Whole-body computed tomography as first-line imaging procedure to exclude cancer in patients with neurological suspicion of paraneoplastic syndromes: shall clinical practice adhere to recommendations?

INTRODUCTION: To assess the efficacy of whole-body computed tomography (WB-CT) as imaging procedure to exclude cancer in patients with neurological symptoms and signs at clinical onset. METHODS: A retrospective observational study was designed to identify consecutive WB-CT requested by the Neurology Unit with a suspicion of an underlying tumor potentially linked to a paraneoplastic neurological syndrome (PNS) between January 2019 and February 2022. The following data were collected: diagnosis at admission and at discharge, the presence of onconeural antibodies, the scans dose length product (DLP), the estimated effective dose (ED), the total estimated time requested; the PNS-Care-Score was retrospectively calculated only in subjects with available antibodies. RESULTS: The total number of patients included was 158. In 13/158 (positive group) a malignant or locally aggressive neoplasm was found while in 145/158 no malignant lesions were found on the WB-CT. Among the positive group, in 7/13 onconeural antibodies were diagnosed, resulting negative in all cases and the most frequent tumor was lung cancer (30.8%). PNS-Care-Score was of 6-7 in 2/7 (probable PNS) and in no case the PNS-Care-Score was ≥8 (definite PNS). The mean DLP for all the scans was 2798 ± 952 mGy cm (average estimated ED of 42 ± 14 mSv). The total estimated time requested for all scans was 11,060 min. CONCLUSION: If a PNS is suspected, we encourage the prescription of unenhanced chest CT and/or abdomen/testis/female pelvis ultrasound and/or mammography based on clinical picture. The WB-CT using a single portal phase would be appropriate as a second-line technique while magnetic resonance imaging might be indicated for the exclusion of nervous system diseases. IMPLICATIONS FOR PRACTICE: Our suggestion results in saving in terms of radiation exposure, financial resources and time.

Posterior Circulation Endovascular Thrombectomy for Large-Vessel Occlusion: Predictors of Favorable Clinical Outcome and Analysis of First-Pass Effect.

BACKGROUND AND PURPOSE: Successful vessel recanalization in posterior circulation large-vessel occlusion is considered crucial, though the evidence of clinical usefulness, compared with the anterior circulation, is not still determined. The aim of this study was to evaluate predictors of favorable clinical outcome and to analyze the effect of first-pass thrombectomy. MATERIALS AND METHODS: A retrospective, multicenter, observational study was conducted in 10 high-volume stroke centers in Europe, including the period from January 2016 to July 2019. Only patients with an acute basilar artery occlusion or a single, dominant vertebral artery occlusion ("functional" basilar artery occlusion) who had a 3-month mRS were included. Clinical, procedural, and radiologic data were evaluated, and the association between these parameters and both the functional outcome and the first-pass effect was assessed. RESULTS: A total of 191 patients were included. A lower baseline NIHSS score (adjusted OR, 0.77; 95% CI, 0.61-0.96; P = .025) and higher baseline MR imaging posterior circulation ASPECTS (adjusted OR, 3.01; 95% CI, 1.03-8.76; P = .043) were predictors of better outcomes. The use of large-bore catheters (adjusted OR, 2.25; 95% CI, 1.08-4.67; P = .030) was a positive predictor of successful reperfusion at first-pass, while the use of a combined technique was a negative predictor (adjusted OR, 0.26; 95% CI, 0.09-0.76; P = .014). CONCLUSIONS: The analysis of our retrospective series demonstrates that a lower baseline NIHSS score and a higher MR imaging posterior circulation ASPECTS were predictors of good clinical outcome. The use of large-bore catheters was a positive predictor of first-pass modified TICI 2b/3; the use of a combined technique was a negative predictor.

Cardiovascular impairment in a patient with acute myelitis.

