Daniele Lo Coco

Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients.

BACKGROUND Despite complaints of poor sleep being very common in people with chronic obstructive pulmonary disease (COPD), restless legs syndrome (RLS) symptoms have not been extensively investigated in these patients. OBJECTIVE To assess the prevalence and severity of RLS in patients with COPD and to investigate the factors potentially associated with RLS. METHODS A total of 87 patients with COPD and 110 controls, matched for age and sex, were evaluated regarding the presence and severity of RLS symptoms. A diagnosis of RLS was made according to the criteria of the International RLS Study Group (IRSLSSG), and severity was assessed by the IRLSSG severity scale. Excessive daytime somnolence was assessed using the Epworth sleepiness scale (ESS). RESULTS RLS was significantly more frequent in COPD patients than in controls (36.8% vs. 11%; p < 0.001). Compared to controls, COPD patients with RLS showed higher disease severity (mean IRLSSG severity scale score: 20.5 +/- 2.8 for COPD, and 18 +/- 3.5 for controls; p = 0.016) and more pronounced daytime somnolence (mean ESS score: 11.8 +/- 1.1 for COPD, and 8.6 +/- 3.6 for controls; p = 0.009). Moreover, compared to those without RLS, COPD patients with RLS showed increased daytime sleepiness (mean ESS score: 11.8 +/- 1.1 for COPD/RLS, and 7.3 +/- 4 for COPD/non-RLS; p < 0.001) and longer disease duration (11.9 +/- 7 years for COPD/RLS, and 8.7 +/- 6.9 years for COPD/non-RLS; p = 0.045). Multivariate analysis showed that ESS score was the only factor significantly associated with RLS in COPD patients. CONCLUSIONS RLS is a frequent cause of disabling sleep disturbance in patients with COPD and should be specifically investigated in these patients.

Distribution and cellular localization of high mobility group box protein 1 (HMGB1) in the spinal cord of a transgenic mouse model of ALS.

Although the aetiology of amyotrophic lateral sclerosis (ALS) is still elusive, increased attention has been put forward on events related to neuroinflammation and an active participation of glial cells in the ALS pathogenesis has been suggested. However, the specific role of many proinflammatory mediators that usually accompany the inflammatory changes is still largely unknown. High mobility group box protein 1 (HMGB1) is an ubiquitous nuclear protein that exerts numerous extranuclear and extracellular functions, including a proinflammatory activity, able to induce cytokines expression and activate inflammatory cells. To investigate whether this protein may play a role in the inflammatory events in ALS, we examined both expression and localization of HMGB1 in the lumbar spinal cord of SOD1G93A transgenic mice, a well established mouse model of familial ALS, at different stages of the disease. Intense HMGB1 reactivity was detected in ventral horn motor neurons of both non-transgenic and SOD1G93A mice and there was no difference in its expression between presymptomatic SOD1G93A mice and controls. With the progression of the disease, degenerating neurons showed a reduction of HMGB1 immunoreactivity which could reflect an extracellular release of this protein. By contrast, in the reactive glial cells HMGB1 was remarkably expressed in the nucleus, but not in the cytosol, likely contributing to the proliferation and/or hypertrophy of these cells. These results suggest that HMGB1 may have a different involvement in the motor neurons and glial cells in response to the neurotoxic environment in the spinal cord of SOD1G93A mice, and it may contribute to the progression of inflammatory and neurodegenerative processes.

Restless legs syndrome in patients with amyotrophic lateral sclerosis

We aimed to evaluate the frequency and determinants of restless legs syndrome (RLS) in a group of 76 patients with amyotrophic lateral sclerosis (ALS) and 100 control subjects. A diagnosis of RLS was made according to the criteria of the International RLS Study Group, and severity was assessed by the RLS severity scale. RLS was significantly more frequent in patients with ALS (ALS/RLS+) than in control subjects (25% vs. 8%; P = 0.002). Compared with control subjects, patients with ALS/RLS+ showed shorter history of RLS complaints and higher frequency of symptoms occurrence. Moreover, compared with those without RLS, patients with ALS/RLS+ showed increased functional impairment and more often reported sleep complaints. Multivariate logistic regression confirmed the association between RLS and functional impairment. Our findings suggest that RLS should be considered as a possible cause of disrupted sleep in patients with ALS and should be specifically investigated in these patients.

