Could pure agraphia be the only sign of stroke? Lessons from two case reports.

Agraphia is defined as the disruption of the previously intact writing skills due to an acquired brain damage. Stroke remains the most common cause of language impairment; however, writing disorders, including agraphia, are underestimated in patients with stroke. In this regard, we report two patients presenting with pure agraphia as an early symptom of stroke. Both patients complained of at least two difficulties in visualizing letter formation beforehand, the frequent need for verbal cues, misuse of lines and margins, poorly legible signature, and writing and thinking at the same time (e.g., creative thinking and taking notes). They underwent brain magnetic resonance imaging which revealed a small lacunar infarction of the left insula and external capsule (patient 1) and a small hemorrhagic lesion in the posterior limb of the left internal capsule (patient 2). To our knowledge, this is the first report on pure agraphia as the presenting symptom of stroke. We suggest that all patients with acute agraphia, even when presenting as an isolated symptom, should be evaluated for stroke, in order to better facilitate its diagnosis and treatment.

ERIGO: a possible strategy to treat orthostatic hypotension in progressive supranuclear palsy? A feasibility study.

Progressive supranuclear palsy (PSP) is a neurodegenerative disease of the central nervous system, presenting with different clinical phenotypes, all involving the extrapyramidal system. Orthostatic hypotension (OH) is a common symptom of cardiovascular autonomic dysfunction. OH is defined as a fall in systolic blood pressure of at least 20 mmHg and/or a fall in diastolic blood pressure of at least 10 mmHg on standing or head-up tilt. In this pilot study, we tested the feasibility and efficacy of the ERIGO® device in managing OH non-responsive to conventional treatments in a sample of patients with PSP. OH was chosen as the primary outcome, as the symptom is a serious complication in neurodegenerative disorders, challenging the rehabilitation treatment. Six patients received intensive training using ERIGO®, a robot- assisted tilt table with an integrated leg movement system that allows progressive verticalization of the patient, and application of functional electrical stimulation. In all the participants, OH improved after the training with the device, suggesting that robotic verticalization may be a feasible and effective tool in improving blood pressure stability in patients with PSP. Further studies in larger samples, also including patients with other neurodegenerative disorders associated with OH, are needed to confirm these promising results.

Augmentative and alternative communication improves quality of life in the early stages of amyotrophic lateral sclerosis.

This study aimed to evaluate the efficacy of low-tech augmentative and alternative communication (AAC) aids in improving quality of life (QoL) and mood disorders, as well as the psychosocial impact of assistive devices, in 10 patients affected by amyotrophic lateral sclerosis (ALS) in the early stage of the disease, when speech difficulties appear. The AACtraining (AAC-T) study lasted around six months and comprised two phases of three months each: AAC-intervention (AAC-I) followed by AAC-familiarization (AAC-F). All the patients were assessed at the beginning (T0) and at the end (T1) of AAC-I, as well as at the end of AAC-F (T2). During the AAC-I phase, we applied a three-phase AAC intervention model to evaluate intelligibility of language, participation patterns, communication needs and adaptation to the AAC tools. All the patients showed a gradual and significant improvement, especially in acceptance of the AAC aids, mood and QoL. Moreover, a reduction of caregiver burden was noted. Our study has demonstrated the utility of the AAC aids also in the early stages of the disease in patients with ALS presenting with dysarthria. In our opinion, AAC-T may act as a bridge between the initial and later phases of the disease, when patients need to use high-tech aids, including an eye-tracking communication device. In conclusion, in this study we highlighted how early AAC-T in patients with ALS may be a valuable tool to demonstrate how specific strategies and low-technology aids can improve QoL of these patients and their caregivers, also decreasing stress and depression.

Multiple sclerosis and non-dystrophic myotonias: do they share a common pathophysiology?

