Sleep disorders in multiple sclerosis

Sleep disorders are pervasive in patients with multiple sclerosis (MS) although clinically underrecognized by most physicians. The most common sleep disorders seen in patients with MS include insomnia, nocturnal movement disorders, sleep-disordered breathing, narcolepsy, and rapid eye movement sleep behavior disorder. Factors that influence the quality of sleep in this patient population include pain, nocturia, depression, medication effect, location of lesions, and disease severity. Disrupted sleep has the potential to cause daytime somnolence, increased fatigue, and nonrefreshing sleep, and it may be associated with dangerous respiratory events. Awareness and treatment of these conditions is vital to improving health and quality of life in patients with MS.     

Glossopharyngeal neuralgia and MS

Glossopharyngeal neuralgia (GPN) is characterized by a severe lancing pain in the posterior pharynx, tonsillar fossa, and base of the tongue. It is induced frequently by swallowing and yawning. GPN has not been described previously in MS patients. The authors report four MS patients with GPN. Three responded to carbamazepine and one resolved during treatment with adrenocorticotrophin hormone (ACTH) and cyclophosphamide. Withdrawal of carbamazepine after 1 week in one patient resulted in recurrence of pain. GPN may be associated with MS and responds to carbamazepine.     

Hypomanic reactions to ACTH and prednisone treatment for multiple sclerosis

Nine of 50 MS patients became hypomanic or manic during treatment with ACTH or prednisone. Symptoms did not occur with every drug exposure and were more common with ACTH. Patients at risk were identified by episodes of major depression before and after the onset of MS and by family histories of depression or alcoholism.     

Sleep disorders and fatigue in multiple sclerosis: evidence for association and interaction

Fatigue is highly prevalent in multiple sclerosis (MS). It appears to be multifactorial, with "primary" or disease-related factors involved, as well as "secondary" factors, including comorbidities. Sleep disturbances are frequent in MS as well, and often result from disease-related factors. Subjective sleep disturbances in MS have been extensively studied and have been associated with fatigue. Sleep disorders in the general population have been associated with fatigue as well. However, data on objectively diagnosed sleep disorders in MS are less conclusive. Studies of sleep in MS have often suffered from low numbers of study subjects and suboptimal methodology. We review the current knowledge on sleep disturbances in MS and the relationship to fatigue. Data from neuroimaging studies and studies of molecular consequences of sleep disorders in the general population, with particular attention to sleep-disordered breathing (SDB), are briefly reviewed. Potential biologic interactions with MS are discussed in this context. We conclude that further studies of sleep disorders in MS are needed, to objectively establish their significance in this disease, and also to document any impact of treatment of sleep disorders on biologic and clinical outcomes such as fatigue.     

Paroxysmal dystonia as an initial presentation of multiple sclerosis posing a diagnostic challenge

Tremor is the most common and frequently reported movement disorder in multiple sclerosis (MS). Paroxysmal dystonia (PD), also known as painful tonic spasm (PTS), is a relatively less common but well-recognized movement disorder in multiple sclerosis (MS). These are characterized by episodic attacks of involuntary flexion, extension movements of body. Such paroxysmal symptoms as an initial presenting feature raise many differential diagnoses and can often be mistaken as epileptic seizures as well as psychogenic events and may sometimes lead to delay in diagnosis as well. Diagnosis is clinical with the help of supportive investigations to rule out other paroxysmal disorders, especially epileptic seizures. We describe a case of a young lady, who was referred to us as a case of refractory seizure and diagnosed as having paroxysmal dystonia as a first manifestation of MS, with complete resolution of her symptoms after successful treatment with anti-epileptic drugs.

