Maja Kojovic

Myoclonic disorders: a practical approach for diagnosis and treatment.

Myoclonus is a sudden, brief, involuntary muscle jerk. It is caused by abrupt muscle contraction, in the case of positive myoclonus, or by sudden cessation of ongoing muscular activity, in the case of negative myoclonus (NM). Myoclonus may be classified in a number of ways, although classification based on the underlying physiology is the most useful from the therapeutic viewpoint. Given the large number of possible causes of myoclonus, it is essential to take a good history, to clinically characterize myoclonus and to look for additional findings on examination in order to limit the list of possible investigations. With regards to the history, the age of onset, the character of myoclonus, precipitating or alleviating factors, family history and associated symptoms and signs are important. On examination, it is important to see whether the myoclonus appears at rest, on keeping posture or during action, to note the distribution of jerks and to look for the stimulus sensitivity. Electrophysiological tests are very helpful in determining whether myoclonus is cortical, subcortical or spinal. A single pharmacological agent rarely control myoclonus and therefore polytherapy with a combination of drugs, often in large dosages, is usually needed. Generally, antiepileptic drugs such as valproate, levetiracetam and piracetam are effective in cortical myoclonus, but less effective in other forms of myoclonus. Clonazepam may be helpful with all types of myoclonus. Focal and segmental myoclonus, irrespective of its origin, may be treated with botulinum toxin injections, with variable success.

Functional reorganization of sensorimotor cortex in early Parkinson disease

Objective: Compensatory reorganization of the nigrostriatal system is thought to delay the onset of symptoms in early Parkinson disease (PD). Here we sought evidence that compensation may be a part of a more widespread functional reorganization in sensorimotor networks, including primary motor cortex. Methods: Several neurophysiologic measures known to be abnormal in the motor cortex (M1) of patients with advanced PD were tested on the more and less affected side of 16 newly diagnosed and drug-naive patients with PD and compared with 16 age-matched healthy participants. LTP-like effects were probed using a paired associative stimulation protocol. We also measured short interval intracortical inhibition, intracortical facilitation, cortical silent period, and input/output curves. Results: The less affected side in patients with PD had preserved intracortical inhibition and a larger response to the plasticity protocol compared to healthy participants. On the more affected side, there was no response to the plasticity protocol and inhibition was reduced. There was no difference in input/output curves between sides or between patients with PD and healthy participants. Conclusions: Increased motor cortical plasticity on the less affected side is consistent with a functional reorganization of sensorimotor cortex and may represent a compensatory change that contributes to delaying onset of clinical symptoms. Alternatively, it may reflect a maladaptive plasticity that provokes symptom onset. Plasticity deteriorates as the symptoms progress, as seen on the more affected side. The rate of change in paired associative stimulation response over time could be developed into a surrogate marker of disease progression in PD.

Believing is perceiving: mismatch between self-report and actigraphy in psychogenic tremor

We assessed the duration and severity of tremor in a real-life ambulatory setting in patients with psychogenic and organic tremor by actigraphy, and compared this with self-reports of tremor over the same period. Ten participants with psychogenic tremor and eight with organic tremor, diagnosed using standardized clinical criteria, were studied. In an explicit design, participants were asked to wear a small actigraph capable of continuously monitoring tremor duration and intensity for 5 days while keeping a diary of their estimates of tremor duration during the same period. Eight patients with psychogenic tremor and all patients with organic tremor completed the study. Psychogenic patients reported significantly more of the waking day with tremor compared with patients with organic tremor (83.5 ± 14.0% of the waking day versus 58.0 ± 19.0% of the waking day; P < 0.01), despite having almost no tremor recorded by actigraphy (3.9 ± 3.7% of the waking day versus 24.8 ± 7.7% of the waking day; P = 0.001). Patients with organic tremor reported 28% more tremor than actigraphy recordings, whereas patients with psychogenic tremor reported 65% more tremor than actigraphy. These data demonstrate that patients with psychogenic tremor fail to accurately perceive that they do not have tremor most of the day. The explicit study design we employed does not support the hypothesis that these patients are malingering. We discuss how these data can be understood within models of active inference in the brain to provide a neurobiological framework for understanding the mechanism of psychogenic tremor.

Physical precipitating factors in functional movement disorders

BACKGROUND A traditional explanation for functional (psychogenic) neurological symptoms, including functional movement disorders (FMD), is that psychological stressors lead to unconsciously produced physical symptoms. However, psychological stressors can be identified in only a proportion of patients. Patients commonly reported a physical event at onset of functional symptoms. In this study, we aim to systematically describe physical events and surrounding circumstances which occur at the onset of FMD and discuss their potential role in generation of functional symptoms. METHODS We recruited 50 consecutive patients from a specialized functional movement disorders clinic. Semi-structured interviews provided a retrospective account of the circumstances in the 3 months prior to onset of the FMD. Questionnaires to assess mood disturbance and life events were also completed. RESULTS Eleven males and 39 females were recruited. Forty (80%) patients reported a physical event shortly preceding the onset of the FMD. The FMD occurred after an injury in 11 patients and after an infection in 9. Neurological disorders (n=8), pain (n=4), drug reactions (n=3), surgery (n=3) and vasovagal syncope (n=2) also preceded the onset of the functional motor symptom. 38% of patients fulfilled criteria for a panic attack in association with the physical event. CONCLUSIONS In our cohort, physical events precede the onset of functional symptoms in most patients with FMD. Although historically neglected in favour of pure psychological explanation, they may play an important role in symptoms development by providing initial sensory data, which along with psychological factors such as panic, might drive subsequent FMD.