STUDY DESIGN: Case report. OBJECTIVE: to report and discuss the development of sudden symptomatic sinus bradycardia in a 35-year-old woman with acute myelitis. CASE REPORT: A 35-year-old woman presented rapidly progressive weakness and hypoesthesia in the left hemibody. Five days after symptom onset, she developed symptomatic sinus bradycardia up to 30 b.p.m. Bradycardia was completely resolved ∼36 h after its onset. RESULTS: Cervical spine magnetic resonance imaging showed a focal T2-hyperintense intramedullary lesion at C2 level, with moderate cord swelling. The lesion involved bilaterally dorsal funiculi, and left lateral and ventral funiculi. Cardiac I-123 metaiodobenzylguanidine (MIBG) scintigraphy showed a decreased cardiac MIBG uptake suggesting sympathetic denervation. CONCLUSION: The most likely explanation for bradycardia in our patient is the myelitis-related disruption of descending vasomotor pathways, resulting in sympathetic hypoactivity. Our case extends the spectrum of the clinical presentations of cervical myelitis and emphasizes the importance of careful cardiac monitoring in acute phase of cervical myelitis.

Synaptic plasticity in neurodegenerative diseases evaluated and modulated by in vivo neurophysiological techniques.

Several studies demonstrated in experimental models and in humans synaptic plasticity impairment in some neurodegenerative and neuropsychiatric diseases such as Parkinson's disease, Alzheimer's disease, Huntington's disease, and schizophrenia. Recently new neurophysiological tools, such as repetitive transcranial magnetic stimulation and transcranial direct current stimulation, have been introduced in experimental and clinical settings for studying physiology of the brain and modulating cortical activity. These techniques use noninvasive transcranial electrical or magnetic stimulation to modulate neurons activity in the human brain. Cortical stimulation might enhance or inhibit the activity of cortico-subcortical networks, depending on stimulus frequency and intensity, current polarity, and other stimulation parameters such as the configuration of the induced electric field and stimulation protocols. On this basis, in the last two decades, these techniques have rapidly become valuable tools to investigate physiology of the human brain and have been applied to treat drug-resistant neurological and psychiatric diseases. Here we describe these techniques and discuss the mechanisms that may explain these effects.

Dystonia in Costello syndrome.

BACKGROUND: Costello Syndrome is a rare multiple congenital anomaly disorder caused by de novo heterozygous mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homolog (HRAS) gene. Recent studies seem to support apparent autosomal dominant inheritance and somatic mosaicism and an association with advanced parental age. Abnormal hand posture has been reported as a typical feature of Costello Syndrome but the pathophysiology of this is unclear. METHODS: We evaluated and described posture and movement in six consecutive subjects with genetically proven Costello Syndrome, in order to better characterize the phenomenology of the associated postural abnormalities and any related motor abnormalities. We also evaluated motor cortex plasticity by applying Paired Associative Stimulation. RESULTS: All the patients presented the typical postural abnormalities reported in Costello Syndrome, in particular the ulnar deviation of fingers. The latter was reducible and not fixed. In addition, patients exhibited more explicit dystonic features of the face, limbs and trunk and altered sensorimotor plasticity consistent with generalized dystonia. CONCLUSIONS: These findings suggest that dystonia may underlie the abnormal postures described in Costello Syndrome patients.

Modulation of LTP at rat hippocampal CA3-CA1 synapses by direct current stimulation.

Transcranial direct current stimulation (tDCS) can produce a lasting polarity-specific modulation of cortical excitability in the brain, and it is increasingly used in experimental and clinical settings. Recent studies suggest that the after-effects of tDCS are related to molecular mechanisms of activity-dependent synaptic plasticity. Here we investigated the effect of DCS on the induction of one of the most studied N-methyl-d-aspartate receptor-dependent forms of long-term potentiation (LTP) of synaptic activity at CA3-CA1 synapses in the hippocampus. We show that DCS applied to rat brain slices determines a modulation of LTP that is increased by anodal and reduced by cathodal DCS. Immediate early genes, such as c-fos and zif268 (egr1/NGFI-A/krox24), are rapidly induced following neuronal activation, and a specific role of zif268 in the induction and maintenance of LTP has been demonstrated. We found that both anodal and cathodal DCS produce a marked subregion-specific increase in the expression of zif268 protein in the cornus ammonis (CA) region, whereas the same protocols of stimulation produce a less pronounced increase in c-fos protein expression in the CA and in dentate gyrus regions of the hippocampus. Brain-derived neurotrophic factor expression was also investigated, and it was found to be reduced in cathodal-stimulated slices. The present data demonstrate that it is possible to modulate LTP by using DCS and provide the rationale for the use of DCS in neurological diseases to promote the adaptive and suppress the maladaptive forms of brain plasticity.