Paroxysmal dystonia (PD), also called Painful tonic spasm (PTS), is a well-recognized and the most frequently observed movement disorder in multiple sclerosis.1 The PD is classified as 4 types according to the precipitating factors, phenomenology, duration of attacks, and etiology. Paroxysmal kinesigenic dyskinesia (PKD) is induced by sudden movement, paroxys¬mal non-kinesigenic dyskinesia occurs spontaneously, paroxysmal exertion-induced dyskinesia appears after prolonged exercise, and paroxysmal hypnogenic dyskinesia occurs during sleep.2 These disorders have often been misdiagnosed as partial onset epilepsy initially and later identified as movement disorder secondary to MS. Treatment of underlying disease along with symptomatic treatment may alleviate the symptoms significantly. We described a case of a young lady who was referred to us as a case of psychogenic non-epileptic events. Diagnosis of MS manifesting with PD was established. She was started on disease modifying therapy for MS as well as Carbamazepine for her PD. She showed a remarkable improvement on these treatments and was followed up in MS clinic with no new MS relapse or recurrence of PD for 18 months after the initial presentation.     

Paroxysmal dystonia and paroxysmal tremor in a young patient with multiple sclerosis

A 16-year-old patient with multiple sclerosis (MS) showed paroxysmal movement disorders during a recurrence of the disease. The paroxysms took the form ot brief unilateral dystonic posturings of the right body suggestive of paroxysmal dystonia (PD); they completely receded with acetazolamide. A single episode of a high amplitude, rythmic slow and coarse generalized tremor, present at rest and increasing with movement, particularly involving the head in a no-no movement, occurred soon after recovery from PD and lasted three hours. The present report provides evidence that MS has to be considered in the diagnostic approach to symptomatic childhood PD and underlines the efficacy of acetazolamide in the treatment of PD attacks. It also describes a rare paroxysmal movement disorder, defined as paroxysmal dystonic tremor, that can be considered as falling within the spectrum of PD.This study was partially supported by the Paolo Zorzi Association for Neurosciences, and the Harry De Jur Foundation.     

Movement disorders in multiple sclerosis: Causal or coincidental association?

Despite the relatively frequent involvement of the basal ganglia and subthalamic nucleus by multiple sclerosis (MS) plaques, movement disorders (MD), other than tremor secondary to cerebellar or brainstem lesions, are uncommon clinical manifestations of MS. MD were present in 12 of 733 patients with MS (1.6%): three patients had parkinsonism, two blepharospasm, five hemifacial spasm, one hemidystonia, and one tourettism. MD in patients with MS are often secondary to demyelinating disease. Also in cases without response to steroid treatment and demyelinating lesions in critical regions, it is not possible to exclude that MD and MS are causally related.     

Functional magnetic resonance imaging movers and shakers: Does subject‐movement cause sampling bias?

Head movement during functional magnetic resonance imaging (fMRI) degrades data quality. The effects of small movements can be ameliorated during data postprocessing, but data associated with severe movement is frequently discarded. In discarding these data, it is often assumed that head‐movement is a source of random error, and that data can be discarded from subjects with severe movement without biasing the sample. We tested this assumption by examining whether head movement was related to task difficulty and cognitive status among persons with multiple sclerosis (MS). Thirty‐four persons with MS were scanned while performing a working memory task with three levels of difficulty (the N‐back task). Maximum movement (angle, shift) was estimated for each difficulty level. Cognitive status was assessed by combining performance on a working memory and processing speed task. An interaction was found between task difficulty and cognitive status (high vs. low cognitive ability): there was a linear increase in movement as task difficulty increased that was larger among subjects with lower cognitive ability. Analyses of the signal‐to‐noise ratio (SNR) confirmed that increases in movement degraded data quality. Similar, though far smaller, effects were found in a cohort of healthy control (HC) subjects. Therefore, discarding data with severe movement artifact may bias MS samples such that only those with less‐severe cognitive impairment are included in the analyses. However, even if such data are not discarded outright, subjects who move more (MS and HC) will contribute less to the group‐level results because of degraded SNR. Hum Brain Mapp 35:1–13, 2014. © 2012 Wiley Periodicals, Inc.     