Cognitive impairment and stroke in elderly patients

We reviewed current knowledge about the interaction between stroke and vascular risk factors and the development of cognitive impairment and dementia. Stroke is increasingly recognized as an important cause of cognitive problems and has been implicated in the development of both Alzheimer’s disease and vascular dementia. The prevalence of cognitive impairment after stroke is high, and their combined effects significantly increase the cost of care and health resource utilization, with reflections on hospital readmissions and increased mortality rates. There is also substantial evidence that vascular risk factors (such as hypertension, diabetes, obesity, dyslipidemia, and tobacco smoking) are independently associated with an increased risk of cognitive decline and dementia. Thus, a successful management of these factors, as well as optimal acute stroke management, might have a great impact on the development of cognitive impairment. Notwithstanding, the pathological link between cognitive impairment, stroke, and vascular risk factors is complex and still partially unclear so that further studies are needed to better elucidate the boundaries of this relationship. Many specific pharmacological treatments, including anticholinergic drugs and antihypertensive medications, and nonpharmacological approaches, such as diet, cognitive rehabilitation, and physical activity, have been studied for patients with vascular cognitive impairment, but the optimal care is still far away. Meanwhile, according to the most recent knowledge, optimal stroke care should also include cognitive assessment in the short and long term, and great efforts should be oriented toward a multidisciplinary approach, including quality-of-life assessment and support of caregivers.

Restless legs syndrome in a patient with multifocal motor neuropathy

Restless legs syndrome (RLS) has been frequently reported in association with peripheral neuropathy, and it is especially frequent in some forms of polyneuropathy with preferential involvement of small sensory fibers. Here, we describe a patient with multifocal motor neuropathy, who developed RLS during the course of the disease. Our findings support the notion that RLS may develop in the context of immune-mediated neuropathies and it should be specifically investigated even in those patients with preferentially or exclusive motor involvement.

Exposure to ototoxic agents and hearing loss: A review of current knowledge

Abstract Several experimental and clinical studies have shown that a variety of ototoxic agents (such as drugs, industrial chemicals and noise) can cause sensorineural hearing loss. The most common ototoxic drugs used in clinical practice include: aminoglycoside and macrolide antibiotics, quinoline anti-malarials, platinum analog antineoplastics, loop diuretics, and acetylsalicylic acid. Among chemical agents with potential ototoxic properties are: organic solvents, heavy metals, organotins, nitriles, asphyxiants, and pesticides/herbicides. Acoustic exposure to high intensity and/or prolonged noise can also cause permanent threshold shifts in auditory perception. Ototoxic agents can influence auditory function by different mechanisms: ROS overload, inhibition of mitochondrial protein synthesis, DNA/RNA damage, activation of the apoptotic pathways, excessive calcium influx, increase of proinflammatory cytokines, interference with fluid and electrolyte balance of the endolymph, atrophy of the stria vascularis, changes in blood-labyrinth barrier and overstimulation of the stereocilia of the ear cells. Since noise exposure and many drugs or chemical compounds frequently share the same ototoxic mechanisms, this may explain why hearing loss can be potentiated by combined exposure to these agents. However, a great variability in the individual’s response to a given xenobiotic exists and depends on a complex interplay between endogenous and exogenous factors.

Amyotrophic Lateral Sclerosis, a Multisystem Pathology: Insights into the Role of TNFα

Amyotrophic lateral sclerosis (ALS) is considered a multifactorial, multisystem disease in which inflammation and the immune system play important roles in development and progression. The pleiotropic cytokine TNFα is one of the major players governing the inflammation in the central nervous system and peripheral districts such as the neuromuscular and immune system. Changes in TNFα levels are reported in blood, cerebrospinal fluid, and nerve tissues of ALS patients and animal models. However, whether they play a detrimental or protective role on the disease progression is still not clear. Our group and others have recently reported opposite involvements of TNFR1 and TNFR2 in motor neuron death. TNFR2 mediates TNFα toxic effects on these neurons presumably through the activation of MAP kinase-related pathways. On the other hand, TNFR2 regulates the function and proliferation of regulatory T cells (Treg) whose expression is inversely correlated with the disease progression rate in ALS patients. In addition, TNFα is considered a procachectic factor with a direct catabolic effect on skeletal muscles, causing wasting. We review and discuss the role of TNFα in ALS in the light of its multisystem nature.

