Evidence-based consensus guidelines for the management of catatonia: Recommendations from the British Association for Psychopharmacology.

The British Association for Psychopharmacology developed an evidence-based consensus guideline on the management of catatonia. A group of international experts from a wide range of disciplines was assembled. Evidence was gathered from existing systematic reviews and the primary literature. Recommendations were made on the basis of this evidence and were graded in terms of their strength. The guideline initially covers the diagnosis, aetiology, clinical features and descriptive epidemiology of catatonia. Clinical assessments, including history, physical examination and investigations are then considered. Treatment with benzodiazepines, electroconvulsive therapy and other pharmacological and neuromodulatory therapies is covered. Special regard is given to periodic catatonia, malignant catatonia, neuroleptic malignant syndrome and antipsychotic-induced catatonia. There is attention to the needs of particular groups, namely children and adolescents, older adults, women in the perinatal period, people with autism spectrum disorder and those with certain medical conditions. Clinical trials were uncommon, and the recommendations in this guideline are mainly informed by small observational studies, case series and case reports, which highlights the need for randomised controlled trials and prospective cohort studies in this area.

Shaky hands are a part of motor neuron disease phenotype: clinical and electrophysiological study of 77 patients.

BACKGROUND: In the sharp contrast with the existing literature, we frequently observe minipolymyoclonus, tremor and pseudodystonic thumb posturing in patients with motor neuron disease. We conducted a clinical and electrophysiological study to describe phenomenology, prevalence and pathophysiology of involuntary movements in motor neuron disease. METHODS: We included 77 consecutive patients. Involuntary movements were assessed at rest and on action. Patients were videotaped. Arm muscle tone, power and deep tendon reflexes were evaluated. Accelerometry with electromyography was recorded in a subset of patients. RESULTS: Involuntary movements were observed in 68.9% of patients and could be separated into rest minipolymyoclonus, thumb tremor, pseudodystonic thumb posture, action minipolymyoclonus, and action tremor. One-third of patients reported negative impact of involuntary movements on hand use. Logistic regression showed that rest minipolymyoclonus and thumb tremor were more likely to occur in patients with more prominent distal muscle weakness and less spasticity. Similarly, action involuntary movements were more likely to appear in weaker patients. Patients with brisk tendon reflexes were more likely to display action tremor than action minipolymyoclonus. Action tremor was characterized by accelerometer and corresponding electromyography peak frequency, which decreased with mass loading, suggesting a mechanical-reflex tremor. CONCLUSIONS: Involuntary movements are common, but poorly recognized feature of motor neuron disease that may add to functional impairment. Results of our study suggest that involuntary movements are likely of peripheral origin, with a non-fused contraction of enlarged motor units being a common driving mechanism. Minipolymyoclonus appears if no synchronization of motor units occurs. When synchronization occurs via stretch reflex, mechanical-reflex tremor is generated.

Opicapone Efficacy and Tolerability in Parkinson's Disease Patients Reporting Insufficient Benefit/Failure of Entacapone.

BACKGROUND: Opicapone, a recently introduced catechol-o-methyl transferase (COMT) inhibitor has the advantage of being administered once daily, and has pharmacokinetic data to indicate it offers a greater degree of COMT inhibition than entacapone. Although trial data indicate it is non-inferior to entacapone, there are no data to indicate whether it offers any clinical advantages. METHODS: In this audit, we present data from 57 individuals prescribed opicapone at the National Hospital for Neurology and Neurosurgery, Queen Square who had either not tolerated or reported insufficient benefit following previous prescription of entacapone. RESULTS: A total of 20 of 57 patients switched directly from entacapone to opicapone ("entacapone switchers") whereas 37 of 57 patients had previously discontinued entacapone because of lack of benefit or adverse events ("entacapone failures"). A total of 21 of 57 (37%) patients stopped opicapone prior to 6 months. A total of 7 of 20 (35%) "entacapone switchers" experienced adverse events with opicapone of which 5 stopped the drug prior to the 6 month evaluation of efficacy. A total of 23 of 37 (62%) "entacapone failures" reported adverse events of which 16 stopped the drug. Among 36 of 57 (63%) patients who continued to use opicapone at 6 months, there was an improvement in OFF time of ~2 hours per day as measured by interview. CONCLUSIONS: We conclude that opicapone can be an effective additional treatment for wearing off in Parkinson's disease (PD) in a subgroup of patients. The use of opicapone in our cohort with prior entacapone exposure, however, was associated with higher rates of adverse effects and treatment discontinuation than reported in published trial data of COMT inhibitor naïve patients.