A differential diagnosis of central nervous system demyelination: beyond multiple sclerosis

Although multiple sclerosis (MS) is the most common demyelinating disorder of the central nervous system (CNS), it lacks any definitive diagnostic test. Instead, diagnosis of MS primarily depends upon clinical criteria, supported by abnormalities characteristic of MS on para-clinical investigations including magnetic resonance imaging of the brain and spine, in the absence of an alternative explanation for underlying neurologic symptoms. While many of the potential disorders that may mimic MS in routine clinical practice are either extremely rare, or associated with specific and characteristic distinguishing diagnostic features, some inflammatory demyelinating disorders of the CNS may be particularly challenging to distinguish from MS, especially during initial presentation. In particular, acute disseminated encephalomyelitis, neuromyelitis optica, and idiopathic transverse myelitis may closely resemble MS, impeding prompt and accurate diagnosis. In this review, we describe the clinical features, diagnosis, pathology, and treatment of these other CNS demyelinating disorders. In addition, we review relevant features of other CNS inflammatory disorders that may mimic MS, including Sj?gren's syndrome, systemic lupus erythematosus, Beh?et's disease, and primary CNS vasculitis.     

A computer-assisted method for averaging movement-related cortical potentials with respect to EMG onset

The recording of movement-related cortical potentials (MRCP) relies on the use of EMG activity or some other index of movement as a trigger for averaging. EMG activity can vary considerably from one movement to the next, particularly in patients with movement disorders. This results in an MRCP formed from individual sweeps which are averaged with respect to differing periods during the EMG activity. We describe a computer-assisted method for identifying EMG onset associated with each movement made by the subject. The method allows the experimenter to reject trials associated with artefacts or with spurious trigger pulses produced by resting EMG activity. It is also possible to average the MRCP into categories associated with differing EMG characteristics such as EMG duration, peak EMG amplitude and the duration from EMG onset to peak. Using this method we have been able to record reliable MRCP from patients with movement disorders in whom this would otherwise have been technically impossible.     

Altered sensorimotor cortical oscillations in individuals with multiple sclerosis suggests a faulty internal model

Multiple sclerosis (MS) is a demyelinating disease that results in a broad array of symptoms, including impaired motor performance. How such demyelination of fibers affects the inherent neurophysiological activity in motor circuits, however, remains largely unknown. Potentially, the movement errors associated with MS may be due to imperfections in the internal model used to make predictions of the motor output that will meet the task demands. Prior magnetoencephalographic (MEG) and electroencephalographic brain imaging experiments have established that the beta (15‐30 Hz) oscillatory activity in the sensorimotor cortices is related to the control of movement. Specifically, it has been suggested that the strength of the post‐movement beta rebound may indicate the certainty of the internal model. In this study, we used MEG to evaluate the neural oscillatory activity in the sensorimotor cortices of individuals with MS and healthy individuals during a goal‐directed isometric knee force task. Our results showed no difference between the individuals with MS and healthy individuals in the beta activity during the planning and execution stages of movement. However, we did find that individuals with MS exhibited a weaker post‐movement beta rebound in the pre/postcentral gyri relative to healthy controls. Additionally, we found that the behavioral performance of individuals with MS was aberrant, and related to the strength of the post‐movement beta rebound. These results suggest that the internal model may be faulty in individuals with MS. Hum Brain Mapp 38:4009–4018, 2017. © 2017 Wiley Periodicals, Inc.     

Anti-basal ganglia antibodies in patients with atypical dystonia and tics: a prospective study

Anti-basal ganglia antibodies (ABGA) are associated with movement disorders in children, but have not been assessed in adult onset movement disorders. In a prospective assessment ABGA were positive in 65% of a group of 65 patients with atypical movement disorders, but were very rare in healthy adults and adults with idiopathic dystonia. An autoimmune mechanism may underlie a proportion of cases of atypical movement disorders.     

Adrenocorticotropin hormone 1‐39 promotes proliferation and differentiation of oligodendroglial progenitor cells and protects from excitotoxic and inflammation‐related damage

