Margherita Capasso

Background: Amyotrophic Lateral Sclerosis (ALS) is a degenerative disorder which affects the motor neurons. Growing evidence suggests that ALS may impact the metabolic system, including the glucose metabolism. Several studies investigated the role of Diabetes Mellitus (DM) as risk and/or prognostic factor. However, a clear correlation between DM and ALS has not been defined. In this review, we focus on the role of DM in ALS, examining the different hypotheses on how perturbations of glucose metabolism may interact with the pathophysiology and the course of ALS. Methods: We undertook an independent PubMed literature search, using the following search terms: ((ALS) OR (Amyotrophic Lateral Sclerosis) OR (Motor Neuron Disease)) AND ((Diabetes) OR (Glucose Intolerance) OR (Hyperglycemia)). Review and original articles were considered. Results: DM appears not to affect ALS severity, progression, and survival. Contrasting data suggested a protective role of DM on the occurrence of ALS in elderly and an opposite effect in younger subjects. Conclusions: The actual clinical and pathophysiological correlation between DM and ALS is unclear. Large longitudinal prospective studies are needed. Achieving large sample sizes comparable to those of common complex diseases like DM is a challenge for a rare disease like ALS. Collaborative efforts could overcome this specific issue.

Introduction Recent studies suggest that endoplasmic reticulum stress may play a critical role in the pathogenesis of amyotrophic lateral sclerosis (ALS) through an altered regulation of the proteostasis, the cellular pathway-balancing protein synthesis and degradation. A key mechanism is thought to be the dephosphorylation of eIF2α, a factor involved in the initiation of protein translation. Guanabenz is an alpha-2-adrenergic receptor agonist safely used in past to treat mild hypertension and is now an orphan drug. A pharmacological action recently discovered is its ability to modulate the synthesis of proteins by the activation of translational factors preventing misfolded protein accumulation and endoplasmic reticulum overload. Guanabenz proved to rescue motoneurons from misfolding protein stress both in in vitro and in vivo ALS models, making it a potential disease-modifying drug in patients. It is conceivable investigating whether its neuroprotective effects based on the inhibition of eIF2α dephosphorylation can change the progression of ALS. Methods and analyses Protocolised Management In Sepsis is a multicentre, randomised, double-blind, placebo-controlled phase II clinical trial with futility design. We will investigate clinical outcomes, safety, tolerability and biomarkers of neurodegeneration in patients with ALS treated with guanabenz or riluzole alone for 6 months. The primary aim is to test if guanabenz can reduce the proportion of patients progressed to a higher stage of disease at 6 months compared with their baseline stage as measured by the ALS Milano-Torino Staging (ALS-MITOS) system and to the placebo group. Secondary aims are safety, tolerability and change in at least one biomarker of neurodegeneration in the guanabenz arm compared with the placebo group. Findings will provide reliable data on the likelihood that guanabenz can slow the course of ALS in a phase III trial. Ethics and dissemination The study protocol was approved by the Ethics Committee of IRCCS ‘Carlo Besta Foundation’ of Milan (Eudract no. 2014-005367-32 Pre-results) based on the Helsinki declaration.

A patient has been recently described with frontotemporal cognitive decline and C9orf72 repeat expansion who presented abnormally slowed background and photoparoxysmal response at electroencephalographic (EEG) recording. Our data, based on five patients with repeat expansions in C9orf72 and EEG recordings suggest that abnormally slowed background and epilepsy represent previously unrecognized features of the C9orf72 phenotype in some patients.

Olanzapine‐related seizures have rarely been reported despite associated proconvulsant risk factors described in the literature: myoclonic status, increased frequency of seizures, tonic‐clonic seizures, as well as fatal status epilepticus. We present a psychiatric patient who developed repetitive focal motor seizures and lingual dystonia when olanzapine was added for psychomotor agitation and aggressiveness. Olanzapine was immediately suspended and the seizures progressively disappeared. A control EEG showed no paroxysmal discharges. Olanzapine shares some pharmacological similarities with clozapine, a neuroleptic with a high risk of dose‐dependent seizures. This adverse effect should be taken into account, and olanzapine should be used with caution if concomitant circumstances decrease the seizure threshold. [Published with video sequence online]

Akinetic crisis (AC) is a life-threatening complication of parkinsonism characterized by an acute severe akinetic-hypertonic state, consciousness disturbance, hyperthermia, and muscle enzymes elevation. Injectable dopaminomimetic drugs, high-dose methylprednisolone, and dantrolene are advocated as putative specific treatments. The course of the illness is frequently complicated by infections, pulmonary embolism, renal failure, disseminated intravascular coagulation, and cardiac arrhythmias. Critical illness neuromyopathy (CINM) is an acquired neuromuscular disorder characterized by flaccid quadriparesis and muscle enzyme elevation, often occurring in intensive care units and primarily associated with inactivity, sepsis, multiorgan failure, neuromuscular blocking agents, and steroid treatment. In 3 parkinsonian patients, during the course of AC we observed disappearance of rigidity but persistent hypoactivity. In all, neurological examination showed quadriparesis with loss of tendon reflexes and laboratory investigation disclosed a second peak of muscle enzymes elevation, following the first increment due to AC. Electrophysiological studies showed absent or reduced sensory nerve action potentials and compound muscular action potentials, myopathic changes, and fibrillation potentials at electromyography recordings, and reduced excitability or inexcitability of tibialis anterior at direct muscle stimulation, leading to a diagnosis of CINM in all 3 patients. In 1 patient, the diagnosis was also confirmed by muscle biopsy. Outcome was fatal in 2 of the 3 patients. Although AC is associated with most of the known risk factors for CINM, the cooccurrence of the 2 disorders may be difficult to recognize and has never been reported. We found that CINM can occur as a severe complication of AC, and should be suspected when hypertonia-rigidity subsides despite persistent akinesia. Strict monitoring of muscle enzyme levels may help diagnosis. This finding addresses possible caveats in the use of putative treatments for AC.

Akinetic crisis (AC) is akin to neuroleptic malignant syndrome (NMS) and is the most severe and possibly lethal complication of parkinsonism. Diagnosis is today based only on clinical assessments yet is often marred by concomitant precipitating factors. Our purpose is to evidence that AC and NMS can be reliably evidenced by FP/CIT single-photon emission computerized tomography (SPECT) performed during the crisis. Prospective cohort evaluation in 6 patients. In 5 patients, affected by Parkinson disease or Lewy body dementia, the crisis was categorized as AC. One was diagnosed as having NMS because of exposure to risperidone. In all FP/CIT, SPECT was performed in the acute phase. SPECT was repeated 3 to 6 months after the acute event in 5 patients. Visual assessments and semiquantitative evaluations of binding potentials (BPs) were used. To exclude the interference of emergency treatments, FP/CIT BP was also evaluated in 4 patients currently treated with apomorphine. During AC or NMS, BP values in caudate and putamen were reduced by 95% to 80%, to noise level with a nearly complete loss of striatum dopamine transporter-binding, corresponding to the “burst striatum” pattern. The follow-up re-evaluation in surviving patients showed a recovery of values to the range expected for Parkinsonisms of same disease duration. No binding effects of apomorphine were observed. By showing the outstanding binding reduction, presynaptic dopamine transporter ligand can provide instrumental evidence of AC in Parkinsonism and NMS.