Tremor.

INTRODUCTION OR BACKGROUND: Tremor is one of the commonest movement disorders and can be disabling. There are many causes and treatment options include medications, adaptations, botulinum toxin injections and functional neurosurgery. SOURCES OF DATA: Pubmed.gov peer-reviewed journal articles and reviews. AREAS OF AGREEMENT: A new tremor classification has been published. Axis 1 of this classification highlights the clinical characteristics of tremor and axis 2 is dedicated to aetiology. The cerebello-thalamo-cortical network and connections to other brain areas is emerging as pivotal to many types of tremor. AREAS OF CONTROVERSY: There has been ongoing debate around the clinical entity of essential tremor and its pathophysiological basis. GROWING POINTS: Increasing understanding of the pathophysiology underpinning tremor is helping to improve classification and is pushing forward trials of new treatment options, particularly surgical options. AREAS TIMELY FOR DEVELOPING RESEARCH: With deeper phenotyping from the new classification, genetics of common forms of tremor are ripe for discovery. New pharmacological therapeutic options are needed to complement the better understanding of the basis of tremor.

Susac syndrome presenting with acute hemibody paraesthesia.

Susac syndrome is an orphan disease characterised by encephalopathy, branch retinal artery occlusion and sensorineural hearing loss. As the clinical triad is rarely present at symptom onset, it is often initially misdiagnosed and appropriate treatment is often delayed. Herewith, we report a case of Susac syndrome in a 47-year-old man presenting with acute hemisensory loss and highlight the challenges of early diagnosis, particularly relevant in the era of hyperacute stroke management.

Reappraising the role of motor surround inhibition in dystonia.

BACKGROUND: Surround inhibition (SI) in the motor system has been described to be decreased in patients with focal hand dystonia (FHD) but no evidence currently exists for patients with cervical dystonia (CD). OBJECTIVE: To characterise the SI profiles in three groups of participants: healthy volunteers, patients with FHD and patients with CD. To provide sample size calculations for future studies. METHODS: SI was assessed using Transcranial Magnetic Stimulation (TMS) in 31 right-handed healthy participants, 11 patients with CD and 12 patients with FHD. In addition data of SI in patients with FHD were extracted from previously published and analysed for sample size calculations and assessment of SI variability. RESULTS: No statistically significant difference in SI was found amongst the groups (healthy, FHD, CD). Analysis of combined current and previous data suggests that our study and all prior studies were underpowered. At least 26 participants in each group are required for a simple comparison of two groups. Analysis of published data indicated that SI is more variable in FHD patients compared to healthy controls. CONCLUSIONS: The highly variable SI in patients with dystonia can confound statistical comparisons of mean differences. Larger studies are needed to assess SI in dystonia and to explore the origins of its variability.

A Pilot Study of Botulinum Toxin for Jerky, Position-Specific, Upper Limb Action Tremor.