Secondary and primary dystonia: pathophysiological differences

Primary dystonia is thought to be a disorder of the basal ganglia because the symptoms resemble those of patients who have anatomical lesions in the same regions of the brain (secondary dystonia). However, these two groups of patients respond differently to therapy suggesting differences in pathophysiological mechanisms. Pathophysiological deficits in primary dystonia are well characterized and include reduced inhibition at many levels of the motor system and increased plasticity, while emerging evidence suggests additional cerebellar deficits. We compared electrophysiological features of primary and secondary dystonia, using transcranial magnetic stimulation of motor cortex and eye blink classical conditioning paradigm, to test whether dystonia symptoms share the same underlying mechanism. Eleven patients with hemidystonia caused by basal ganglia or thalamic lesions were tested over both hemispheres, corresponding to affected and non-affected side and compared with 10 patients with primary segmental dystonia with arm involvement and 10 healthy participants of similar age. We measured resting motor threshold, active motor threshold, input/output curve, short interval intracortical inhibition and cortical silent period. Plasticity was probed using an excitatory paired associative stimulation protocol. In secondary dystonia cerebellar-dependent conditioning was measured using delayed eye blink classical conditioning paradigm and results were compared with the data of patients with primary dystonia obtained previously. We found no difference in motor thresholds, input/output curves or cortical silent period between patients with secondary and primary dystonia or healthy controls. In secondary dystonia short interval intracortical inhibition was reduced on the affected side, whereas it was normal on the non-affected side. Patients with secondary dystonia had a normal response to the plasticity protocol on both the affected and non-affected side and normal eye blink classical conditioning that was not different from healthy participants. In contrast, patients with primary dystonia showed increased cortical plasticity and reduced eye blink classical conditioning. Normal motor cortex plasticity in secondary dystonia demonstrates that abnormally enhanced cortical plasticity is not required for clinical expression of dystonia, and normal eye blink conditioning suggests an absence of functional cerebellar involvement in this form of dystonia. Reduced short interval intracortical inhibition on the side of the lesion may result from abnormal basal ganglia output or may be a consequence of maintaining an abnormal dystonic posture. Dystonia appears to be a motor symptom that can reflect different pathophysiological states triggered by a variety of insults.

Movement Disorders in Adult Patients With Classical Galactosemia

Classical galactosemia is an autosomal recessive inborn error of metabolism leading to toxic accumulation of galactose and derived metabolites. It presents with acute systemic complications in the newborn. Galactose restriction resolves these symptoms, but long‐term complications, such as premature ovarian failure and neurological problems including motor dysfunction, may occur despite adequate treatment. The objective of the current study was to determine the frequency and phenotype of motor problems in adult patients with classical galactosemia. In this cross‐sectional study, adult patients with a biochemically confirmed diagnosis of galactosemia attending our clinic were assessed with an interview and neurological examination and their notes retrospectively reviewed. Patients were classified according to the presence/absence of motor dysfunction on examination. Patients with motor dysfunction were further categorized according to the presence/absence of reported motor symptoms. Forty‐seven patients were included. Thirty‐one patients showed evidence of motor dysfunction including: tremor (23 patients), dystonia (23 patients), cerebellar signs (6 patients), and pyramidal signs (4 patients). Tremor and dystonia were often combined (16 patients). Thirteen patients reported motor symptoms, with 8 describing progressive worsening. Symptomatic treatment was effective in 4 of 5 patients. Nonmotor neurological features (cognitive, psychiatric, and speech disorders) and premature ovarian failure were more frequent in patients with motor dysfunction. Motor dysfunction is a common complication of classical galactosemia, with tremor and dystonia the most frequent findings. Up to one third of patients report motor symptoms and may benefit from appropriate treatment. Progressive worsening is not uncommon and may suggest ongoing brain damage in a subset of patients.

Botulinum toxin injections reduce associative plasticity in patients with primary dystonia.

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long‐term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation‐evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short‐interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity.

Transcranial magnetic stimulation follow-up study in early Parkinson's disease: A decline in compensation with disease progression?

A number of neurophysiological abnormalities have been described in patients with Parkinsons disease, but very few longitudinal studies of how these change with disease progression have been reported. We describe measures of motor cortex inhibition and plasticity at 6 and 12 mo in 12 patients that we previously reported at initial diagnosis. Given the well‐known interindividual variation in these measures, we were particularly concerned with the within‐subject changes over time.

Functional (psychogenic) symptoms in Parkinson's disease

It has been reported that patients who have Parkinsons disease have a high prevalence of somatisation (functional neurological symptoms) compared with patients who have other neurodegenerative conditions. Numerous explanations have been advanced for this phenomenon. Here, with illustrative cases, we discuss this topic, including its clinical importance, and suggest a link between the pathophysiology of Parkinsons disease and the proposed propensity to develop functional symptoms.

C2orf37 mutational spectrum in Woodhouse–Sakati syndrome patients

Alazami AM, Schneider SA, Bonneau D, Pasquier L, Carecchio M, Kojovic M, Steindl K, de Kerdanet M, Nezarati MM, Bhatia KP, Degos B, Goh E, Alkuraya FS. C2orf37 mutational spectrum in Woodhouse–Sakati syndrome patients.