Iatrogenic and toxic myopathies

There has been increasing awareness of the adverse effects of therapeutic agents and exogenous toxins on the structure and function of muscle. The resulting clinical syndrome varies from one characterized by muscle pain to profound myalgia, paralysis, and myoglobinuria. Because toxic myopathies are potentially reversible, their prompt recognition may reduce their damaging effects or prevent a fatal outcome. Interest in the toxic myopathies, however, derives not only from their clinical importance but also from the fact that they serve as useful experimental models in muscle research. Morphological and biochemical studies have increased our understanding of the basic cellular mechanisms of myotoxicity. Toxins may produce, for instance, necrotizing, lysosomal-related, inflammatory, anti-microtubular, mitochondrial, hypokalemia-related, or protein synthesis-related muscle damage.     

Atypical parkinsonian syndromes: a general neurologist's perspective

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non‐fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson‐plus syndromes in the past, they are now classified as FTD‐related disorders, reflecting that they pathologically differ from α‐synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.     

The impact of baroreflex function on endogenous pain control: a microneurography study

The interaction between sympathetic vasoconstrictor activity to muscles [muscle sympathetic nerve activity (MSNA), burst frequency (BF) and burst incidence (BI)] and different stress and somatosensory stimuli is still unclear. Eighteen healthy men (median age 28 years) underwent microneurography recordings from the peroneal nerve. MSNA was recorded during heat pain (HP) and cold pain (CP) alone as well as combined with different stress tasks (mental arithmetic, singing, giving a speech). An additional nine healthy men (median age 26 years) underwent the stimulation protocol with an additional control task (thermal pain combined with listening to music) to evaluate possible attentional confounders. MSNA was significantly increased by CP and HP. CP‐evoked responses were smaller. The diastolic blood pressure followed the time course of MSNA while heart rate remained unchanged. The mental stress tasks further increased MSNA and were sufficient to reduce pain while the control task had no effect. MSNA activity correlated negatively with pain intensity and positively with analgesia. High blood pressure values were associated with lower pain intensity. Our study indicates an impact of central sympathetic drive on pain and pain control.     

Rostro‐caudal maturation of glial cells in the accessory olfactory system during development: involvement in outgrowth of GnRH neurites

During mammalian embryonic development, GnRH neurones differentiate from the nasal placode and migrate through the nasal septum towards the forebrain. We previously showed that a category of glial cells, the olfactory ensheathing cells (OEC), forms the microenvironment of migrating GnRH neurones. Here, to characterize the quantitative and qualitative importance of this glial, we investigated the spatiotemporal maturation of glial cells in situ and the role of maturing glia in GnRH neurones development ex vivo. More than 90% of migrating GnRH neurones were found to be associated with glial cells. There was no change in the cellular microenvironment of GnRH neurones in the regions crossed during embryonic development as glial cells formed the main microenvironment of these neurones (53.4%). However, the phenotype of OEC associated with GnRH neurones changed across regions. The OEC progenitors immunoreactive to brain lipid binding protein formed the microenvironment of migrating GnRH neurones from the vomeronasal organ to the telencephalon and were also present in the diencephalon. However, during GnRH neurone migration, maturation of OEC to [GFAP+] state (glial fibrillary acid protein) was only observed in the nasal septum. Inducing depletion of OEC in maturation, using transgenic mice expressing herpes simplex virus thymidine kinase driven by the GFAP promoter, had no impact on neurogenesis or on triggering GnRH neurones migration in nasal explant culture. Nevertheless, depletion of [GFAP+] cells decreased GnRH neurites outgrowth by 57.4%. This study suggests that specific maturation of OEC in the nasal septum plays a role in morphological differentiation of GnRH neurones.     

Oxaliplatin-induced neurotoxicity: acute hyperexcitability and chronic neuropathy

Oxaliplatin, a platinum-based chemotherapeutic agent, is effective in the treatment of solid tumors, particularly colorectal cancer. During and immediately following oxaliplatin infusion, patients may experience cold-induced paresthesias, throat and jaw tightness, and occasionally focal weakness. We assessed nerve conduction studies and findings on needle electromyography of patients with metastatic colorectal cancer before and during treatment with oxaliplatin. Twenty-two patients had follow-up studies within 48 h following oxaliplatin infusions, and 14 patients had follow-up studies after 3-9 treatment cycles. Repetitive compound muscle action potentials and neuromyotonic discharges were observed in the first 24-48 h following oxaliplatin infusion, but resolved by 3 weeks. After 8-9 treatment cycles, sensory nerve action potential amplitudes declined, without conduction velocity changes or neuromyotonic discharges. The acute neurological symptoms reflect a state of peripheral nerve hyperexcitability that likely represents a transient oxaliplatin-induced channelopathy. Chronic treatment causes an axonal neuropathy similar to other platinum-based chemotherapeutic agents.     

Heterogeneous neuronal activity in the lateral habenula after short‐ and long‐term cocaine self‐administration in rats

Cocaine addiction is thought to be the result of drug‐induced functional changes in a neural network implicated in emotions, learning and cognitive control. Recent studies have implicated the lateral habenula (LHb) in drug‐directed behavior, especially its aversive aspects. Limited cocaine exposure has been shown to alter neuronal activity in the LHb, but the impact of long‐term drug exposure on habenula function has not been determined. Therefore, using c‐fos as a marker, we here examined neuronal activity in LHb in rats that self‐administered cocaine for either 10 or 60 days. Both the density of labeled cells and the cellular labeling intensity were measured in the lateral (LHbL) and medial (LHbM) parts of LHb. After 10 days of cocaine self‐administration, both the density and intensity of c‐fos‐positive cells were significantly increased in LHbL, but not LHbM, while after 60 days, an increased density (but not intensity) of labeled neurons in both LHbL and LHbM was observed. Most c‐fos‐labeled neurons were glutamatergic. In addition, we found increased GAD65 expression after 10 but not 60 days of cocaine self‐administration in the rostral mesencephalic tegmental nucleus. These data shed light on the complex temporal dynamics by which cocaine self‐administration alters activity in LHb circuitry, which may play an important role in the descent to compulsive drug use as a result of prolonged cocaine‐taking experience.     