I-wave origin and modulation.

The human motor cortex can be activated by transcranial magnetic stimulation (TMS) evoking a high-frequency repetitive discharge of corticospinal neurones. The exact physiologic mechanisms producing the corticospinal activity still remain unclear because of the complexity of the interactions between the currents induced in the brain and the circuits of cerebral cortex, composed of multiple excitatory and inhibitory neurons and axons of different size, location, orientation and function. The aim of current paper is to evaluate whether the main characteristics of the activity evoked by single- and paired-pulse and repetitive TMS, can be accounted by the interaction of the induced currents in the brain with the key anatomic features of a simple cortical circuit composed of the superficial population of excitatory pyramidal neurons of layers II and III, the large pyramidal neurons in layer V, and the inhibitory GABA cells. This circuit represents the minimum architecture necessary for capturing the most essential cortical input-output operations of neocortex. The interaction between the induced currents in the brain and this simple model of cortical circuitry might explain the characteristics and nature of the repetitive discharge evoked by TMS, including its regular and rhythmic nature and its dose-dependency and pharmacologic modulation. The integrative properties of the circuit also provide a good framework for the interpretation of the changes in the cortical output produced by paired and repetitive TMS.

Recurrent subarachnoid bleeding and superficial siderosis in a patient with histopathologically proven cerebral amyloid angiopathy.

A 68-year-old man with a history of hypertension presented with recurrent subarachnoid bleeding. Brain MRI showed superficial siderosis, and diagnostic cerebral angiograms did not show any intracranial vascular malformation or arterial aneurism. Post mortem neuropathological examination of the brain was consistent with a diagnosis of cerebral amyloid angiopathy. Clinicians should be aware that cerebral amyloid angiopathy should be considered in patients with unexplained recurrent subarachnoid bleeding, even in cases without familial clustering or transthyretin variant.

Neurophysiological evaluation of the pedunculopontine nucleus in humans.

The pedunculopontine nucleus (PPTg) is constituted by a heterogeneous cluster of neurons located in caudal mesencephalic tegmentum which projects to the thalamus to trigger thalamocortical rhythms and the brainstem to modulate muscle tone and locomotion. It has been investigated as potential deep brain stimulation (DBS) target for treating Parkinson's disease (PD) symptoms. Neurophysiological studies conducted in humans using DBS electrodes for exploring functional properties of PPTg in vivo, reviewed in this paper, demonstrated that the functional connections between PPTg and cortex, basal ganglia, brainstem network involved in sleep/wake control, and spinal cord can be explored in vivo and provided useful insights about the physiology of this nucleus and pathophysiology of PD.

Modulation of motor cortex neuronal networks by rTMS: comparison of local and remote effects of six different protocols of stimulation.

Repetitive transcranial magnetic stimulation (rTMS) of human motor cortex can produce long-lasting changes in the excitability of excitatory and inhibitory neuronal networks. The effects of rTMS depend critically on stimulus frequency. The aim of our present study was to compare the effects of different rTMS protocols. We compared the aftereffects of 6 different rTMS protocols [paired associative stimulation at interstimulus intervals of 25 (PAS(25)) and 10 ms (PAS(10)); theta burst stimulation delivered as continuous (cTBS) or intermittent delivery pattern (iTBS); 1- and 5-Hz rTMS] on the excitability of stimulated and contralateral motor cortex in 10 healthy subjects. A pronounced increase of cortical excitability, evaluated by measuring the amplitude of motor evoked potentials (MEPs), was produced by iTBS (+56%) and PAS(25) (+45%). Five-hertz rTMS did not produce a significant increase of MEPs. A pronounced decrease of cortical excitability was produced by PAS(10) (-31%), cTBS (-29%), and 1-Hz rTMS (-20%). Short-interval intracortical inhibition was suppressed by PAS(10). Cortical silent period duration was increased by 1-Hz stimulation. No significant effect was observed in the contralateral hemisphere. Head-to-head comparison of the different protocols enabled us to identify the most effective paradigms for modulating the excitatory and inhibitory circuits activated by TMS.

