Lorenzo Stanzani

Increased plasma glutamate in stroke patients might be linked to altered platelet release and uptake

Experimental studies have shown the role of excitotoxicity in the pathogenesis of ischemic brain lesions, and glutamate levels have been found to be elevated in CSF and plasma from patients, early after stroke. In this study, we investigated whether platelets could be involved in the mechanism of altered plasma glutamate levels after stroke. Forty four patients, from 6 hours to 9 months after ischemic stroke, 15 age-related healthy controls and 15 controls with stroke risk factors or previous transient ischemic attack were enrolled. Glutamate plasma levels, platelet glutamate release after aggregation and platelet glutamate uptake were assessed. Plasma glutamate levels were increased up to 15 days after the ischemic event in stroke patients, and the levels at day 3 were inversely correlated with the neurologic improvement between day 3 and 15. Ex vivo platelet glutamate release was decreased by 70% in stroke patients, suggesting previous in vivo platelet activation. Moreover, platelet glutamate uptake in these patients was decreased by 75% up to 15 days and was still reduced 90 days after stroke. Our data show a prolonged increase of glutamate in plasma after stroke, which might presumably be linked to altered platelet functions, such as excessive release of the amino acid or impaired uptake.

Extracorporeal photochemotherapy: A safety and tolerability pilot study with preliminary efficacy results in refractory relapsing-remitting multiple sclerosis

Extracorporeal photochemotherapy (ECP) is an immunomodulating procedure consisting of autologous reinfusion of peripheral blood mononuclear cells (PBMC) after direct exposure to 8-methoxy-psoralen and UV-A. It has been described as a successful treatment for different T-cell-mediated diseases and preliminary results suggest that ECP might be effective in the treatment of relapsing–remitting multiple sclerosis, but does not significantly alter the course of the progressive form of MS. In this study, we report the safety data and some preliminary efficacy evidence obtained using ECP in the treatment of five patients with refractory relapsing-remitting (RR) MS: in most cases ECP induced a reduction in the relapse rate and an EDSS stabilisation, with an apparent general MRI stabilisation. In conclusion, our results confirm ECP safety and tolerability and suggest that this treatment might be useful as a therapeutic alternative in the subgroup of RRMS patients not responsive to or not eligible for traditional immunomodulating or immunosuppressive treatments.

Non-paraneoplastic voltage-gated calcium channels antibody-mediated cerebellar ataxia responsive to IVIG treatment

Non-paraneoplastic cerebellar ataxia associated with voltage-gated calcium channel (VGCC) antibodies is a rare entity with only few cases reported in literature. We describe a 60 year-old man with subacute cerebellar ataxia and subclinical Lambert-Eaton myasthenic syndrome (LEMS) in whom VGCC antibodies were detected at high titer in serum and cerebrospinal fluid. Screening for underlying malignancies was negative. Intravenous immunoglobulin treatment led to the improvement of clinical picture and reduction of serum antibody titer over a 13-month follow-up period. We emphasize that VGCC antibodies should be included in the diagnostic work-up of patients with subacute cerebellar ataxia and that treatment with IVIG can improve the clinical picture and prevent disability.

Acute isolated ophthalmoplegia with anti-GQ1b antibodies.

Ophthalmoplegia without ataxia, areflexia or both has been designated as atypical Miller Fisher syndrome (MFS) or acute ophthalmoplegia (AO). This entity, first reported by Chiba et al. is associated with anti-GQ1b IgG antibodies.We report a patient with isolated acute ophthalmoplegia with high titer of anti-GQ1b IgG antibody activity in the acute phase in whom treatment with intravenous immunoglobulin (IVIg) led to the clinical recovery and the decrease in antibody titer.