Oligodendroglia (OL) are highly susceptible to damage and, like neurons, are terminally differentiated. It is important to protect OL precursors (OPC) because they are reservoirs of differentiating cells capable of myelination following perinatal insult and remyelination in white matter diseases, including multiple sclerosis (MS). Patients with relapsing‐remitting MS are commonly treated with high‐dose corticosteroids (CS) when experiencing an exacerbation. Adrenocorticotropin hormone (ACTH), a primary component of another approved MS exacerbation treatment, is a melanocortin peptide that stimulates production of CS by the adrenals. Melanocortin receptors are also found in the central nervous system (CNS) and on immune cells. ACTH is produced within the CNS and may have CS‐independent effects on glia. We found that ACTH 1‐39 stimulated proliferation of OPC, and to a lesser extent astroglia (AS) and microglia (MG), in rat glial cultures. ACTH accelerated differentiation of PDGFRα⁺ OPC to a later stage marked by galactolipid expression and caused greater expansion of OL myelin‐like sheets compared with untreated cells. Protective effects of ACTH on OPC were assessed by treating cultures with selected toxic agents, with or without ACTH. At 200 nM, ACTH protected OPC from death induced by staurosporine, glutamate, NMDA, AMPA, kainate, quinolinic acid, H₂O₂, and slow NO release, but not against kynurenic acid or rapid NO release. These agents and ACTH were not toxic to AS or MG. Our findings indicate that ACTH 1‐39 provides benefits by increasing the number of OPC, accelerating their development into mature OL, and reducing OPC death from toxic insults. © 2014 Wiley Periodicals, Inc.     

Blood lymphocyte subpopulations show characteristic changes during ACTH therapy in acute exacerbations of multiple sclerosis

The percentages of the various lymphocyte subpopulations in blood samples of 22 patients suffering from acute bouts of multiple sclerosis (MS) were determined by E rosette formation and peroxidase staining techniques, respectively, before and during ACTH therapy. In accordance with earlier reports, most of the subjects showed a normal increase of their plasma cortisol concentrations in an ACTH quick test, which was routinely performed before the beginning of therapy. We observed a significant transitory decrease of the absolute and relative T-cell proportions with a minimum around the tenth day of treatment, accompanied by inverse changes of the null-cell numbers. The concentrations of total white blood cells, total lymphocytes, B-cells, and monocytes did not change significantly. Our results are consistent with data reported in the literature on follow-up studies of lymphocyte subpopulations in patients with myasthenia gravis undergoing treatment with ACTH and corticosteroids, respectively. Recent experimental findings indicate that T-helper cell activity can be regulated by a negative feedback control mechanism. In consideration of these reports, we discuss the significance of changes in the distribution of lymphocyte subpopulations for the therapeutic action of ACTH and corticosteroids in MS.     

ACTH protects mature oligodendroglia from excitotoxic and inflammation‐related damage in vitro

Corticosteroids (CS) are widely employed to treat relapses in multiple sclerosis (MS). Endogenous ACTH is a 39‐amino acid peptide that, among other functions, stimulates CS production. Exogenous ACTH 1‐39 is used to treat MS relapses, presumably by stimulating endogenous CS production. However, unlike CS, ACTH binds to melanocortin receptors, found in the central nervous system (CNS) as well as on inflammatory cells. Since glia are implicated in MS and other neurodegenerative diseases, and oligodendroglia (OL) are more sensitive to injury than other glia, we characterized the protective effects of ACTH on OL in vitro without the confounding effects of CS. Rat brain cultures containing OL, astrocytes (AS), and microglia (MG) were incubated for 1 day with potentially cytotoxic agents with or without preincubation with ACTH 1‐39. The cytotoxic agents killed 55–70% of mature OL, but caused little or no death of AS or MG at the concentrations used. ACTH protected OL from death induced by staurosporine, AMPA, NMDA, kainate, quinolinic acid, or reactive oxygen species, but did not protect against kynurenic acid or nitric oxide. The protective effects of ACTH were dose dependent, and decreased OL death induced by the different agents by 30–60% at 200 nM ACTH. We show for the first time that melanocortin 4 receptor is expressed on OL in addition to MG and AS. In summary, ACTH 1‐39 protects OL in vitro from several excitotoxic and inflammation‐related insults. ACTH may be activating melanocortin receptors on OL or alternately on AS or MG to prevent OL death. GLIA 2013;61:1206–1217     

Movement disorders in pregnancy

Movement disorders are not commonly seen during pregnancy. As a result, there are few studies on whether disease manifestations are affected by the hormonal changes that occur during pregnancy or on the teratogenicity of commonly used medications for movement disorders on the developing fetus. This article discusses movement disorders that are seen only during pregnancy (chorea gravidarum) or that may present during pregnancy (restless legs syndrome), the effect that pregnancy has on symptoms and treatment (in Parkinson's disease, essential tremor, dystonia, tic disorders, and Wilson's disease), and the role of genetic testing for movement disorders in genetic counseling for pregnant women.     

