Drug-induced myoclonus: a French pharmacovigilance database study

Various drugs have been reported to induce myoclonus. However, this adverse event is not well known because of the difficult diagnosis and the lack of pharmaco-epidemiological or controlled studies. As far as we know, there are only case reports. In the literature, antiparkinsonian medications, antipsychotics, antidepressants, anesthetics, opiates and anti-infectious drugs have been reported in the occurrence of myoclonus. In a French pharmacovigilance database study, only 423 reports (0.2%) involved drug-induced myoclonus. The median age of patients was 55 years and 10% of these patients had a concomitant neurological disease. Only 16% of these reports had a strong imputability score (likely). The most frequently involved drugs were anti-infectious (15%), antidepressants (15%), anxiolytics (14%), and opiates agents (12%). Fifty-six percent of these reports were classified as serious adverse event. Concerning outcome, most patients (84%) recovered without sequels.     

Negative myoclonus. An overview of its clinical features, pathophysiological mechanisms, and management

Negative myoclonus (NM) is an unspecific motor disorder that can characterize a variety of neurological conditions. From the clinical point of view, NM appears as a shock-like involuntary jerky movement caused by a sudden, brief interruption of muscle activity. Asterixis is a type of NM that occurs typically in toxic-metabolic encephalopathies. NM of epileptic nature, or epileptic negative myoclonus (ENM), is defined as an interruption of tonic muscle activity, which is time-locked to an epileptic EEG abnormality, without evidence of an antecedent positive myoclonia in the agonist-antagonist muscles. ENM can be observed in idiopathic, cryptogenic, and symptomatic epileptic disorders. Pathophysiological hypotheses on the origin of NM involve subcortical as well as cortical mechanisms. Recent neuroimaging and neurophysiologic investigations, including intracerebral recordings and electrical stimulation procedures in epileptic patients, suggest the participation of premotor, primary motor, primary sensory, and supplementary motor areas in the genesis of NM. Polygraphic monitoring is essential for the diagnosis of NM, allowing the demonstration of brief interruptions of a tonic EMG activity, not preceded by a positive myoclonus in the agonist and antagonist muscles of the affected limb. Simultaneous EEG-EMG monitoring demonstrating the association of NM with an epileptic potential is consistent with the diagnosis of ENM. Evolution and prognosis of NM is mainly related to aetiology. In childhood idiopathic partial epilepsy, ENM can respond to some drugs (in particular, ethosuximide), whereas other medications (such as carbamazepine or phenytoin) have been reported to induce or worsen it.     

Some genetic and biochemical aspects of myoclonus

Can a gene defect be responsible for the occurrence in an individual, at a particular age, of such a muscle twitch followed by relaxation called: “myoclonus” and defined as sudden, brief, shock-like movements? Genetic defects could indeed determine a subsequent cascade of molecular events (caused by abnormal encoded proteins) that would produce new aberrant cellular relationships in a particular area of the CNS leading to re-builded “myoclonogenic” neuronal networks. This can be illustrated reviewing some inherited neurological entities that are characterized by a predominant myoclonic picture and among which a clear gene defect has been identified. In the second part of this chapter, we will also propose a new point of view on how some structural genes could, under certain conditions, when altered, produced idiopathic generalized epilepsy with myoclonic jerks, taking juvenile myoclonic epilepsy (JME) and the myoclonin (EFHC-1) gene as examples.     

Propriospinal myoclonus at sleep onset

AIMS: To describe the clinical and polygraphic features of propriospinal myoclonus (PSM) at sleep onset. MATERIAL AND METHODS: PSM was first described in 1997 in patients with jerks occurring in the relaxation period preceding sleep. EMG showed jerks to arise in spinally innervated muscles, propagating thereafter to rostral and caudal muscles at a low speed, typical of propriospinal pathways. RESULTS: PSM arose when EEG alpha activity spread over the scalp and disappeared during either active wakefulness or actual sleep. In some patients EMG activity could sometimes remain localized to the abdominal muscles, propagating to other segments only in fully developed jerks. Neurological examination, brain and spinal MRI were usually normal and clonazepam afforded partial improvement. PSM has been recently observed also in restless legs syndrome, during relaxed wakefulness preceding falling asleep, coexisting with motor restlessness and sensory discomfort. PSM disappeared when spindles and K-complexes and typical Periodic Limb Movements appeared with EMG activity limited to leg muscles, without propriospinal propagation. CONCLUSIONS: Conceivably, PSM arises in axial muscles due to some spinal generator set into motion by facilitating influences characteristic of the wake-sleep transition and then undergoes multimeric propriospinal propagation. In the International Classification of Sleep Disorders (ICSD-2), PSM is listed in chapter VII, among the "Isolated symptoms, apparently normal variants and unresolved issues".     