BACKGROUND: We aimed to investigate the efficacy and safety of botulinum toxin (BT) injections for jerky action tremor of the upper limb. METHODS: We performed an uncontrolled, prospective study of electromyography (EMG)-guided BT injections for jerky, position-specific, upper limb action tremor. The primary outcome was clinical global impression at 3-6 weeks after baseline. RESULTS: Eight patients with jerky, position-specific action tremor involving the upper limb were consecutively recruited. After a median follow-up of 4.4 weeks (interquartile range [IQR] 3.6-6 weeks), four of them rated themselves as "improved" and two as "much improved." Five of these six subjects reported improvements in specific activities of daily living (bringing liquids to mouth, feeding, shaving, and dressing). Upper limb subscore of the Fahn-Tolosa-Marin Tremor Rating Scale (FTM) significantly decreased from 4.5 (4-6) to 3 (2-5) (p = 0.01). DISCUSSION: This pilot, prospective cohort study suggests that EMG-guided BT injections may improve jerky, position-specific, upper limb action tremor. Placebo-controlled studies evaluating larger samples of patients are warranted to confirm these findings.

Validation of "laboratory-supported" criteria for functional (psychogenic) tremor.

BACKGROUND: In a small group of patients, we have previously shown that a combination of electrophysiological tests was able to distinguish functional (psychogenic) tremor and organic tremor with excellent sensitivity and specificity. OBJECTIVES: This study aims to validate an electrophysiological test battery as a tool to diagnose patients with functional tremor with a "laboratory-supported" level of certainty. METHODS: For this prospective data collection study, we recruited 38 new patients with functional tremor (mean age 37.9 ± 24.5 years; mean disease duration 5.9 ± 9.0 years) and 73 new patients with organic tremor (mean age 55.4 ± 25.4 years; mean disease duration 15.8 ± 17.7 years). Tremor was recorded at rest, posture (with and without loading), action, while performing tapping tasks (1, 3, and 5 Hz), and while performing ballistic movements with the less-affected hand. Electrophysiological tests were performed by raters blinded to the clinical diagnosis. We calculated a sum score for all performed tests (maximum of 10 points) and used a previously suggested cut-off score of 3 points for a diagnosis of laboratory-supported functional tremor. RESULTS: We demonstrated good interrater reliability and test-retest reliability. Patients with functional tremor had a higher average score on the test battery when compared with patients with organic tremor (3.6 ± 1.4 points vs 1.0 ± 0.8 points; P < .001), and the predefined cut-off score for laboratory-supported functional tremor yielded a test sensitivity of 89.5% and a specificity of 95.9%. CONCLUSION: We now propose this test battery as the basis of laboratory-supported criteria for the diagnosis of functional tremor, and we encourage its use in clinical and research practice.

Estimation of the phase response curve from Parkinsonian tremor.

Phase response curves (PRCs), characterizing the response of an oscillator to weak external perturbation, have been estimated from a broad range of biological oscillators, including single neurons in vivo. PRC estimates, in turn, provide an intuitive insight into how oscillatory systems become entrained and how they can be desynchronized. Here, we explore the application of PRC theory to the case of Parkinsonian tremor. Initial attempts to establish a causal effect of subthreshold transcranial magnetic stimulation applied to primary motor cortex on the filtered tremor phase were unsuccessful. We explored the possible explanations of this and demonstrate that assumptions made when estimating the PRC in a traditional setting, such as a single neuron, are not arbitrary when applied to the case of tremor PRC estimation. We go on to extract the PRC of Parkinsonian tremor using an iterative method that requires varying the definition of the tremor cycle and estimating the PRC at multiple peristimulus time samples. Justification for this method is supported by estimates of PRC from simulated single neuron data. We provide an approach to estimating confidence limits for tremor PRC and discuss the interpretational caveats introduced by tremor harmonics and the intrinsic variability of the tremor's period.

Developing a Tool for Remote Digital Assessment of Parkinson's Disease.

BACKGROUND: The natural fluctuation of motor symptoms of Parkinson's disease (PD) makes judgement of any change challenging and the use of clinical scales such as the International Parkinson and Movement Disorder Society (MDS)-UPDRS imperative. Recently developed commodity mobile communication devices, such as smartphones, could possibly be used to assess motor symptoms in PD patients in a convenient way with low cost. We provide the first report on the development and testing of stand-alone software for mobile devices that could be used to assess both tremor and bradykinesia of PD patients. METHODS: We assessed motor symptoms with a custom-made smartphone application in 14 patients and compared the results with their MDS-UPDRS scores. RESULTS: We found significant correlation between five subscores of MDS-UPDRS (rest tremor, postural tremor, pronation-supination, leg agility, and finger tapping) and eight parameters of the data collected with the smartphone. CONCLUSIONS: These results provide evidence as a proof of principle that smartphones could be a useful tool to objectively assess motor symptoms in PD in clinical and experimental settings.