Cytokine network in acute stroke

inflammatory mechanisms in the pathophysiology of ischemic brain damage [1]. Central and peripheral activation of a cytokine network, with proor anti-inflammatory activity, has been widely demonstrated; various cytokine release events in the central nervous system (CNS) or in peripheral blood have been correlated to stroke severity and outcome [2]. In this issue, Perini and colleagues [3] provide further evidence for peripheral immune involvement in stroke. They found increased interleukin (IL)–6 serum levels during the first two weeks after onset, with a significant correlation with severity and outcome, assessed on the Scandinavian stroke scale, the Rankin scale and the Barthel index. Serum IL-6 correlated also with cell count and with neutrophils at different times after the event. On the other hand, IL-10 was decreased in stroke patients during all considered times. Most interestingly, in control subjects the authors found a significant inverse correlation between serum levels of these two cytokines, which seem to display opposite activities (IL6 is mainly pro-inflammatory, while IL-10 is anti-inflammatory). However, this correlaton was lost in stroke patients, although IL-6 increase and IL-10 decrease should virtually enforce this inverse trend. Supposing that the inverse correlation described in healthy subjects reflects a reciprocal regulation of the two cytokines, the stroke event may then trigger the release of other mediators, which disrupt the physiological cytokine network. Interestingly, in a similar cohort of stroke patients in which we previously demonstrated increased peripheral release of IL-6 [4], we recently observed a significant direct correlation between serum levels of transforming growth factor (TGF)-β and nerve growth factor (NGF). This correlation was present only in stroke patients and was absent in controls, suggesting a common or reciprocal regulation of the two neurotrophins, triggered by stroke [5]. All together, data from the literature show the existence of a complex network of interactions between proand antiinflammatory mediators and trophic factors, whose meaning is still to be determined. Cytokine pathways may be differentially regulated in physiological conditions and after stroke, which perturbs such regulation and triggers a new cascade of cytokine interactions. Altered cytokine networks may work as putative risk factors for stroke, and are involved in the pathogenesis of brain damage after stroke. Although the role of each cytokine in stroke is still difficult to define, the value of these studies is not only for a better understanding of the pathophysiology of stroke, but also for future clinical implications: therapeutic trials with drugs that prevent leukocyte infiltration in ischemic brain and neutralize the subsequent cytokine production are already in progress [6].

A case of multifocal motor neuropathy with conduction block associated with gastric and lung adenocarcinoma

Dear Editor, Multifocal motor neuropathy (MMN) with conduction block is a disorder characterized by slowly progressive asymmetrical weakness of limbs without sensory loss (Lange et al., 1992; Nobile-Orazio et al., 2001). The disorder is considered to be immunomediated, possibly through immunoglobulin M (IgM) antibodies that bind gangliosides on human peripheral nerves (Freddo et al., 1986; Van Asseldonk et al., 2005). We report a patient who developed MMN at the time of discovery of two unrelated tumors, a gastric and a pulmonary adenocarcinoma, and discuss the possibility that in this patient MMN could be a paraneoplastic condition. The patient is a 67-year-old man with a previous history of hypertension, atrial fibrillation, and myocardial infarction. In August 2010, he was admitted to a medical department for a 2-month history of loss of dexterity and grip weakness in left hand, weight loss, hyporexia, and diffuse asthenia. Endoscopy of the stomach and upper gastrointestinal tract revealed a tumor located in the lesser curvature of the gastric angle and biopsied specimens were compatible with gastric adenocarcinoma. Total-body computed tomography disclosed the presence of a right pulmonary mass and bronchoscopy with multiple biopsies suggested the diagnosis of lung adenocarcinoma. In September 2010, the patient underwent gastrectomy. After surgery he complained of distal weakness in left leg, right hand, and worsening of weakness in left hand; however, these symptoms were attributed to cachexia and he was not further investigated. In October 2010, he underwent pulmonary lobectomy, and only after this intervention a neurological consultation was required. Neurological examination showed bilateral distal upper limb weakness (finger and wrist extensors, interossei, and thumb abductor 3/5 Medical Research Council

Bilateral Radiation-Induced Hypoglossal Nerve Palsy Responsive to Steroid Treatment