Neurophysiology of myoclonus

Myoclonus may be generated by any area in the central nervous system. Finding its generator is helpful in the diagnostic process. Although clinical features have to be carefully analyzed as they may give a first idea, neurophysiologic study of myoclonus provides the most important clues for the determination of the generator. Surface electromyography (EMG) allows analyzing the recruitment order in generalized myoclonus, thereby suggesting either a cortical, brainstem, or spinal origin. It also reveals whether myoclonus is positive (jerks that are caused by muscle activation) or negative (jerks that are caused by brief muscle inhibition). In non-generalized myoclonus the EMG burst duration gives an idea of the level of the generator. Repetitive peripheral nerve stimulation is required to record somatosensory evoked potentials (SEPs) as well as long latency reflexes (LLR), especially the C reflex. The presence of giant cortical SEPs is an indirect argument for cortical myoclonus. Similarly the existence of LLR at rest orientates towards cortical reflex (sensitive to sensory stimuli) myoclonus. Finally EEG-EMG polygraphy is the only test which is able to prove directly the cortical origin of myoclonus. This is the case when focal cortical events precede myoclonus with a fixed delay. These premyoclonic cortical potentials may either be seen directly on raw recordings or require the use of jerk-locked back averaging (JLBA). This technique allows the averaging of the EEG prior to myoclonus onset (as determined by EMG) in order to reveal a premyoclonic spike that otherwise would remain undetected in the global EEG.     

Proprioception and myoclonus

This review focuses on sensory information originating from muscle spindles and its role in proprioception and motor control. The first part reminds of the structural and functional properties of these muscle mechanoreceptors, with arguments for an independent fusimotor command, i.e. the gamma-motoneurons, that would regulate spindle mechanical sensitivity in keeping with the requirements of ongoing motor action. The possibility that dysfunction of the fusimotor system might be responsible for clinical signs is discussed with respect to the hyperexcitability of the sensorimotor cortex that is observed in myoclonus of cortical origin. What is known about the spindle afferents projections into the spinal cord and about the dysfunction of the spinal sensorimotor networks in patients with neurological disorders, is put together in the second part. It is stressed on the significant complexity of the monosynaptic reflex in spite of its "simple" organization. The monosynaptic reflex constitutes the only possible way for testing the excitability of motoneurons and spinal networks. This method is extensively used clinically to examine changes in the nervous system with diseases. When studying changes from the norm, it is important to understand how the reflex functions in neurologically normal conditions. Different mechanisms such as pre-synaptic inhibition, post-activation depression and motoneuronal intrinsic properties are reviewed as they may induce changes in reflex amplitude and have therefore consequences for interpretation of spinal excitability.     

Electroencephalographic staging of hepatic encephalopathy by an artificial neural network and an expert system

AIM OF THE STUDY: To provide an objective EEG assessment of hepatic encephalopathy (HE), we set up and tested an entirely automatic procedure based on an artificial neural network-expert system software (ANNESS). PATIENTS AND METHODS: A training set sample of 50 EEG (group A) and a test sample of 50 EEG (group B) of 100 cirrhotic patients were considered. The EEGs had been visually classified by an expert electroencephalographer, using a modified five-degree Parsons-Simith classification of HE. The efficiency of the ANNESS, trained in group A, was tested in group B. RESULTS: Both the ANNESS and the visually-based classifications were found to be correlated to liver insufficiency, as assessed by the Child-Pugh score (Spearman's coefficient rho=0.485, P<0.0001; rho=0.489, P<0.0001, respectively) and by the biochemical indexes of hepatic function (bilirubin: rho=0.31 vs. 0.27; albumin: rho=-0.13 vs. -0.18; prothrombin time rho=-0.35 vs. -0.52). The classifications were found to be correlated to each other (rho=0.84 P<0.0001, Cohen's kappa=0.55). However, the ANNESS overestimated grade 2 EEG alterations. CONCLUSION: An ANNESS-based classification of EEG in HE provided data comparable with a visually-based classification, except for mild alterations (class 2) that tended to be overestimated. Further optimization of automatic EEG staging of HE is desirable, as well as a prospective clinical evaluation.     

