Cardiovascular diseases may play a negative role in the prognosis of amyotrophic lateral sclerosis.

BACKGROUND AND PURPOSE: Only a few studies have considered the role of comorbidities in the prognosis of amyotrophic lateral sclerosis (ALS) and have provided conflicting results. METHODS: Our multicentre, retrospective study included patients diagnosed from 1 January 2009 to 31 December 2013 in 13 referral centres for ALS located in 10 Italian regions. Neurologists at these centres collected a detailed phenotypic profile and follow-up data until death in an electronic database. Comorbidities at diagnosis were recorded by main categories and single medical diagnosis, with the aim of investigating their role in ALS prognosis. RESULTS: A total of 2354 incident cases were collected, with a median survival time from onset to death/tracheostomy of 43 months. According to univariate analysis, together with well-known clinical prognostic factors (age at onset, diagnostic delay, site of onset, phenotype, Revised El Escorial Criteria and body mass index at diagnosis), the presence of dementia, hypertension, heart disease, chronic obstructive pulmonary disease, haematological and psychiatric diseases was associated with worse survival. In multivariate analysis, age at onset, diagnostic delay, phenotypes, body mass index at diagnosis, Revised El Escorial Criteria, dementia, hypertension, heart diseases (atrial fibrillation and heart failure) and haematological diseases (disorders of thrombosis and haemostasis) were independent prognostic factors of survival in ALS. CONCLUSIONS: Our large, multicentre study demonstrated that, together with the known clinical factors that are known to be prognostic for ALS survival, hypertension and heart diseases (i.e. atrial fibrillation and heart failure) as well as haematological diseases are independently associated with a shorter survival. Our findings suggest some mechanisms that are possibly involved in disease progression, giving new interesting clues that may be of value for clinical practice and ALS comorbidity management.

Monocytes of patients with amyotrophic lateral sclerosis linked to gene mutations display altered TDP-43 subcellular distribution.

AIMS: Cytoplasmic accumulation of the nuclear protein transactive response DNA-binding protein 43 (TDP-43) is an early determinant of motor neuron degeneration in most amyotrophic lateral sclerosis (ALS) cases. We previously disclosed this accumulation in circulating lymphomonocytes (CLM) of ALS patients with mutant TARDBP, the TDP-43-coding gene, as well as of a healthy individual carrying the parental TARDBP mutation. Here, we investigate TDP-43 subcellular localization in CLM and in the constituent cells, lymphocytes and monocytes, of patients with various ALS-linked mutant genes. METHODS: TDP-43 subcellular localization was analysed with western immunoblotting and immunocytofluorescence in CLM of healthy controls (n = 10), patients with mutant TARDBP (n = 4, 1 homozygous), valosin-containing protein (VCP; n = 2), fused in sarcoma/translocated in liposarcoma (FUS; n = 2), Cu/Zn superoxide dismutase 1 (SOD1; n = 6), chromosome 9 open reading frame 72 (C9ORF72; n = 4), without mutations (n = 5) and neurologically unaffected subjects with mutant TARDBP (n = 2). RESULTS: TDP-43 cytoplasmic accumulation was found (P < 0.05 vs. controls) in CLM of patients with mutant TARDBP or VCP, but not FUS, in line with TDP-43 subcellular localization described for motor neurons of corresponding groups. Accumulation also characterized CLM of the healthy individuals with mutant TARDBP and of some patients with mutant SOD1 or C9ORF72. In 5 patients, belonging to categories described to carry TDP-43 mislocalization in motor neurons (3 C9ORF72, 1 TARDBP and 1 without mutations), TDP-43 cytoplasmic accumulation was not detected in CLM or in lymphocytes but was in monocytes. CONCLUSIONS: In ALS forms characterized by TDP-43 mislocalization in motor neurons, monocytes display this alteration, even when not manifest in CLM. Monocytes may be used to support diagnosis, as well as to identify subjects at risk, of ALS and to develop/monitor targeted treatments.

[Amyotrophic lateral sclerosis: an assessment of the needs of patients and caregivers in the Liguria region of Italy]. / Sclerosi laterale amiotrofica: rilevazione dei bisogni in un gruppo di pazienti e di caregiver dello regione Liguria.