Some patients with multiple sclerosis (MS) complain of symptoms, such as myokymia, myotonia, spasms, and stiffness, which have been demonstrated to be due to a concurrent non-dystrophic myotonia, i.e. myotonia congenita or paramyotonia congenita. Beyond the known casual association between MS and non-dystrophic myotonia, a channelopathy representing a primary trait of MS rather than an epiphenomenon of demyelization (i.e., an acquired channelopathy) may exist. Indeed, the finding of MS patients with no genetic evidence of non-dystrophic myotonia but showing a clinical picture resembling this condition would support this hypothesis. Thirty patients with MS and no concurrent diagnosis of myotonia congenita or paramyotonia congenita were submitted to the Fournier protocol. Some of these MS patients presented abnormal muscle excitability with scarce myotonic discharges, but only a few of them had clinical features compatible with myotonia congenita or paramyotonia congenita syndromes. Even though the low number of recruited patients did not allow a robust statistical analysis, our data seemed to indicate the presence of an ion channel dysfunction that is independent of the acquired channelopathies and likely represents a common pathophysiological mechanism underlying a unique channelopathy simultaneously involving the peripheral and the central nervous system in individuals with MS. Confirming the presence of such a primary channelopathy in MS patients is of non-negligible importance, since dysfunction of ion channels may represent a suitable therapeutic target in MS.

Neural correlates of fatigue in multiple sclerosis: a combined neurophysiological and neuroimaging approach (R1).

The present study is aimed at further exploring structural and functional correlates of fatigue in Relapsing- Remitting Multiple Sclerosis (RRMS) patients by using a combined approach by means of transcranial magnetic stimulation (TMS) and a Diffusion Tensor Imaging (DTI). The physiopathology of fatigue in MS is still poorly understood, although a variety of pathogenic mechanisms has been proposed. Our working hypothesis is that diffuse microstructural white matter damage may subtend the cortico-subcortical functional disconnection described in patients with MS and fatigue. We enrolled 30 RRMS patients (mean age 39±13; age range 24-63 years) with mild neurological impairment Expanded Disability Status Scale <3.5, divided into two groups on the basis of their fatigue severity scale (FSS) scoring (cutoff ≥ 4). All the patients underwent a neurological evaluation, a brain MRI acquisition (including DTI study) and a neurophysiological assessment by means of TMS in a pre-movement facilitation paradigm. Our data showed a significant mean diffusivity (MD) increase (p=0.036) in left thalamo-frontal reconstructions in the MS patients with fatigue compared to those classified as non-fatigued. Moreover, significant correlations were observed between FSS scale and MD as well as planar coefficient (CP) values extracted from frontal-thalamic connections bilaterally. Instead, the pre-movement facilitation showed a significant difference between the groups with particular regard to the Reaction Time- MEP50ms amplitude (p=0.03). Our work confirms that fatigue is associated with a disruption of brain networks involved in motor preparation processes, depending on several frontal-thalamic pathways. Such findings can have an important role when dealing with fatigue management in MS patients and could be eventually used as prognostic marker of MS course.

Should we care about sativex-induced neurobehavioral effects? A 6-month follow-up study.

OBJECTIVE: Sativex® is an exclusive cannabinoid-based drug approved for the treatment of spasticity due to Multiple Sclerosis (MS). The most common side effects include dizziness, nausea, and somnolence. However, it is still under debate whether the drug could cause negative cognitive effects. The aim of our study was to investigate the effect of Sativex® on functional and psychological status in cannabis-naïve MS patients. PATIENTS AND METHODS: All the study participants (i.e. 40 patients affected by MS) underwent a specific clinical and neuropsychological assessment to investigate spasticity and associated symptoms, besides the cognitive and psychiatric domains commonly impaired in MS, before and after 1 and 6 months of Sativex® administration. RESULTS: After the treatment, we did not observe any significant neurobehavioral impairment in all the patients, but one. CONCLUSIONS: Our findings suggest that Sativex® treatment does not significantly affect the cognitive and neurobehavioral functions. However, the study supports the relevance of an extensive neuropsychological evaluation in MS patients selected for the drug administration, in an attempt to early detect the uncommon but important neurobehavioral side effects.

Do unresponsive wakefulness syndrome patients feel pain? Role of laser-evoked potential-induced gamma-band oscillations in detecting cortical pain processing.