Dear Editor, A 63-year-old woman reported a 2-month history of neck pain followed by progressive deterioration of speech and swallowing and a weight loss of 3 kilograms. Six years ago, she had received radiotherapy for a lymphoepithelial rhinopharyngeal carcinoma. A neurological examination showed dysarthria, dysphagia, impaired tongue protrusion, and amyotrophy on the left side. Blood screening for autoantibodies (antinuclear antibodies, extractable nuclear antibodies, anti-neutrophil cytoplasmic antibodies, and anti-DNA), Lyme-disease serology, angiotensin-converting enzyme, anti-acetylcholine-receptor antibodies, and HIV produced negative findings. A cerebrospinal fluid (CSF) examination showed normal protein levels, the absence of malignant cells, and negativity for an immunoelectrofocusing reaction. A CSF search for viral genomes by PCR excluded active infections with herpes simplex virus types 1 and 2, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus. An echo color Doppler study of the extracranial vessels produced normal findings. Magnetic resonance imaging of the brain, nasopharynx, and neck with gadolinium enhancement excluded locoregional tumor relapse and meningeal carcinomatosis. The findings of a sensorimotor nerve conduction study, F-wave examination, and highand low-frequency repetitive nerve stimulation were normal. In contrast, needle electromyography (EMG) disclosed active denervation of the tongue muscles (abundant fibrillations and positive sharp waves at rest in both genioglossus muscles with the absence of voluntary activity). Her motor evoked potentials were normal. A videofluoroscopic evaluation revealed severe dysphagia with a penetration-aspiration scale (PAS) score of 6 and a pooling score of 10. Percutaneous endoscopic gastrostomy was performed in order to assure adequate feeding and avoid the risk of aspiration. A putative diagnosis of postradiation bilateral hypoglossal palsy was made, and treatment with a steroid (1 mg/kg prednisone) was started and then slowly tapered. At the 7-month follow-up the patient reported improvements of speech and swallowing, while the videofluoroscopic re-evaluation confirmed the improvement of dysphagia (PAS score of 4 and pooling score of 8), and so the patient was allowed to consume semisolid food orally. An EMG evaluation disclosed the absence of spontaneous activity and chronic neurogenic changes associated with diffuse phenomena of collateral reinnervation in the genioglossus muscles, confirming the functional recovery of hypoglossal nerves. The differential diagnosis of bilateral hypoglossal palsy includes metastatic disease at the base of the skull, motor neuron disease, dissection of extracranial vessels, meningeal carcinomatosis, multiple mononeuritis of different etiologies (infective, vasculitic, and immune-mediated), and tumoral nerve infiltration. All of these conditions were ruled out in the present case. Cranial neuropathies are uncommon but well-recognized complications after head and neck radiotherapy, with an incidence ranging from 5% to 10%. The average latency period is reportedly 5 to 7 years.2,3 The hypoglossal nerve is the most frequently involved, often biAndrea Rigamonti Giuseppe Lauria Vittorio Mantero Lorenzo Stanzani Andrea Salmaggi

When it rains it pours: amyotrophic lateral sclerosis concealed with Isaac’s syndrome

Surgical stress may influence neurodegenerative processes; in ALS patients, correlation between site of surgery, region of ALS onset and acceleration of disease progression has been reported [1]. A 63-year-old woman, 2 months after surgery for herniated lumbar disc, developed gait disturbance and paraparesis. She had thyroidectomy for toxic adenoma and adrenalectomy for adenoma, respectively, 30 and 15 years before. Neurological examination revealed spastic paraparesis, diffuse hyper-reflexia, bilateral achillean clonus, Hoffman and Babinski signs, fasciculations in proximal and distal leg muscles. Cranial nerves, bulbar function, coordination and sensory modalities were normal. At the general examination, hyperhidrosis was noted. Routine haematologic tests, dehydroepiandrosterone, B12 and folic acid were normal. Plasmatic parathormone (6 pg/ml, nv 15–65), aldosterone (18.3 pg/ml, nv 30–150), calcaemia (0.91 mmol/l, nv 2.1–2.6) and vitamin D (8.8 ng/ml, nv 30–100) were below normal limits, so pharmacological correction was started. Antibodies against glutamic acid decarboxylase (anti-GAD), voltage gated potassium channel (VGKC), anti-amphiphysin, antithyroperoxidase, anti-thyroglobulin, anti-GM1 and antiGD1b gangliosides, antinuclear and antinative DNA were negative. Dosage of very long chain fatty acids was normal. Cerebrospinal fluid examination was unremarkable. Nerve conduction studies (NCS), including F-waves, were normal. Needle electromyography (EMG) showed presence of abundant spontaneous activity: fibrillation, positive sharp waves and fasciculations were recorded in distal leg muscles whereas high frequency bursts were recorded in proximal leg and arm, distal arm and cranial muscles. Diffuse chronic neurogenic changes were found at all limbs. Ischaemia-hyperpnea test documented doublets, triplets and multiplets single motor unit discharges with high-intraburst frequency. Motor evoked magnetic potentials (MEPs) examination demonstrated prolonged central motor conduction time recording from opponens pollicis whereas MEPs potentials were absent recording from abductor hallucis. Brain and spinal MRI were normal. Total-body CT scan excluded malignancy. Diagnosis of suspected ALS in hypocalcaemia was postulated. The clinical picture rapidly deteriorated: the patient became wheelchair bound, developed arm weakness and diffuse muscular atrophy; moreover, a continuous muscle activity involving limb muscles was evident. Neurological revaluation demonstrated normal bulbar functions, spastic hypertonia with stiffness in cervical, abdominal and spinal muscles, weakness at four limbs, diffuse muscular hypotrophy, widespread fasciculations, continuous muscular activity at limbs and paraspinal muscles, hyper-reflexia with bilateral achillean clonus, Hoffman and Babinski signs. NCS persisted normal. Needle EMG showed very intense neuromyotonic discharges prevalent in axial muscles, diffuse acute denervation (fibrillation and positive sharp waves), fasciculations and chronic & Vittorio Mantero vittorio.mantero@hotmail.com