UNLABELLED: Two surveys were carried out to assess ALS patients and caregivers' care and treatment needs in Liguria Region mainly during the first stage of the disease. One inquiry concerned patients during their first year of illness--the other concerned caregivers during different stages of the disease, excepting the terminal one. METHODS: A semistructured interview was given to 18 patients during first year from diagnosis. The Caregivers Needs Assessment questionnaire was administered to 27 caregivers during different phases of their parents' illness. RESULTS: The clinical interview emphasized that the patients need to be prepared for the future. In spite of strong (75%), or uncontrolled (50%) emotional aspects, in our group an active and fighting attitude (45%) prevailed. Caregivers' needs appeared to be generally high for the whole group, they mainly requested to be enabled to meet the appropriate assistance, to be informed on the cure and to cooperate and be involved in decision taking. Needs for spiritual, psychological or self-help and support group were apparently little required but during the first year emotional and social support are more desired. CONCLUSION: This survey shows that the psychological support for such patients must be planned for each of them and trimmed upon their single peculiarities after a careful evaluation and enhancement of their capability in facing difficulties. Caregivers barely asked for personal help or support--rather they asked to be enabled to tackle the practical aspects of the disease and for an improved cooperation share with doctors.

Motor evoked potentials following cervical electrical stimulation in brachial plexus lesions.

The diagnostic relevance of recording motor evoked potentials (MEPs) after electrical stimulation of the cervical region, as compared with conventional needle electromyography (EMG), was evaluated in 26 patients with brachial plexus (BP) damage of different aetiology, severity and topography. MEP abnormalities (absence or latency increase) were observed in at least one muscle of all the patients, with a global incidence of 61.5% of the muscles examined. Neurogenic EMG signs were present in all but one patient with an incidence of 62.2% of the muscles examined. Combining the two methods, the global incidence of abnormalities rose to 69.9%. MEP abnormalities were consistent with the clinical topography and severity of BP lesions and were fairly parallel with EMG findings. Recording MEPs after percutaneous electrical stimulation of the cervical region may be regarded as a rapid, non-invasive method for quantitative electrophysiological assessment of BP damage.

Ubiquitin-reactive neurites in cerebral cortex of subjects with Huntington's chorea: a pathological correlate of dementia?

We studied the prevalence of ubiquitin-reactive dystrophic neurites in neocortex of cases with Huntington's disease (HD), with a history of dementia lasting from 5 to 8 years before death, and in four age-matched controls. The ubiquitin-reactive neurites, identified as round structures localized outside neuronal and glial cells, were quantified in six microscopic fields of cingulate, 2nd temporal and 2nd parietal cortical gyri. The number of ubiquitin-reactive neurites in HD was 12 to 16 times that of controls in the three cortical areas examined. The finding indicates that in HD neocortex there is a severe degeneration of neuronal processes and suggests that it may represent a pathological correlate of dementia.

Amyloid beta protein deposition in brains from elderly subjects with leukoaraiosis.

We studied immunocytochemically with 2 amyloid beta protein (ABP) antisera brains from 5 non-demented elderly subjects with evidence of diffuse periventricular white matter hypodensity on computed tomography. In periventricular white matter of all brains we found ABP reactive deposits arranged around small vessels walls. Furthermore ABP reactive deposits, identical to those currently called diffuse plaques, were detected in neocortex in amount proportional to that of white matter deposits. We suggest that ABP microangiopathy and parenchymal deposition is responsible of white matter rarefaction in a subset of cases with a diffuse hypodensity on CT scan which has been called leukoaraiosis.

The integrity of the blood-brain barrier in Alzheimer's type and multi-infarct dementia evaluated by the study of albumin and IgG in serum and cerebrospinal fluid.

Albumin and IgG have been determined in the serum and cerebrospinal fluid (CSF) of 64 patients affected by Alzheimer's disease and senile dementia of Alzheimer type (SDAT/AD), 17 multi-infarct dementia (MID) patients and 52 controls. The concentrations of albumin and IgG in the serum and CSF have been taken into account to evaluate the integrity of the blood-brain barrier (BBB) and the occurrence of intrathecal immunological activation in demented patients. Clear-cut signs of BBB damage have been shown only in the group of patients affected by MID, whilst none of the two groups of patients displayed signs of immunological activation, expressed by an increase in IgG index, nor abnormally low CSF/serum ratios for IgG, previously suggested as expressive of a "consumption" of IgG by the brain parenchyma.

[Subarachnoid hemorrhage. Etiopathogenetic aspects]. / Emorragia subaracnoidea. Aspetti eziopatogenetici.

Data from existent literature and from analysis of 60 personal cases of subarachnoid hemorrhage are examined in order to clarify the etiologic and pathogenetic mechanisms. In about 50% of the patients intracranial arterial aneurysms are found; in a lower percentage arteriovenous malformations or arterial atherosclerotic lesions are seen. Specific activities or events related to the onset of subarachnoid hemorrhage are found in about 50% of the cases.

