Iron dysregulation in Friedreich ataxia

Friedreich ataxia is the most common hereditary ataxia. The signs and symptoms of the disorder derive from decreased expression of the protein frataxin, which is involved in iron metabolism. Frataxin chaperones iron for iron-sulfur cluster biogenesis and detoxifies iron in the mitochondrial matrix. Decreased expression of frataxin is associated with impairments of iron-sulfur cluster biogenesis and heme synthesis, as well as with mitochondrial dysfunction and oxidative stress. Compounds currently in clinical trials are directed toward improving mitochondrial function and lessening oxidative stress. Iron chelators and compounds that increase frataxin expression are under evaluation. Further elucidation of frataxin's function should lead to additional therapeutic approaches.     

Epigenetic dysregulation in cognitive disorders

Epigenetic mechanisms are not only essential for biological functions requiring stable molecular changes such as the establishment of cell identity and tissue formation, they also constitute dynamic intracellular processes for translating environmental stimuli into modifications in gene expression. Over the past decade it has become increasingly clear that both aspects of epigenetic mechanisms play a pivotal role in complex brain functions. Evidence from patients with neurodegenerative and neurodevelopmental disorders such as Alzheimer's disease and Rett syndrome indicated that epigenetic mechanisms and chromatin remodeling need to be tightly controlled for proper cognitive functions, and their dysregulation can have devastating consequences. However, because they are dynamic, epigenetic mechanisms are also potentially reversible and may provide powerful means for pharmacological intervention. This review outlines major cognitive disorders known to be associated with epigenetic dysregulation, and discusses the potential of 'epigenetic medicine' as a promising cure.     

Dopamine dysregulation of movement control in L-DOPA-induced dyskinesia

The nigrostriatal dopamine (DA) system has an essential role in the selection and control of movement sequences, and its degeneration causes the characteristic motor symptoms of Parkinson's disease. Parkinsonian motor symptoms are alleviated by L-DOPA, but this treatment induces motor fluctuations and dyskinesias (abnormal involuntary movements). Clinical and experimental findings indicate that the motor complications of L-DOPA pharmacotherapy are triggered by transient and large changes in extracellular DA levels. The disruption of presynaptic DA homeostasis sets in motion a cascade of postsynaptic alterations, which prime the brain for a complicated motor response to dopaminomimetic treatment. L-DOPA-induced dyskinesia provides a paradigm to study how the dysregulation of DA release and clearance results in maladaptive neuroplasticity sustaining abnormal patterns of movement.     

Neurochemical and neuroendocrine dysregulation in affective disorders

Depressed patients demonstrate dysregulation in multiple neurochemical and neuroendocrine systems. The observed abnormalities are often subtle, involving "inefficiencies" in stress-responsive systems. Norepinephrine, acetylcholine, the hypothalamic-pituitary-adrenal axis, and the hypothalamic-pituitary-thyroid axis are among the major biochemical and hormonal sites of dysregulation in depression.     

Calamities in movement disorders

The field of movement disorders largely covers subacute or chronic diseases that are usually treated in outpatient clinics. However, the much less frequent acute disorders require urgent recognition and treatment. The present article reviews the entities that frequently require neurointensive management and whose development can prove "calamitous". These include neuroleptic malignant syndrome and related conditions, status dystonicus, and hemiballism.     

MicroRNA dysregulation in neuropsychiatric disorders and cognitive dysfunction

MicroRNAs (miRNA), a class of non-coding RNAs, are emerging as important modulators of neuronal development, structure and function. A connection has been established between abnormalities in miRNA expression and miRNA-mediated gene regulation and psychiatric and neurodevelopmental disorders as well as cognitive dysfunction. Establishment of this connection has been driven by progress in elucidating the genetic etiology of these phenotypes and has provided a context to interpret additional supporting evidence accumulating from parallel expression profiling studies in brains and peripheral blood of patients. Here we review relevant evidence that supports this connection and explore possible mechanisms that underlie the contribution of individual miRNAs and miRNA-related pathways to the pathogenesis and pathophysiology of these complex clinical phenotypes. The existing evidence provides useful hypotheses for further investigation as well as important clues for identifying novel therapeutic targets.     

Iron status, movement disorders, and acute phase response in elderly psychiatric patients.