Immunohistological and electrophysiological evidence that N‐acetylaspartylglutamate is a co‐transmitter at the vertebrate neuromuscular junction

Immunohistochemical studies previously revealed the presence of the peptide transmitter N‐acetylaspartylglutamate (NAAG) in spinal motor neurons, axons and presumptive neuromuscular junctions (NMJs). At synapses in the central nervous system, NAAG has been shown to activate the type 3 metabotropic glutamate receptor (mGluR3) and is inactivated by an extracellular peptidase, glutamate carboxypeptidase II. The present study tested the hypothesis that NAAG meets the criteria for classification as a co‐transmitter at the vertebrate NMJ. Confocal microscopy confirmed the presence of NAAG immunoreactivity and extended the resolution of the peptide's location in the lizard (Anolis carolinensis) NMJ. NAAG was localised to a presynaptic region immediately adjacent to postsynaptic acetylcholine receptors. NAAG was depleted by potassium‐induced depolarisation and by electrical stimulation of motor axons. The NAAG receptor, mGluR3, was localised to the presynaptic terminal consistent with NAAG's demonstrated role as a regulator of synaptic release at central synapses. In contrast, glutamate receptors, type 2 metabotropic glutamate receptor (mGluR2) and N‐methyl‐d ‐aspartate, were closely associated with acetylcholine receptors in the postsynaptic membrane. Glutamate carboxypeptidase II, the NAAG‐inactivating enzyme, was identified exclusively in perisynaptic glial cells. This localisation was confirmed by the loss of immunoreactivity when these cells were selectively eliminated. Finally, electrophysiological studies showed that exogenous NAAG inhibited evoked neurotransmitter release by activating a group II metabotropic glutamate receptor (mGluR2 or mGluR3). Collectively, these data support the conclusion that NAAG is a co‐transmitter at the vertebrate NMJ.     

Cognitive and psychiatric symptoms in genetically determined Parkinson’s disease: a systematic review

The aim was to review the existing reports on cognitive and behavioural symptoms in monogenic forms of Parkinson’s disease (PD) and to identify recurring patterns of clinical manifestations in those with specific mutations. A systematic literature search was conducted to retrieve observational studies of monogenic PD. Data pertaining to cognitive and psychiatric manifestations were extracted using standardized templates. The PRISMA guidelines were followed. Of the 1889 citations retrieved, 95 studies on PD‐related gene mutations were included: 35 in SNCA, 35 in LRRK2, four in VPS35, 10 in Parkin, three in DJ1 and eight in PINK1. Nineteen studies (20%) provided adequate data from comprehensive cognitive assessment and 31 studies (32.6%) outlined psychiatric manifestations through the use of neuropsychiatric scales. Cognitive impairment was reported in all monogenic PD forms with variable rates (58.8% PINK1, 53.9% SNCA, 50% DJ1, 29.2% VPS35, 15.7% LRRK2 and 7.4% Parkin). In this regard, executive functions and attention were the domains most affected. With respect to psychiatric symptoms, depression was the most frequent symptom, occurring in 37.5% of PINK1 cases and 41.7% of VPS35 and LRRK2 cases. Co‐occurrence of cognitive decline with visual hallucinations was evidenced. Widespread accumulation of Lewy bodies, distinctive of SNCA, PINK1 and DJ1 mutations, results in higher rates of cognitive impairment. Similarly, a higher degree of visual hallucinations is observed in SNCA mutations, probably owing to the more widespread accumulation. The lower rates of α‐synuclein pathology in LRRK2 and Parkin may underpin the more benign disease course in these patients.     

Prognostic significance of genetic biomarkers in isocitrate dehydrogenase‐wild‐type lower‐grade glioma: the need to further stratify this tumor entity – a meta‐analysis

The clinical outcomes of isocitrate dehydrogenase‐wild‐type (IDH‐wt) lower‐grade glioma (LGG) have been the subject of debate for some time. In this meta‐analysis, we aimed to assess the prognostic values of several known genetic markers (e.g. TERT promoter mutation, H3F3A mutation, CDKN2A loss) in this tumor group. Four electronic databases, including PubMed, Scopus, Web of Science and Virtual Health Library, were searched for relevant articles. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) for overall survival were calculated using a random‐effect model weighted by an inverse variance method. A total of 11 studies were finally selected from 2274 articles for meta‐analyses. Several genetic alterations were demonstrated to have a negative impact on prognosis of IDH‐wt LGGs, specifically TERT promoter mutation (HR, 1.96; 95% CI, 1.42–2.70), H3F3A mutation (HR, 3.21; 95% CI, 1.86–5.55) and EGFR amplification (HR, 1.67; 95% CI, 1.02–2.74). However, CDKN loss, ATRX mutation and coexisting gain of chromosome 7/loss of chromosome 10 showed no clinical significance in this glioma entity. Our study results demonstrated that IDH‐wt LGGs are heterogeneous in clinical outcome and not all tumors have a poor prognosis. The presence of TERT promoter mutation, H3F3A mutation and EGFR amplification showed negative prognostic impacts in this tumor entity. These genetic events can be used to better stratify patient outcomes.