Lithium carbonate in amyotrophic lateral sclerosis: lack of efficacy in a dose-finding trial.

BACKGROUND: A neuroprotective effect of lithium in amyotrophic lateral sclerosis (ALS) has been recently reported. We performed a multicenter trial with lithium carbonate to assess its tolerability, safety, and efficacy in patients with ALS, comparing 2 different target blood levels (0.4-0.8 mEq/L, therapeutic group [TG], vs 0.2-0.4 mEq/L, subtherapeutic group [STG]). METHODS: The study was a multicenter, single-blind, randomized, dose-finding trial, conducted from May 2008 to November 2009 in 21 Italian ALS centers. The trial was registered with the public database of the Italian Agency for Drugs (http://oss-sper-clin.agenziafarmaco.it/) (EudraCT number 2008-001094-15). RESULTS: As of October 2009, a total of 171 patients had been enrolled, 87 randomized to the TG and 84 to the STG. The interim data analysis, performed per protocol, showed that 117 patients (68.4%) discontinued the study because of death/tracheotomy/severe disability, adverse events (AEs)/serious AEs (SAEs), or lack of efficacy. The Data Monitoring Committee recommended stopping the trial on November 2, 2009. CONCLUSIONS: Lithium was not well-tolerated in this cohort of patients with ALS, even at subtherapeutic doses. The 2 doses were equivalent in terms of survival/severe disability and functional data. The relatively high frequency of AEs/SAEs and the reduced tolerability of lithium raised serious doubts about its safety in ALS. CLASSIFICATION OF EVIDENCE: The study provides Class II evidence that therapeutic (0.4-0.8 mEq/L) vs subtherapeutic (0.2-0.4 mEq/L) lithium carbonate did not differ in the primary outcome of efficacy (survival/loss of autonomy) in ALS. Both target levels led to dropouts in more than 30% of participants due to patient-perceived lack of efficacy and AEs.

Pseudobulbar palsy: a clinical computed tomography study.

61 of 1,590 (3.8%) patients with cerebrovascular disease showed suprabulbar palsy of the pure form (42 patients; 2 had autopsy) and striate form (19 patients; 3 had autopsy). 25 patients with the pallidopyramidal syndrome were included since the clinical picture bordered on the striate form. The pure variety was characterized by dysarthria, dysphagia and automatic voluntary dissociation of facial movements. Half of the patients also had hemiparesis, primitive reflexes and short-step gait. In the striate form, the main signs were dysarthria, dysphagia, automatic voluntary dissociation, rigidity and hypokinesia. Brisk tendon reflexes, primitive reflexes, short-step gait and mental deterioration were also present in half of the patients. The pure variety was caused by multiple infarcts and/or lacunae (85.7%), while the striate form had vascular lesions by computed tomography in only 36.8% of the cases. Histological findings, showing lipohyalinosis of the arterial wall leading to stenosis and occlusion of the lumen and tissue rarefaction and disintegration, support the assumption that microinfarctions, sometimes found only by histopathological examination, are the leading pathogenetic factor in this form. Hypertension, cardiopathy, smoking habit, dyslipemia and diabetes are the most frequent risk factors in both forms.

Risk factors in lacunar syndromes: a case-control study.

The association between some hypothetical risk factors (previous TIA, hypertension, ECG ischemic abnormalities, diabetes, cigarette smoking, atrial fibrillation, hypercholesterolemia, hypertriglyceridemia, high hematocrit) and lacunar syndromes has been evaluated by a matched sample case-control study involving 108 consecutive, incident cases with lacunar syndrome and 216 hospital control subjects, matched for sex and age. A significant increase of Relative Risk (RR) has been shown for: 1. Previous history of TIA; 2. Hypertension; 3. Smoking; 4. Diabetes. No relevance was shown for: 1. Atrial fibrillation; 2. Hypercholesterolemia; 3. Hypertriglyceridemia; 4. High hematocrit. The analysis of the triplets of subjects (1 case + 2 controls) without hypertension showed a significant RR increase for: 1. Previous history of TIA; 2. Ischemic cardiac abnormalities; 3. Atrial fibrillation. Such findings support the hypothesis that, in a minority of cases with lacunar syndrome, the pathogenetic mechanism could be different from occlusion of penetrating arteries in hypertensive patients.

Prognosis of transient global amnesia: a long-term follow-up study.