Contrast transoesophageal echocardiography remains superior to contrast-enhanced cardiac magnetic resonance imaging for the diagnosis of patent foramen ovale.

AIMS: In 30-40% of patients with acute ischaemic stroke, the cause remains undefined (cryptogenic stroke). Contrast transoesophageal echocardiography (TEE) is considered the gold standard for patent foramen ovale (PFO) detection. Recently, however, cardiac magnetic resonance (CMR) has also been applied to detect PFO. In this study, we compared the diagnostic value of CMR and TEE in detecting PFO in a group of patients with apparently cryptogenic stroke. METHODS AND RESULTS: Twenty-five patients (age 50 ± 13 years, 16 males) with apparently cryptogenic ischaemic stroke underwent contrast-enhanced TEE and contrast CMR for detection of possible PFO. Both imaging studies were performed during Valsalva manoeuvre. PFO grading results were assessed visually both for TEE and for CMR, according to the entity of contrast passage in the left atrium (grade 0 = no PFO; grades 1, 2, and 3 = mild, medium, and wide PFO, respectively). TEE detected PFO in 16 patients (64%). Contrast-enhanced CMR identified a PFO in 7 (44%) of these patients. TEE showed a grade 1 PFO in five patients, a grade 2 PFO in eight patients, and a grade 3 PFO in three patients. Of these patients, CMR failed to identify PFO in all five patients with a grade 1 PFO, in one patient with a grade 2 PFO, and one patient with grade 3 PFO according to TEE. None of the nine patients without PFO at TEE was shown to have a PFO at CMR. When compared with TEE, the present methodology of CMR had a sensitivity of 50%, specificity of 100%, negative predictive value of 31%, and a positive predictive value of 100%. CONCLUSION: Our data suggest that TEE is the cornerstone imaging diagnostic test to detect and characterize PFO in patients with ischaemic stroke, and is shown to be better compared with the current CMR sequences.

Bronchial glomus tumor mimicking a COPD exacerbation.

We report the case of a glomus tumor originating in the left main bronchus diagnosed in a 79 year old Caucasian man. A glomus tumor is an extremely rare neoplasm in the bronchi with nonspecific clinical features. Bronchoscopy allows the diagnosis through biopsy and subsequent histopathological examination of the tissue and in selected cases may represent a valid alternative to surgery permitting a radical tumor excision.

Enhanced human brain associative plasticity in Costello syndrome.

Costello syndrome (CS) is a rare multiple congenital anomaly disorder which is caused by germline mutations in the v-Ha-ras Harvey rat sarcoma viral oncogene homologue (HRAS) proto-oncogene. Experimental data suggest perturbing effects of the mutated protein on the functional and structural organization of networks of cerebral cortex and on the activity-dependent strengthening of synaptic transmission known as long term potentiation (LTP). In five patients with molecularly proven diagnosis of CS and in a group of 13 age-matched control subjects we investigated activity-dependent synaptic plasticity. To this end, we used a paired associative stimulation (PAS) protocol, in which left ulnar nerve stimuli were followed by transcranial magnetic stimulation (TMS) pulses to right cortical hand area, and recorded motor evoked potentials (MEPs) by single pulse TMS from left first dorsal interosseus (FDI) muscle before and after PAS. In 4 out of 5 CS patients and in a subgroup of nine control subjects we also evaluated the time course and the topographical specificity of PAS after-effects. In these two subgroups, MEPs were measured before, immediately after and 30 min after PAS in the left FDI and left abductor pollicis brevis (APB). While the PAS protocol led to a 65% increase of the FDI MEP amplitude in controls, the LTP-like phenomenon was significantly more pronounced in CS patients, with motor responses increased by 230%. In addition, CS patients showed a similar MEP increase in both muscles while control subjects showed a slight increase in APB and only immediately after PAS. We hypothesize that the extremely enhanced PAS after-effects could be due to the influence of HRAS activity on the susceptibility of synapses to undergo LTP.