It has been proposed that a neural signature of aware pain perception could be represented by the modulation of gamma-band oscillation (GBO) power induced by nociceptive repetitive laser stimulation (RLS). The aim of our study was to correlate the RLS-induced GBO modulation with the Nociception Coma Scale-Revised (NCS-R) scores (a validated scale assessing possible aware pain perception in patients with chronic disorders of consciousness), in an attempt to differentiate unresponsive wakefulness syndrome (UWS) patients from minimally conscious state (MCS) ones (both of them are awake but exhibit no or limited and fluctuant behavioral signs of awareness and mentation, and low and high NCS-R scores, respectively). In addition, we attempted to identify those among UWS patients who probably experienced pain at covert level (i.e. being aware but unable to show pain-related purposeful behaviors, which are those sustained, reproducible, and voluntary behavioral responses to nociceptive stimuli). Notably, the possibility of clearly differentiating UWS from MCS patients has outmost consequences concerning prognosis (worse in UWS) and adequate pain treatment. RLS consisted in 80 trains of three laser stimuli (delivered at 1Hz), at four different energies, able to evoke Aδ-fiber related laser evoked potentials. After each train, we assessed the NCS-R score. EEG was divided into epochs according to the laser trains, and the obtained epochs were classified in four categories according to the NCS-R score magnitude. We quantified the GBO absolute power for each category. RLS protocol induced a strongly correlated increase in GBO power and NCS-R score (the higher the laser stimulation intensity, the higher the NCS-R, independently of stimulus repetition) in all the MCS patients, thus confirming the presence of aware pain processing. Nonetheless, such findings were present even in five UWS individuals. This could suggest the presence of covert pain processing in such subjects, despite the low NCS-R scores. In conclusion, RSL-induced GBO power evaluation could be helpful in the differential diagnosis between MCS and UWS patients, besides the clinical assessment, and in identifying covert pain perception in some UWS individuals.

Assessment of nociceptive system in vegetative and minimally conscious state by using laser evoked potentials.

PRIMARY OBJECTIVE: The aim of this study is to assess if laser evoked potentials (LEPs) examination should be considered as an objective evidence of potential or residual pain perception capacity in vegetative (VS) and minimally conscious state (MCS) patients and if it could be a feasible methodology in order to differentiate these two clinical entities. RESEARCH DESIGN: This is a cross-sectional observational study focusing on the role of LEP examination, which is an easy and objective neurophysiological approach of the nociceptive system. METHODS AND PROCEDURES: Thirteen VS and 10 MCS patients were enrolled. All subjects were evaluated clinically by using validated behavioural scales and underwent to upper and lower limbs LEP recording. MAIN OUTCOMES AND RESULTS: Intra-group LEPs analysis in VS patients highlighted significant differences for N2P2 latency (p = 0.036) and amplitude (p = 0.018). Inter-group LEPs analysis showed significant differences in post-anoxic condition for N2P2 latency (p = 0.034), amplitude (p = 0.034) and a trend in N2P2 latency in brain trauma (p = 0.07). Interestingly, correlation analysis showed a significant relationship between N2P2 amplitude and Coma Recovery Scale-Revised scoring in the post-traumatic VS (r = 0.823, p = 0.044). CONCLUSIONS: The findings lead to detection of potential markers of conscious pain perception in patients with DOC, with important impact on therapeutic and rehabilitative management, and provide new information that may allow a better differential diagnosis.

Obsessive-compulsive disorder: a "sensory-motor" problem?

Obsessive-compulsive disorder (OCD) is a clinically heterogeneous condition. Although its pathophysiology is not completely understood, neurophysiologic and neuroimaging data have disclosed functional abnormalities in the networks linking frontal cortex, supplementary motor and premotor areas, striatum, globus pallidus, and thalamus (CSPT circuits). By means of transcranial magnetic stimulation (TMS) it is possible to test inhibitory and excitatory circuits within motor cortex. Previous studies on OCD patients under medication have demonstrated altered cortical inhibitory circuits as tested by TMS. On the other hand there is growing evidence suggesting an alteration of sensory-motor integration. Therefore, the aim of the present study was to evaluate sensory-motor integration (SAI and LAI), intracortical inhibition, and facilitation in drug-naïve OCD patients, using TMS. In our sample, we have demonstrated a significant SAI reduction in OCD patients when compared to a cohort of healthy individuals. SAI abnormalities may be related to a dysfunction of CSPT circuits which are involved in sensory-motor integration processes. Thus, it can be speculated that hypofunctioning of such system might impair the ability of OCD patients to suppress internally triggered intrusive and repetitive movements and thoughts. In conclusion, our data suggest that OCD may be considered as a sensory motor disorder where a dysfunction of sensory-motor integration may play an important role in the release of motor compulsions.