A long-term follow-up study was performed on patients with transient global amnesia (TGA) in order to evaluate the prognosis, the recurrence rate and the occurrence of stroke and dementia. 102 patients (57 women, 45 men; mean age 62.8 +/- 9.4 years) were prospectively included and followed up. The follow-up duration ranged between 12 and 241 months with an average value of 82.2 +/- 51.1 (mean +/- SD). The death rate showed no difference from that of sex- and age-matched subjects. TGA recurred in 19 cases (18.63%). Only 4 patients suffered subsequent stroke, and only 3 showed intellectual deterioration. TGA prognosis was shown to be better than that of RIA and lacunar patients.

Responses of masseter muscles to transcranial magnetic stimulation in patients with amyotrophic lateral sclerosis.

We recorded motor responses evoked by transcranial magnetic stimulation (TMS) in the masseter muscles of 30 patients with amyotrophic lateral sclerosis (ALS), 10 patients with cervical spondylotic myelopathy (CSM) and 22 age-matched normal controls. Responses to direct activation of the trigeminal motor root (R-MEPs) were normal both in ALS and CSM patients. Responses to activation of cortico-bulbar descending fibers (C-MEPs) were absent or delayed in 19 ALS patients (63.3%). Abnormalities of masseter C-MEPs were more frequent than abnormalities of limb MEPs and could be observed both in patients with (77.8%) and without (41.7%) clinical bulbar signs. Masseter C-MEPs were normal in all CSM patients. Recording masseter responses to TMS can reveal the frequent impairment of cortico-bulbar projections in ALS and can be useful in the differential diagnosis of spinal cord compression disorders mimicking ALS because of combination of upper and lower motor neuron signs.

Unusual neurological manifestations of Lyme disease: a case report.

We describe a case of Lyme disease with a prolonged relapsing-remitting course, in which peripheral facial palsy, optic neuritis and myopathy were associated. After high-dose penicillin therapy the patient completely recovered.

[Huntington chorea. Review of the most recent aspects of research]. / Corea di Huntington. Rassegna degli aspetti più attuali delle ricerche.

The authors are presenting a review concerning the most visible aspects of the research directed to emphasize that Huntington's Chorea cannot be compared, either clinically or pathologically, to Parkinson's Disease. It is a hereditary disease in which we can discern an alteration of some neurotransmitters, neuromodulators, neurohormones that are not necessarily opposite in respect to pathophysiological findings of Parkinson disease.

Impairment of central motor conduction in diabetic patients.

In 70 patients with diabetes mellitus (DM) we recorded the motor evoked potentials (MEPs) following magnetic stimulation of the motor cortex and spinal roots. Central motor conduction time (CMCT) was determined as the difference between MEP latencies after cortical and spinal stimulation. The mean CMCTs for the biceps, thenar and tibialis anterior muscles were prolonged in the DM group, as compared to normal controls, and 21 patients exceeded the CMCT upper confidence limit for at least one muscle. CMCT changes and peripheral conduction velocity abnormalities occurred independently and were related to different clinical parameters. We conclude that a subclinical impairment of central motor conduction is present in 30% of DM patients, independently from the occurrence of a diabetic peripheral neuropathy and possibly reflecting different pathophysiological mechanisms.

Protective effect of cyproheptadine in a gerbil model of cerebral ischemia.

The efficacy of Cyproheptadine, a serotonin antagonist, in preventing the cerebral ischemic damage was tested on experimental model of transient global cerebral ischemia in Mongolian Gerbil. The semi-quantitative histological evaluation of the severity of ischemic damage showed a protective effect of Cyproheptadine, mainly in the anterior cortical areas.

Correlation between PMP-22 messenger RNA expression and phenotype in hereditary neuropathy with liability to pressure palsies.

Hereditary neuropathy with liability to pressure palsies (HNPP) is associated with a deletion in chromosome 17p11.2, which includes the gene for the peripheral myelin protein 22 (PMP-22). A "gene dosage" effect is probably the mechanism underlying HNPP, but the amount of PMP-22 mRNA in sural nerves of HNPP patients is highly variable and the role of PMP-22 underexpression in impairing myelination has yet to be clarified. We have studied 6 genetically proven HNPP patients, to evaluate the relationship between PMP-22 mRNA levels, and clinical, neurophysiological, and neuropathological findings. Underexpression of PMP-22 mRNA correlates with disease severity and with mean axon diameter and g ratio, but not with myelin thickness, number of "tomacula," or nerve conduction parameters. Our findings further confirm that underexpression of PMP-22 is the main pathogenetic mechanism underlying the severity of clinical symptoms and signs in HNPP. Smaller axons in sural nerves of HNPP patients with lower PMP-22 levels suggests that underexpression of PMP-22 may also affect axon development.