Repetitive transcranial magnetic stimulation for ALS.

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease affecting upper and lower motor neurons characterized by progressive weakness, respiratory failure and death within 3-5 years. It has been proposed that glutamate-related excitotoxicity may promote motor neuron death in ALS. Glutamatergic circuits of the human motor cortex can be activated noninvasively using transcranial magnetic stimulation (TMS) of the brain, and repetitive TMS (rTMS) can produce changes in neurotransmission that outlast the period of stimulation. In recent years a remarkable number of papers about the potential effects of rTMS in several neurological disorders including ALS has been published. Preliminary studies have shown that rTMS of the motor cortex, at frequencies that decrease cortical excitability, causes a slight slowing in the progression rate of ALS, suggesting that these effects might be related to a diminution of glutamate-driven excitotoxicity. RTMS could also interfere with motor neuron death through different mechanisms: rTMS could modulate the production of brain-derived neurotrophic factor (BDNF), a potent survival factor for neurons, that in turn might represent a promoter of motor neuron sparing in ALS. Despite some promising preliminary data, recent studies have demonstrated a lack of significant long-term beneficial effects of rTMS on neurological deterioration in ALS. However, further studies are warranted to evaluate the potential efficacy of different protocols of motor cortex stimulation (in terms of technique, duration and frequency of stimulation), particularly during the early stages of the disease when the progression rate is more pronounced.

The effects of motor cortex rTMS on corticospinal descending activity.

Repetitive transcranial magnetic stimulation (rTMS) of the human motor cortex can produce long-lasting changes in the excitability of the motor cortex to single pulse transcranial magnetic stimulation (TMS). rTMS may increase or decrease motor cortical excitability depending critically on the characteristics of the stimulation protocol. However, it is still poorly defined which mechanisms and central motor circuits contribute to these rTMS induced long-lasting excitability changes. We have had the opportunity to perform a series of direct recordings of the corticospinal volley evoked by single pulse TMS from the epidural space of conscious patients with chronically implanted spinal electrodes before and after several protocols of rTMS that increase or decrease brain excitability. These recordings provided insight into the physiological basis of the effects of rTMS and the specific motor cortical circuits involved.

Motor cortex plasticity predicts recovery in acute stroke.

Repetitive transcranial magnetic stimulation of the brain given as intermittent theta burst stimulation (iTBS) can induce long-term potentiation (LTP)-like changes in the stimulated hemisphere and long-term depression (LTD)-like changes in the opposite hemisphere. We evaluated whether LTP- and LTD-like changes produced by iTBS in acute stroke correlate with outcome at 6 months. We evaluated the excitability of affected hemisphere (AH) and unaffected hemisphere (UH) by measuring motor threshold and motor-evoked potential (MEP) amplitude under baseline conditions and after iTBS of AH in 17 patients with acute ischemic stroke. Baseline amplitude of MEPs elicited from AH was significantly smaller than that of MEPs elicited from UH, and baseline motor threshold was higher for the AH. Higher baseline MEP values in UH correlated with poor prognosis. iTBS produced a significant increase in MEP amplitude for AH that was significantly correlated with recovery. A nonsignificant decrease in MEP amplitude was observed for the UH. When the decrease in the amplitude of UH MEPs was added to the regression model, the correlation was even higher. Functional recovery is directly correlated with LTP-like changes in AH and LTD-like changes in UH and inversely correlated with the baseline excitability of UH.