Assessment and Management of Respiratory Dysfunction in Patients with Amyotrophic Lateral Sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a relatively rare neurodegenerative disorder that causes progressive dysfunction of voluntary muscle groups secondary to motor neurons death. The relentless involvement of all skeletal muscles of the body, characterized by weakness and atrophy to complete paralysis, invariably involves respiratory muscles (particularly the diaphragm) resulting in a failure to deliver adequate amounts of oxygen to, and remove carbon dioxide from blood. As a result, respiratory failure, frequently complicated by pneumonia related to respiratory muscle weakness and ineffective cough, is the most frequent cause of death in these patients (Lo Coco et al., 2008). Considering the natural history of ALS, only a few number of patients shows respiratory muscle dysfunction at the onset of the disease (Marti-Fabregas et al., 1995; De Carvalho et al., 1996), and the majority of patients maintains an almost normal pulmonary function for months or years. Patients thus need to be regularly and progressively evaluated to identify early signs of respiratory muscle weakness so that adequate treatment can be implemented. Indeed, in the last few years it has been repeatedly shown that non-invasive positivepressure ventilation (NIPPV), the treatment of choice for chronic hypoventilation and respiratory failure in ALS, allows a significant improvement in survival and quality of life (Heiman-Patterson & Miller, 2006). Many tests are available to objectively assess the performances of the respiratory system, and there is increasing interest toward those able to sensitively detect mild impairment. Moreover, great attention has to be put on monitoring of cough effectiveness, management of respiratory secretions and prevention of respiratory infections. For all these reasons the management of respiratory dysfunction has become a

Thoracic Syringomyelia in a Patient with Amyotrophic Lateral Sclerosis

We report a patient with bulba r - onset, clinically defined, sporadic amyotrophic lateral sclerosis bearing an isolated syringomyelia of the lower thoracic portion of the spinal cord. This is a very unusual association between two rare and progressive disorders, both affecting the spinal motoneurons. Syringomyelia might have acted as a phenotypic modifier in this ALS patient.

Stroke after tadalafil use

Tadalafil, a phosphodiesterase type 5 (PDE5) inhibitor, which augments cyclic guanine monophosphate in the central nervous system, has been shown to increase neurogenesis, angiogenesis, and synaptogenesis, and to improve functional outcomes compared with placebo in a rat model of ischemic stroke [1]. Sildenafil, another PDE5 inhibitor, also showed similar effects in preclinical studies of stroke models in the rat [1]. Although infrequently, sildenafil has been also associated with serious cardiovascular events such as ischemic stroke, intracerebral hemorrhage, and anterior ischemic optic neuropathy [2–6]. There is only one study reporting an association between tadalafil usage and stroke [7]. Here, we describe a patient who sustained a subcortical infarction after tadalafil use. A 52-year-old man was admitted to our institution because of right facial weakness, slurred speech, and right hemiparesis developed about 2 h after taking 10 mg of tadalafil without participating in sexual intercourse. Four months before the beginning of the present complaints, after he had ingested the first and only other dose of 10 mg of tadalafil, he experienced the same neurologic symptoms, again without achieving an erection or participating in sexual intercourse. In that occasion, however, his symptoms slowly returned to baseline over 1 h. On admission to our hospital, the neurologic examination showed that the patient was mildly dysarthric, had right lower facial weakness, 3/5 strength (Medical Research Council Scale) in his right upper extremity, and 4/5 strength in his right lower extremity. Sensory examination and coordination tests were normal. His medical history was normal, and he was taking no medications. He was a non-smoker and did not drink alcohol. His blood pressure and the cardiovascular examination were normal. Brain MRI performed the day after admission demonstrated an acute/subacute infarction of the posterior limb of the left internal capsule (Fig. 1). On magnetic resonance angiography there were no significant stenoses of extracranial or intracranial vessels. Cardiac evaluation including heart ultrasound was normal. Immunologic tests and screening for thrombophilias were also normal. A therapy with 300 mg of aspirin per day was started for 1 week, and was then reduced to 150 mg per day. After 1and 2-year follow-up, the patient showed good recovery. He did not take tadalafil or others PDE5 inhibitors and did not suffer more stroke episodes. Oral PDE5 inhibitors (sildenafil, vardenafil, tadalafil) are the recommended first-line therapy for erectile dysfunction [8]. All three PDE5 inhibitors share a common mechanism of action, preventing cyclic guanosine monophosphate (cGMP) breakdown. Sildenafil and vardenafil have similar molecular structures, but tadalafil is structurally different, which is reflected in its pharmacokinetic profile and its selectivity for PDE isozymes [8]. All three PDE5 inhibitors are rapidly absorbed from the gastrointestinal tract and peak plasma concentrations of tadalafil are reached after approximately 2 h. Sildenafil and E. Cannizzaro C. Cannizzaro Dipartimento Per La Promozione Della Salute ‘‘G. D’Alessandro’’, Università di Palermo, Palermo, Italy