or idiopathic dystonia. TMS studies may thus lead to the implementation of correct rehabilitation strategies in CRPS‐I patients. Two studies have begun to therapeutically use rTMS. This non‐invasive brain stimulation technique could have therapeutic utility in CRPS, but further well‐designed studies are needed to corroborate initial findings.

Passive cycling in neurorehabilitation after spinal cord injury: A review

Context/Objective: Passive cycling (PC) may represent a potential alternative neurorehabilitation program for patients who are too weak or medically unstable to repeatedly practice active movements. We review here the most important animal and human studies addressing PC after spinal cord injury (SCI). Methods: A MEDLINE search was performed using following terms: “passive”, “cycling”, “pedaling”, “pedalling”,“spinal cord injury”. Results: Experimental studies revealed that PC modulated spinal reflex and reduced spasticity. PC also reduced autonomic dysreflexia and elicited cardio-protective effects. Increased levels of mRNA for brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor and neurotrophin-4 were found. In contrast, human studies failed to show an effect of PC on spasticity reduction and did not support its application for prevention of cardiovascular disease-related secondary complications. Conclusion: Available evidence to support the use of PC as standard treatment in patients with SCI is still rather limited. Since it is conceivable that PC motion could elicit sensory inputs to activate cortical structures and induce cortical plasticity changes leading to improved lower limb motor performance, further carefully designed prospective studies in subjects with SCI are needed.

Cortical afferent inhibition abnormalities reveal cholinergic dysfunction in Parkinson’s disease: a reappraisal

Parkinson’s disease (PD) is a multisystem neurodegenerative disorder affecting, besides the dopaminergic function, multiple neurotransmission systems, including the cholinergic system. Central cholinergic circuits of human brain can be tested non-invasively by coupling peripheral nerve stimulation with transcranial magnetic stimulation (TMS) of motor cortex; this test is named short latency afferent inhibition (SAI). SAI abnormalities have been reported in PD patients with gait disturbances and many non-motor symptoms, such as visual hallucinations (VHs), REM sleep behavior disorder (RBD), dysphagia, and olfactory impairment. The findings of these TMS studies strongly suggest that cholinergic degeneration is an important contributor to a number of clinical features of PD. TMS and neuropsychological raise the possibility that the presence of RBD, VHs and olfactory dysfunction indicate increased risk of cognitive impairment in patients with PD. Longitudinal studies of the patients are required to verify whether SAI abnormalities can predict a future severe cognitive decline. TMS can provide simple measures that may represent suitable biomarkers of cholinergic neurotransmission in PD. SAI studies enable an early recognition of PD patients with cholinergic system degeneration, and this might allow future targeted cholinergic treatment approaches, in addition to dopaminergic therapy, to ameliorate non-motor and motor clinical symptoms in PD patients.

Cortical morphometric changes after spinal cord injury

Neuroimaging studies suggest that spinal cord injury (SCI) may lead to significant anatomical alterations in the human sensorimotor system. In particular, voxel-based morphometry (VBM) of cortical volume has revealed a significant gray and white matter atrophy bilaterally in the primary sensory cortex (S1). By contrast, some structural studies failed to detect changes in gray matter volume (GMV) in the primary motor cortex (M1) following SCI, whereas others have reported a substantial decrease of GMV also in M1. In addition to direct degeneration of the sensorimotor cortex, SCI can also lead to atrophy of the non-sensorimotor cortex, such as anterior cingulate cortex, insular cortex, middle frontal gyrus and supplementary motor area. These findings suggest that SCI can cause remote atrophy of brain gray matter in the salient network. Furthermore, pain-related remodelling may occur in SCI. In fact, structural changes in SCI are also related to the presence and degree of below-level pain. We performed a systematic review of the neuroimaging studies showing morphometric cortical changes and subsequent functional reorganization in humans with SCI. Literature search was conducted using PubMed and Embase. We identified 12 articles matching the inclusion criteria and 195 patients were included in these studies. The wide range of disease duration, rehabilitation training, drug intervention, and different research methodology, especially the identification of region of interest and the statistical approach to correct for multiple comparisons, may have contributed to some inconsistencies between the reviewed studies. Nevertheless, neuroimaging biomarkers can assess the extent of neural damage, elucidate the mechanisms of neural repair, and predict clinical outcome. A better understanding of the structural and functional changes that occur at cortical level following SCI may be useful in tracking potential treatment induced changes and identifying potential therapeutic targets, thus developing evidence-based rehabilitation therapies.

Repetitive Transcranial Magnetic Stimulation (rTMS) for the Improvement of Upper Limb Function in Stroke Patients

Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique able to influence cortical excitability. In stroke patients, both excitatory and inhibitory protocols have been used to favour functional recovery of the upper limb function. In more than 30 clinical trials, inhibitory rTMS of the unaffected (contralesional) primary motor cortex (M1) has been shown effective to improve function of the affected hand in mild stroke patients. Excitatory rTMS of the affected (ipsilesional) M1 has been less investigated. Nonetheless, its safety and the possible clinical efficacy is supported by several data. However, there is considerable heterogeneity across studies in the stimulation protocols, patient populations, lesion site, outcome measures, stroke aetiology and duration. That means that the studies are not readily comparable, the reproducibility of the results can be limited, and an analysis of the real clinical significance is very difficult. For these reasons, the need for a multicentre clinical trial is advocated by many authors.

Abnormal cortical neuroplasticity induced by paired associative stimulation after traumatic spinal cord injury: A preliminary study

We aimed at assessing in this pilot study whether patients with spinal cord injury (SCI) show alterations of sensorimotor plasticity within the primary motor cortex (M1). Since learning in human M1 occurs through LTP-like mechanisms, we employed the paired associative stimulation (PAS) protocol by transcranial magnetic stimulation (TMS), which is able to induce LTP-like effects in M1, in subjects with chronic SCI. We found that PAS protocol significantly increased corticospinal excitability as long as 30min in healthy subjects and in SCI patients with good motor recovery, while it was followed by a non-significant increase of MEP amplitude in the SCI patients with poor functional recovery. These findings suggest that the level of LTP-like phenomena is correlated with long term recovery and support the correlation between the ability of inducing excitability changes using TMS and the process of motor recovery. Increased cortical plasticity might imply greater capability for neuromodulation.