Phenomenology of psychogenic movement disorders in children

Psychogenic movement disorders are heterogeneous and diagnostically challenging. Despite the growing literature on adult forms, clinical features in children have received relatively little attention. We retrospectively reviewed medical records and video of patients <18 years diagnosed with a psychogenic movement disorder at our institute between 2007 and 2010. We identified 14 patients (6 males and 8 females) with a mean onset age of 11.5 years. Levels of diagnostic confidence were documented (2 patients), clinically established (8 patients), and probable (4 patients). A single movement disorder was present in 10 patients (71%); 4 patients (29%) presented an association of two or more movement disorders. Eleven patients presented other medically unexplained symptoms associated with their movement disorders. Five patients, among 6 with chronic occurrence, performed a polymyographic study showing significant modifications of frequency, amplitude, and distribution of electromyographic activity, related to distracting maneuvers. The present series represents 5% of all movement disorders observed in the considered period and 32% of nonorganic neurological manifestations. The most frequent movement disorders were tremor (36%) and dystonia (29%). We describe two phenotypes not previously reported among psychogenic movement disorders: myoclonus and association of myoclonus with dystonia. We remark on the presence of psychogenic symptoms associated with movement disorders (79%) as being one of the most useful clinical clues as well as on the value of polymyographic study in chronic psychogenic movement disorders, which provide evidence of the inconsistency of movement disorders.     

Psychogenic movement disorders

PURPOSE OF REVIEW: This review focuses on recent studies assessing clinical features and laboratory findings that may help diagnose psychogenic movement disorders, and the ongoing controversy about the relationship of these disorders with preceding peripheral injury. RECENT FINDINGS: 'Organic' movement disorders may still be misdiagnosed as psychogenic. Probably more commonly, however, psychogenic movement disorders are underdiagnosed. Most features typically associated with recognized movement disorders, including geste antagoniste or treatment-induced dyskinesias, can be seen in psychogenic movement disorder, and abnormal movements that would not normally be considered psychogenic or produced by psychological factors, such as palatal tremor, may occur on a psychogenic basis. On the other hand, psychiatric features are sometimes seen in neurologically based movement disorders. The diagnostic criteria for psychogenic movement disorders provide a degree of diagnostic certainty based on a combination of clinical and psychiatric features. Laboratory investigations can help exclude specific diagnoses, such as Parkinson's disease with (123I)beta-CIT single photon emission computed tomography, and neurophysiological methods can demonstrate characteristic features of psychogenic movement disorders, such as entrainment or suppression of psychogenic tremor with contralateral hand movements. However, some tests reported to differentiate psychogenic from neurological movement disorders may have incomplete specificity; for example, psychogenic tremor may not always be associated with complete coherence of tremor frequency. An ongoing controversy surrounds movement disorders following peripheral injuries, but recent evidence suggests that such patients should always be screened for the presence of a psychogenic movement disorder. SUMMARY: Psychogenic movement disorder continues to be a difficult diagnosis to make and is likely to be underrecognized. Clinical and laboratory features are emerging, however, that support this diagnosis. The controversy regarding posttraumatic movement disorders continues, but a diagnosis of a psychogenic movement disorder should be actively sought in such patients.     

ACTH release during passive avoidance behavior

ACTH was measured by radioimmunoassay during learning and retention of a passive avoidance response. Electric footshock, used during the learning trial, appeared to be a weaker stimulus for ACTH release than was the retention test. Moreover high latency scores during retention were associated with high plasma ACTH levels, whereas shorter latencies were associated with lower levels. The results indicate that psychological mechanisms organizing behavioral coping are important in the response of the pituitary-adrenocortical system to stimuli which are related to a previous adversive experience.