The previously reported relation between iron deficiency and movement disorders was studied in a population with a high prevalence of both problems. There was no evidence of a direct statistical relation between iron deficiency and movement disorders. Significant associations were, however, found between movement disorders and features of the acute phase response to physiological stress. Indices of iron status are known to be affected by the acute phase response and it is suggested that the previously reported abnormalities in iron status may be secondary to this.     

Toxin-induced movement disorders

Toxins can be cited as a cause of several movement disorders, but this association is rare and the resultant syndromes usually include additional signs that are not typical for the idiopathic movement disorders. Most instances of confirmed toxin-induced movement disorders show lesions on CT and MRI scans of cortical or subcortical structures. A common underlying element in these toxin-induced syndromes is the development of lesions primarily in the pallidum and striatum. Because many toxins result in lesions affecting these structures, a selective vulnerability to hypoxic or metabolic insults has long been postulated. The susceptibility of these structures may relate to a number of factors, including the pattern of oxidative metabolism, heavy metal concentration, vascular perfusion, and neuronal innervation. Finally, in addition to causing disability, certain neurotoxins have led to a better understanding of human disease through the development of research models. As an example, the MPTP model has not only provided an animal model to study therapeutic strategies in PD but has also contributed important insights into the mechanism of neuronal degeneration.     

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.     

Paraneoplastic movement disorders

Neurologic paraneoplastic syndromes (NPSs) result from damage to the nervous system due to the remote effects of cancer not related to metastasis, infection, or metabolic derangements. NPSs are rare, affecting 1 in 10,000 patients with cancer. Pathogenesis is likely related to the immune mechanisms: normal neural tissue is mistakenly attacked due to the similarity in the onconeural antigens expressed by the tumor cells. Among the various “classic” and other NPSs, this review focuses on paraneoplastic movement disorders, including ataxia due to cerebellar degeneration, stiffperson syndrome, opsoclonus-myoclonus syndrome, chorea, parkinsonism, and tremor. The recently described syndrome of paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis is also included, given that these patients have complex movements such as stereotypies and dyskinesias in addition to psychiatric symptoms, altered sensorium, and other neurologic signs. Although variable, treatment and prognosis of NPSs rely heavily on treatment of the underlying malignancy and immunotherapy.     

Psychogenic movement disorders

Psychogenic movement disorders are common, but the diagnosis may be difficult. Visual appearance alone is typically not sufficient to make a diagnosis, but such information is certainly important. That a movement is bizarre can be helpful, but still must be considered thoughtfully since organic movement disorders can have endless variety. The diagnosis should rest on positive findings such as paroxysmal nature, maximum severity at or near onset, variability of tremor direction, frequency and amplitude, entrainment of tremor, distractability and suggestibility, and wildly swaying gait and balance problems with no falling. Psychogenic parkinsonism often poses a problem because of the relatively high frequency of overlap of psychogenic and organic disease. In regard to psychogenic parkinsonism, there are special features to look for. There might be tremor with kinetic movement as well as rest and posture, and finger tremor might be absent. With sequential movements, the sequence effect is typically lacking. Extreme slowness and grunting with great effort may be seen. Improvement in arm swing while running, a feature of organic parkinsonism, may not be seen.     

Sleep-related movement disorders

Several movement disorders may occur during nocturnal rest disrupting sleep. A part of these complaints is characterized by relatively simple, non-purposeful and usually stereotyped movements. The last version of the International Classification of Sleep Disorders includes these clinical conditions (i.e. restless legs syndrome, periodic limb movement disorder, sleep-related leg cramps, sleep-related bruxism and sleep-related rhythmic movement disorder) under the category entitled sleep-related movement disorders. Moreover, apparently physiological movements (e.g. alternating leg muscle activation and excessive hypnic fragmentary myoclonus) can show a high frequency and severity impairing sleep quality. Clinical and, in specific cases, neurophysiological assessments are required to detect the presence of nocturnal movement complaints. Patients reporting poor sleep due to these abnormal movements should undergo non-pharmacological or pharmacological treatments.     