Myoclonus and transcranial magnetic stimulation

The neural dysfunction at the origin of myoclonus may locate at various anatomical levels within the central nervous system, including the motor cortices. Transcranial magnetic stimulation (TMS) can be used to assess the balance between inhibitory and excitatory processes involved in the regulation of motor cortex activity and thereby, may be of value to determine the pathophysiological mechanisms of myoclonus. Using paired-pulse paradigms with various interstimulus intervals, TMS studies showed that intracortical inhibition (ICI) was reduced in progressive myoclonic epilepsy (PME). In contrast, ICI was decreased only for short interstimulus intervals in patients with juvenile myoclonic epilepsy (JME). Transcallosal inhibition and sensorimotor integration were also both altered in PME but not in JME. Actually, the loss of inhibitory regulation within the central nervous system might represent an intrinsic mechanism of myoclonus, whether of epileptic origin or not. Finally, the other TMS parameters of excitability (motor threshold, silent period, intracortical facilitation) were found normal in most cases of myoclonus. According to these observations, it was quite conceivable that the application of repetitive trains of TMS (rTMS) at inhibitory low-frequency (around 1 Hz) might be able to relieve myoclonus by restoring ICI. A few reported cases illustrate the efficacy of low-frequency rTMS to alleviate myoclonic symptoms. Therapeutic-like perspectives are opened for rTMS in these forms of myoclonus that are related to motor cortical hyperexcitability secondary to the loss of ICI.     

Syndrome démentiel dans les suites d’une bipolarité

Introduction

Converging evidence suggests that people with bipolar disorder (BPD) exhibit persistent cognitive impairment independently from the emotional state. In old age BPD, the cognitive decline is more severe and can fulfill the criteria of dementia. However, the characteristics of bipolar disorder dementia are still unknown.

Aim of the study

The aim of the study was to characterise the cognitive and imaging profile of the dementia following bipolar disorder.

Method

Patients fulfilling criteria of dementia and followed-up in the memory unit for at least two years were included. Patients with substance abuse were excluded. A battery of specific (assessing verbal memory, attention, frontal executive function, construction and visuospatial impairment), and global (MMSE and Mattis dementia rating scale) neuropsychological tests, behavioural assessment using the frontotemporal behavioural scale, MRI and HMPAO–SPECT imaging were performed in all patients during euthymic state.

Results

We included 13 patients with bipolar disorder (9W/4M). The mean age was 70.8 years (±7.7). Dementia began in average 29.2 years (±10.1) after the onset of the bipolar disorder. The mean score of MMSE was 24.0 (±4.3). The mean score of the Mattis dementia rating scale was 122.5 (±8.9). After an average of 6.1 years (±2.8) of follow-up, the mean score of MMSE was 23.5 (±3.2). The annual MMSE score decrease was of 0.5 (±4.4) per year. In more than 75% of the patients, Trail-Making Test-part B, Go-nogo test, Stroop test, delayed free recall in verbal explicit long-term memory test, category fluency tasks and code test were impaired. In more than 50% of patients, free recall, delayed cued recall, clock test, visuospatial battery and temporal orientation were impaired. On the other hand, spatial orientation and recognition were within the standards. The mean of the BREF score was 10.6 (±3.2). A moderate frontal behavioural syndrome was observed, but never persistent hallucinations. Seven patients had been treated with lithium and seven with antipsychotics, but none during the neurological assessment. Moderate extrapyramidal signs were reported in 10 patients, of which the seven patients treated in the past with antipsychotics. MRI showed no focal atrophy and no vascular lesions. Functional imaging conducted in 10 patients always showed uptake decrease in the frontotemporal regions and sometimes in the parietal region too. After six years of follow-up, no patient fulfilled the probable criteria for the main dementia, Alzheimer disease, vascular dementia, frontotemporal dementia and dementia with Lewy bodies.

Conclusion

The data of this study support a possible specific dementia postbipolar disorder and not only mild cognitive decline. This hypothesis could be tested in a prospective study. Such dementia could be a main differential diagnosis from long lasting frontotemporal dementia. The pathogenic process of this dementia could also be determined.     

Myoclonus and movement disorders

Myoclonus is a movement disorder characterized by the occurrence of an involuntary abrupt muscle contraction causing a sudden unexpected jerk. Many other movement disorders can present with the same jerky, shock-like appearance. This paper reviews the clinical and neurophysiologic arguments supporting the distinction between true myoclonus and various imitators, including chorea, ballism, tics, dystonia, stereotypy, tremor and restless limbs. To be differentiated from myoclonus, these movement disorders, despite their heterogeneity, are distinctive through the patterned profile of muscle activation, the longer duration of the muscle contraction, the conditions in which they occur, and their suppressibility at will.     