Associative cortico-cortical plasticity may affect ipsilateral finger opposition movements.

We have recently demonstrated that cortico-cortical paired associative stimulation (cc-PAS) can modulate interhemispheric inhibition (IHI) in the human brain. Here we further explored the after effects of cc-PAS on fine hand movements. Ten healthy right-handed volunteers received 90 paired transcranial stimuli to the right and left primary motor hand area (M1(HAND)) at an interstimulus interval (ISI) of 8 ms. We studied the after effects of cc-PAS on the performance of repetitive finger opposition movements of different complexity on both hands using a sensor-engineered glove. A quantitative evaluation of the following parameters was performed: Touch Duration (TD), Inter Tapping Interval (ITI) and Number of Errors (NE). We confirmed previous data by showing that left-to-right and right-to-left cc-PAS attenuated IHI. The new finding is that both left-to-right and right-to-left cc-PAS were able to influence the performance of a simple finger opposition movement changing the duration of TD and ITI. Interestingly the effect on the two hands was opposite in direction. These results provide further insight that cc-PAS can induce associative plasticity in connections between the targeted cortical areas influencing motor hand performances. These results may be relevant for future rehabilitative applications.

Comparison of Celsior and University of Wisconsin solutions in cold preservation of liver from octogenarian donors.

BACKGROUND: Celsior (CS) has recently been proposed as a cold storage solution for thoracic and abdominal organs. We compared University of Wisconsin (UW) and CS solutions for the preservation of livers from old donors, with regard to initial function as well as short- and long-term graft and patient survival. METHODS: A multicenter retrospective study from 1998 to 2002 includes 30 livers from octogenarian donors preserved in CS (n = 15) or UW (n = 15) solution prior to transplantation. Donor and recipient clinical and laboratory parameters as well as liver biopsy results were evaluated in all cases. RESULTS: The distribution of the main donor variables as well as recipient characteristics were comparable between groups. Mean cold ischemia time was 421 minutes in the CS group and 474 minutes in the UW group. Mild steatosis was present in 8 cases in the CS group and 7 cases in the UW group. No primary graft dysfunction or arterial or biliary complications were noted. There was 1 acute rejection episode in the CS group and 4 in the UW group. Late postoperative deaths were observed only in the UW group (ie, 7 of 15). Actuarial graft survival was 100% in the CS group vs 86.7% in the UW group (P = NS) at 3 months, and 100% in the CS group vs 52.5% in the UW group (P =.007) at 12 months. Patient survival was 100% in the CS group vs 93.3% in the UW group (P = NS) at 3 months, and 100% in the CS group vs 59.3% in the UW group (P =.01) at 12 months. CONCLUSIONS: Both CS and UW solutions effectively protect livers obtained from donors >80 years of age during the early postoperative course but the CS group had better long-term results.

Kidney preservation with university of Wisconsin and Celsior solution: a prospective multicenter randomized study.

BACKGROUND: Although the University of Wisconsin (U.W.) solution continues to be the most commonly used for intra-abdominal organs, a new solution, Celsior, already used for heart and lungs, has been proposed for kidney and liver preservation. The aim of this research was to assess the effect of Celsior as compared with U.W. on immediate graft function and a 2-year follow-up of kidney transplants. METHODS: A prospective multicenter randomized study was designed to evaluate the efficacy of the Celsior solution in the clinical preservation of the kidney. In this report, we present the data collected as of September 2000. One hundred donors were included in the trial resulting in 187 renal transplants. Ninety-nine kidneys were stored in Celsior solution and 88 in U.W. solution. The groups were comparable with regard to donor and recipient characteristics. RESULTS: Delayed graft function occurred in 31.3% of the Celsior group and in 33.9% of the U.W. group (P=n.s.). Mean serum creatinine levels and mean daily urinary output were also comparable. Two year graft survival in kidneys preserved with Celsior was 84% as compared with 75% for U.W.-preserved kidneys without any significant statistical difference. CONCLUSIONS: Our data show that the preservation of kidneys in Celsior solution in a clinical setting is equivalent to that of U.W. solution. When using Celsior during multiple-organ donor harvesting it would be possible to perform an in situ flush of all intra-abdominal and intrathoracic organs with a single cold storage solution.