Tremor in Charcot-Marie-Tooth disease: No evidence of cerebellar dysfunction.

OBJECTIVES: Tremor in Charcot-Marie-Tooth disease (CMT) can be disabling. Cerebellar abnormalities are thought to underpin neuropathic tremor. Here, we aim to clarify the potential role of the cerebellum in CMT tremor. METHODS: We assessed prevalence of tremor by questionnaire in 84 patients with CMT. Of those, 23 patients with CMT with and without arm tremor and healthy controls underwent a clinical assessment, classical eyeblink conditioning, electro-oculography, visuomotor adaptation test, tremor recording with surface EMG and accelerometry, and retrospective correlation with nerve conduction studies to investigate the possible mechanisms of tremor generation. RESULTS: The prevalence study revealed tremor in 21% of patients and in 42% of those it caused impairment of function. Tremor recordings revealed a mild-to-moderate amplitude tremor with a weight load-invariant 7.7 Hz frequency component. Performance on classical eyeblink conditioning, visuomotor adaptation and electro-oculography were no different between tremulous and non-tremulous patients and healthy controls. CONCLUSIONS: These results argue against a prominent role for an abnormal cerebellum in tremor generation in the patients studied with CMT. Rather, our results suggest an enhancement of the central neurogenic component of physiological tremor as a possible mechanism for tremor in the patients studied. SIGNIFICANCE: This study is the first to propose differing pathogenic mechanisms for subtypes of neuropathic tremor.

Distinguishing the central drive to tremor in Parkinson's disease and essential tremor.

Parkinson's disease (PD) and essential tremor (ET) are the two most common movement disorders. Both have been associated with similar patterns of network activation leading to the suggestion that they may result from similar network dysfunction, specifically involving the cerebellum. Here, we demonstrate that parkinsonian tremors and ETs result from distinct patterns of interactions between neural oscillators. These patterns are reflected in the tremors' derived frequency tolerance, a novel measure readily attainable from bedside accelerometry. Frequency tolerance characterizes the temporal evolution of tremor by quantifying the range of frequencies over which the tremor may be considered stable. We found that patients with PD (N = 24) and ET (N = 21) were separable based on their frequency tolerance, with PD associated with a broad range of stable frequencies whereas ET displayed characteristics consistent with a more finely tuned oscillatory drive. Furthermore, tremor was selectively entrained by transcranial alternating current stimulation applied over cerebellum. Narrow frequency tolerances predicted stronger entrainment of tremor by stimulation, providing good evidence that the cerebellum plays an important role in pacing those tremors. The different patterns of frequency tolerance could be captured with a simple model based on a broadly coupled set of neural oscillators for PD, but a more finely tuned set of oscillators in ET. Together, these results reveal a potential organizational principle of the human motor system, whose disruption in PD and ET dictates how patients respond to empirical, and potentially therapeutic, interventions that interact with their underlying pathophysiology.

Abnormalities of Masseteric Inhibitory Reflex in Hereditary Geniospasm: Evidence for a Brainstem Myoclonus.

We studied two unrelated families with several members suffering from geniospasm. Here, we aim to clarify the pathophysiology underlying the hereditary geniospasm through testing of brainstem excitability by the recovery cycles of the blink reflex (BR) and the masseteric inhibitory reflex (MIR). The R2 component of the BR and the SP2 component of the MIR and their recovery cycle were analyzed in 3 patients and 8 healthy, age-matched subjects as the control group. Patients with geniospasm exhibited a different excitability of the BR, compared to the control, group, as shown by the larger R2 component area of BR in controls than patients. Notably, the mean recovery index was 0.61 ± 0.19 in geniospasm patients and 0.40 ± 0.15 in controls (P ≤ 0.05). Interestingly, the recovery cycle of the MIR showed a loss of inhibition in both patients studied, as indicated by the behavior of the SP2 component. Our cases showed a partial impairment of the activity of brainstem inhibitory interneurons, indicated by the abnormal recovery cycle of MIR. These results would implicate a mechanism akin to brainstem myoclonus for the generation of geniospasm.