Caractérisation clinique et criminologique des meurtriers âgés présentant une démence

Homicide is an extreme outcome of violence which is infrequent in older adults, with a prevalence ranging from 1% to 4%. In those cases, homicide is usually followed by suicide. Homicide appears in different psychopathology contexts: Mood disorder, alcohol disorder and psychosis disorder. An association of mild to moderate dementia with homicide has been reported. The risk factors of homicide in demented patients remain unknown. Dysexecutive syndrome could be a cause of homicide in demented patients. The reported case highlights this issue and shows that neuropsychiatric evaluation of older murderers could be useful in understanding the murder. Clinical and criminological characteristics of elderly murderers with a dementia will also be discussed.     

Psychiatric, psychological comorbidities of typical and atypical Charles-Bonnet syndrome

Objectives

Charles-Bonnet syndrome (CBS) is conventionally defined by the presence of visual hallucinations in patients suffering from lowered visual acuity without having psychosis or dementia. Actually, it is a syndrome that interests many specialties, especially ophthalmology, geriatrics, neurology and psychiatry. “Atypical CBS” or “CBS plus” was introduced to designate any kind of visual hallucinations that could be considered as a CBS but accompanied by a low level of insight, a possible cognitive decline, other hallucinatory modalities etc. Since all patients suffering from CBS have to be psychiatrically evaluated, psychological and psychiatric implications of their syndrome have to be well understood in order to better manage them. These psychiatric and psychological implications are: the relationship between the CBS and dementia, the psychological reaction of the patients towards their hallucinations and psychiatric comorbidities that could be developed during the course of the syndrome.

Methods

A research via MEDLINE for all the articles published in French or in English between January 1999 and December 2009 was done using the following keywords Charles-Bonnet, psychiatric comorbidities and Charles-Bonnet syndrome, Charles-Bonnet syndrome and dementia, psychological reaction and Charles-Bonnet syndrome.

Results

Although some studies report an association between the CBS and dementia, the majority of these studies do not confirm this association and point towards an atypical initial presentation of the syndrome. The psychological reaction accompanying the visual hallucinations of the typical CBS is variable (mild distress, indifference, pleasure). Patients suffering from a typical CBS conserve a full insight during the course of the syndrome. A positive personal psychiatric history or a concomitant psychiatric disorder changes the clinical presentation of the syndrome.

Discussion

Our research allowed us to define the following diagnostic criteria for the atypical CBS: 1) diminished level or absence of insight towards the visual hallucinations; 2) presence of a mild cognitive decline; 3) presence of an atypical psychological reaction towards the visual hallucinations as in the case of a severe and prolonged stressful reaction; 4) presence of other hallucinatory modalities; 5) presence of a positive personal psychiatric history or a concomitant psychiatric disorder. Each patient suffering from CBS should be initially evaluated psychiatrically and neurologically in order to confirm or to eliminate the presence of the most common causes of visual hallucinations. In the presence of a lowered visual acuity and a conserved cognitive functioning, the typical CBS is diagnosed after eliminating more common disorders. Once this diagnosis is established, patients should be evaluated in order to rule out the presence of an atypical clinical presentation.

Conclusion

Atypical CBS is a syndrome that could be eventually associated with dementia, accompanied with a major depressive disorder or another psychiatric disorder, or with vulnerability towards psychiatric disorders. Patients suffering from atypical CBS should be closely followed psychiatrically and neurologically. Patients suffering from the typical CBS should also benefit from a psychiatric follow-up, due to their multiple psychiatric vulnerability factors and their possible management with psychotropic drugs.     

Myoclonus and extrapyramidal diseases

Parkinsonism or dystonia are associated with myoclonus in several extrapyramidal diseases. Although the latter symptom is not always prominent, stimulus-sensitive, distal, or focal reflex myoclonus is frequently observed. This review will consider the clinical and electrophysiological features of myoclonus in Parkinson's disease, multiple system atrophy, corticobasal degeneration, progressive supranuclear palsy, Huntington's disease, dentatorubral−pallidoluysian atrophy, Lewy body dementia, and myoclonus with dystonia. The evidence of a long-latency reflex response, the presence of giant somatosensory evoked potentials, and the demonstration of a back-averaged premyoclonus focal cortical EEG activity often lead to classify myoclonus as a cortical phenomenon. However, a subcortical origin cannot always be ruled out.     