Paraneoplastic movement disorders

Paraneoplastic movement disorders are rare autoimmune nonmetastatic complications of cancer. Common paraneoplastic movement disorders include cerebellar syndrome, opsoclonus myoclonus, basal ganglia disorders, stiff person syndrome, and neuromyotonia. Syndromes usually present before cancer diagnosis and are commonly associated with one or more serum antibodies. Increasing numbers of antibodies have been identified (Hu, Yo, Ri, CV2, amphiphysin, Ma, Ta, Tr, NMDA, mGluR1, PCA2, ANNA‐3, VGCCA). Antibodies are highly correlated with the likelihood of an underlying cancer and are closely associated with certain tumors. Clinical clues to paraneoplastic aetiology include speed of onset, severity, speed of progression, resistance to treatment, and more widespread neurological signs than one would expect from nonparaneoplastic aetiologies. Cancer should be sought in those with classical presentations and those with possible presentations who have paraneoplastic antibodies. If no tumor is found on initial investigation, interval screening is advisable. The most common associated cancers found are small cell lung cancer, breast, gynaecological, testicular, lymphoma, and thymoma. Early identification and treatment sometimes leads to neurological improvement and may improve cancer prognosis. Prognosis is dependent on the tumor type and its likely response to treatment. © 2009 Movement Disorder Society     

Psychogenic movement disorders

All varieties of movement disorders may be mimicked by a psychogenic disorder, most commonly tremor, dystonia, and myoclonus. Approximately 3% of patients seen in specialty clinics have a psychogenic movement disorder (PMD). The diagnosis of a PMD depends on not just ruling out an organic movement disorder, but moreover, recognizing features from the history and examination that are inconsistent or incongruous with an organic movement disorder. Most PMDs represent a conversion disorder, sometimes as part of a somatoform disorder; less common diagnoses include a factitious disorder or malingering. Co-morbid psychiatric illness is prevalent in patients with PMD including depression, anxiety, and personality disorders. Many PMDs remain chronic, but a multidisciplinary approach centering on psychiatric intervention can be successful. A shorter duration of symptoms and a co-existent treatable psychiatric disorder portend a better prognosis, whereas compensation and pending litigation are associated with a poorer prognosis.     

Psychogenic movement disorders

Diagnosis and treatment of psychogenic movement disorders are challenging for both neurologists and psychiatrists. Symptoms can mimic the full range of organic abnormal involuntary movements, affect gait and speech, or present as unusual undifferentiated movements. Typical clinical characteristics of these disorders are acute onset, fast progression, movement patterns incongruent with organic movement disorders, distractibility, variability, and simultaneous occurrence of various abnormal movements and dysfunctions. Avoidance of iatrogenic damage by unnecessary invasive tests or inappropriate medication, as well as use of appropriate psychiatric treatments are pivotal steps in the management of these disorders. The few clinical trials specific to psychogenic movement disorders focus on antidepressants and psychotherapy. Presence of a comorbid psychiatric diagnosis of depression or an anxiety disorder is a positive prognostic factor, whereas long-standing symptoms, insidious onset of movements, and a psychiatric diagnosis of hypochondriasis, factitious disorder, or malingering are associated with poor outcome.     

Involuntary movement disorders

Excluding surgical procedures, this article focuses on clinical pharmacotherapeutic approaches to treatment of parkinsonism and tremor, chorea, dystonia, tic, and tardive dyskinesia.     

Pediatric movement disorders

PURPOSE OF REVIEW: Pediatric movement disorders are a heterogeneous group of symptoms that occur in the context of a large number of different neurological diseases. Accurate diagnosis and quantification of these disorders is essential for determining outcome, appropriate treatment, and criteria for inclusion in research trials. The purpose of this review is to summarize recent advances in diagnosis and treatment for childhood movement disorders. RECENT FINDINGS: The ultimate goal is to discover new treatments that can lead to measurable improvement in functional outcome for affected children. In order to accomplish this goal, we must have consistent definitions and accurate measurements to determine the diagnosis and severity for each child in a clinic or research trial. Recent progress in defining childhood movement disorders has led to consensus definitions of different types of hypertonia. There has also been progress in the development of outcome measures that relate to meaningful functional performance in a variety of skill areas. Most exciting is the prospect of new treatments, and we survey the current non-medical, medical, and surgical therapies for childhood motor disorders. SUMMARY: Although pediatric movement disorders are a complex and often poorly understood group of symptoms, recent work has shown that there is a possibility of defining, measuring, and ultimately treating these debilitating diseases.