Facial tremor in dystonia.

BACKGROUND: Tremor of the upper/middle part of the face, including the perinasal region and the forehead has been very rarely described in some patients with Parkinson's disease or Essential Tremor. It has not yet been reported in patients with idiopathic dystonia. METHODS: We describe here a series of 8 patients with common forms of idiopathic focal/segmental dystonia with tremor involving the upper/middle part of the face, along with demonstrative videos and electrophysiological recordings. RESULTS: The distribution of the tremor was confined to the face in two patients, whereas in six patients tremor was also evident either in the head/lower part of the face or in their upper limbs. Electrophysiological recordings disclosed a slightly irregular tremor with a frequency at about 3-5 Hz. CONCLUSIONS: A number of patients with classical forms of dystonia can show a tremor involving the upper/middle part of the face.

Normal motor adaptation in cervical dystonia: a fundamental cerebellar computation is intact.

The potential role of the cerebellum in the pathophysiology of dystonia has become a focus of recent research. However, direct evidence for a cerebellar contribution in humans with dystonia is difficult to obtain. We examined motor adaptation, a test of cerebellar function, in 20 subjects with primary cervical dystonia and an equal number of aged matched controls. Adaptation to both visuomotor (distorting visual feedback by 30°) and forcefield (applying a velocity-dependent force) conditions were tested. Our hypothesis was that cerebellar abnormalities observed in dystonia research would translate into deficits of cerebellar adaptation. We also examined the relationship between adaptation and dystonic head tremor as many primary tremor models implicate the cerebellothalamocortical network which is specifically tested by this motor paradigm. Rates of adaptation (learning) in cervical dystonia were identical to healthy controls in both visuomotor and forcefield tasks. Furthermore, the ability to adapt was not clearly related to clinical features of dystonic head tremor. We have shown that a key motor control function of the cerebellum is intact in the most common form of primary dystonia. These results have important implications for current anatomical models of the pathophysiology of dystonia. It is important to attempt to progress from general statements that implicate the cerebellum to a more specific evidence-based model. The role of the cerebellum in this enigmatic disease perhaps remains to be proven.

Motor 'surround inhibition' is not correlated with activity in surround muscles.

Surround inhibition (SI) is a neural process that has been extensively investigated in the sensory system and has been recently probed in the motor system. Muscle-specific modulation of corticospinal excitability at the onset of an isolated finger movement has been assumed to reflect the presence of SI in the motor system. This study attempted to characterise this phenomenon in a large cohort of normal volunteers and investigate its relationship with muscle activity in the hand. Corticospinal excitability of the pathways projecting to three hand muscles [first dorsal interosseus (FDI), abductor pollicis brevis (APB) and abductor digiti minimi (ADM)] and electromyographic (EMG) activity of the same muscles were assessed in 31 healthy volunteers during an isolated index finger movement. In the agonist FDI muscle both corticospinal excitability and EMG activity were found to be increased at the onset of the movement (P < 0.001 and P < 0.001, respectively). On the contrary, in the surround ADM, there was dissociation between the corticospinal excitability (decreased: P < 0.001) and EMG activity (increased: P < 0.001). Cross-correlation analysis of the EMG activity showed that neuronal signals driving the agonist and surround muscles are not synchronised when SI is present. The results suggest a distinctive origin of the neuronal signals driving the agonist and surround muscles. In addition, they indicate that cortical output might be simultaneously modulated by voluntary and non-voluntary activity, generated in cortical and subcortical structures, respectively.

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.