How far do patients with sensory ataxia benefit from so-called “proprioceptive rehabilitation”?

A rehabilitation program including foot sensory stimulation, balance and gait training with limited vision was performed in 24 patients with clinically defined sensory ataxia. There were 15 patients with bilateral somatosensory loss related to chronic neuropathy and nine patients with unilateral loss-related to multiple sclerosis. After training, balance control assessed using the Berg Balance Test improved similarly in both groups, and Romberg's sign disappeared in some patients, suggesting an improvement in dynamic balance and in the proprioceptive contribution. Conversely, balance assessed on a static force platform remained similar in the open-eyes condition and improved in the closed-eyes condition only in patients with unilateral sensory loss. These results show that ataxic patients can improve their balance with better results in dynamic conditions and that the relative contribution of proprioceptive and visual inputs may depend on the extent of somatosensory loss.     

Startle and its disorders

Exaggerated startle is an uncommon feature of various neurological diseases, but is still lacking precise analysis in many of them. So far, electrophysiologic and cinematographic analyses allow discriminating two main subtypes. The prototype of primary exaggerated startle is hereditary hyperekplexia, a well-studied disorder of the inhibitory glycine receptor and thus of the neuronal Cl- channel. The involuntary jerking in hereditary hyperekplexia is considered a reticular reflex myoclonus. The prototype of primary normal startle with secondary abnormalities is startle epilepsy where a surprise stimulus typically provokes a normal startle, which in turn initiates a focal (most often frontal lobe) seizure with tonic posturing of the limbs. Clinical differential diagnosis between both subtypes may be difficult in individual cases, but there are abnormalities in clinical and neurophysiologic reflex testing, which need, however, broad validation.     

Carence en vitamine B12, ataxie cérébelleuse et troubles cognitifs

Introduction

Vitamin B12 deficiency is often associated with neurological disorders of which combined sclerosis of the spinal cord is a common manifestation.

Case report

We report the case of a woman who presented cerebellar ataxia and cognitive deficits associated with leukoencephalopathy on the brain MRI. These symptoms were associated with vitamin B12 deficiency due to Biermer's disease. Vitamin B12 supplementation led to symptom improvement. Later her treatment was discontinued and the patient's clinical status worsened to a bedridden status.

Conclusion

Ataxia cerebellar dementia and leukoencephalopathy can result from vitamin B12 deficiency. To limit the risks of sequelae, vitamin B12 supplementation should be started at an early stage.     

Les délires d’infestation cutanée parasitaire. Syndrome d’Ekbom

Ekbom's syndrome (delusional cutaneous parasitosis) is an “uncommon psychiatric syndrome” characterized by a strong certainty that insects, lice, maggots or other small vermin are living or otherwise thriving in the skin and sometimes in other parts of the body (Enoch, Ball, 2001). Described by Thiebierge (1894) and Perrin (1896), two dermatologists, it received the name of zoophobia, parasitophobia, acariophobia. The eponymous designation is Ekbom syndrome from the Swedish neurologist who described its principal manifestations (1937-1938). Annika Skott (1978) published the pivotal monograph (based on 354 cases, 1954-1961) with the title term Dermatozoenwahn coined by Ekbom, as did Michael Musalek in his book published in German (1991). It is a rare condition (7 per 10 000 psychiatric admissions according to Marneros et al (1998). Several other surveys report series of patients seen in dermatology clinics. It is seen occasionally by dermatologists, exceptionally by psychiatrists. Typically it is supposed to be cured by Pimozide or other neuroleptic or new antipsychotic drugs. A majority of patients are aged females, living alone in bad material conditions. Some patients are chronically addicted to cocaine and amphetamine-like drugs. This delusion could be psychologically contagious with cases of “délire à deux (à trois)”, or by proxy… Another phenomenon is called “the Morgellons disease”, described by Thomas Browne (1690) (A Letter to a friend) in Languedoc. For the CDC there is no proof that the Morgellons is a separate pathology. On the contrary, Mary Leitao (McMurray, Pennsylvania 2002) gave the name of “Morgellons disease” to what she considered the resurgence of an ancient and forgotten malady, which affected children of Languedoc in 17th century. There is an Morgellons Research Foundation (MRF) to encourage research about this infectious malady similar to scabies and pediculosis. The website claims that more than 12 000 families affected by Morgellons are registered with the foundation, and self accounts of affected individual are over flowing.