Publications by authors named "Clarissa Crone"

16 Publications

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Novel Homozygous Truncating Variant Widens the Spectrum of Early-Onset Multisystemic SYNE1 Ataxia.

Cerebellum 2021 Jul 28. Epub 2021 Jul 28.

Department of Neurology, University of Copenhagen, Rigshospitalet, Inge Lehmanns Vej 8, 2100, Copenhagen, Denmark.

Pathogenic variants in the SYNE1 gene are associated with a phenotypic spectrum spanning from late-onset, slowly progressive, relatively pure ataxia to early-onset, fast progressive multisystemic disease. Since its first description in 2007 as an adult-onset ataxia in French Canadian families, subsequent identification of patients worldwide has widened the clinical spectrum and increased the number of identified pathogenic variants. We report a 20-year-old Faroese female with early-onset progressive gait problems, weakness, dysphagia, slurred speech, orthostatic dizziness, and urge incontinence. Neurological examination revealed mild cognitive deficits, dysarthria, broken slow pursuit, hypometric saccades, weakness with spasticity, hyperreflexia, absent ankle reflexes, ataxia, and wide-based, spastic gait. Magnetic resonance imaging displayed atrophy of the cerebellum, brainstem, and spinal cord. Severely prolonged central motor conduction time and lower motor neuron involvement was demonstrated electrophysiologically. Fluorodeoxyglucose-positron emission tomography (FDG-PET) scan showed hypometabolism of the cerebellum and right frontal lobe. Muscle biopsy revealed chronic neurogenic changes and near-absent immunostaining for Nesprin-1. Next-generation sequencing revealed a previously undescribed homozygous truncating, likely pathogenic variant in the SYNE1 gene. The patient's mother and paternal grandfather were heterozygous carriers of the variant. Her father's genotype was unobtainable. We expand the list of likely pathogenic variants in SYNE1 ataxia with a novel homozygous truncating variant with proximity to the C-terminus and relate it to a phenotype comprising early-onset cerebellar deficits, upper and lower motor neuron involvement and cognitive deficits. Also, we report novel findings of focally reduced frontal lobe FDG-PET uptake and motor evoked potential abnormalities suggestive of central demyelination.
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http://dx.doi.org/10.1007/s12311-021-01308-wDOI Listing
July 2021

Metastatic melanoma presenting with subacute sensory neuronopathy.

Muscle Nerve 2021 08 30;64(2):E5-E6. Epub 2021 May 30.

Copenhagen Neuromuscular Center, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1002/mus.27327DOI Listing
August 2021

Tetraparetic critically ill patients show electrophysiological signs of myopathy.

Authors:
Clarissa Crone

Muscle Nerve 2017 09 23;56(3):433-440. Epub 2017 Mar 23.

Department of Clinical Neurophysiology 3063, Rigshospitalet, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.

Introduction: Critically ill patients often develop tetraparesis. It has been debated whether this is caused by neuropathy, myopathy, or both. The aim was to determine the incidence of myopathy and neuropathy in weak patients in the intensive care unit by performing several electrophysiological examinations, including quantitative electromyography (qEMG).

Methods: Forty-nine patients referred for electrophysiological examination because of suspected critical illness-related weakness underwent qEMG, nerve conduction studies, and direct muscle stimulation.

Results: The qEMG showed signs of myopathy in 33 of 35 patients. Direct muscle stimulation was consistent with myopathy in 31 of 34 patients. Amplitudes of compound muscle action potentials were decreased in all patients. Four patients also had signs of sensory neuropathy, which could not be explained by preexisting medical conditions.

Conclusions: When combined, the results are compatible with muscle dysfunction in all patients. This will help to direct future studies of the pathophysiology of this serious condition. Muscle Nerve 56: 433-440, 2017.
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http://dx.doi.org/10.1002/mus.25525DOI Listing
September 2017

Clinical and neurophysiological response to pharmacological treatment of DOK7 congenital myasthenia in an older patient.

Clin Neurol Neurosurg 2015 Mar 15;130:168-70. Epub 2015 Jan 15.

Neuromuscular Research Unit and Department of Neurology 2081 Rigshospitalet, University of Copenhagen, 2100 Copenhagen, Denmark.

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http://dx.doi.org/10.1016/j.clineuro.2015.01.010DOI Listing
March 2015

Lyme neuroborreliosis.

Handb Clin Neurol 2013 ;115:559-75

Department of Neurology, Rigshospitalet, University Clinic Copenhagen, Denmark. Electronic address:

Lyme neuroborreliosis (LNB) designates the nervous system disorders caused by the tick-borne spirochete Borrelia burgdorferi (Bb). The clinical syndromes are usually distinct and are classified as early and the rare late or chronic LNB. Early LNB occurs 3-6 weeks after infection most frequently as a lymphocytic meningoradiculoneuritis (LMR). Symptoms are mainly due to a painful sensory radiculitis and a multifocal motor radiculo-neuritis. Fifty percent have cranial nerve involvement predominantly uni- or bilateral facial nerve palsies. Meningitic symptoms occur primarily in children. Nerve biopsies, autopsies, animal models, and nerve conduction studies showed that the pathology is a lymphocytic perineuritis leading to multisegmental axonal injury of nerve roots, spinal ganglia, and distal nerve segments. Due to meningeal and root inflammation cerebrospinal fluid (CSF) shows lymphocytic inflammation. The only evidence that Bb causes peripheral neuropathy without CSF inflammation is seen in patients with acrodermatitis chronica atrophicans (ACA), a chronic dermatoborreliosis. In the rare chronic or late LNB the pathology and thus the clinical presentation is primarily due to chronic meningitis and meningovascular CNS involvement, whereas the peripheral nervous system is not primarily affected. In early and late LNB the diagnosis is based on a characteristic clinical appearance and CSF inflammation with Bb-specific intrathecal antibody production. Both conditions, but not the ACA-associated neuropathy, respond to antibiotic therapy.
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http://dx.doi.org/10.1016/B978-0-444-52902-2.00032-1DOI Listing
April 2014

Neurophysiological approach to disorders of peripheral nerve.

Handb Clin Neurol 2013 ;115:81-114

Department of Clinical Neurophysiology, Rigshospitalet and University of Copenhagen, Copenhagen, Denmark.

Disorders of the peripheral nerve system (PNS) are heterogeneous and may involve motor fibers, sensory fibers, small myelinated and unmyelinated fibers and autonomic nerve fibers, with variable anatomical distribution (single nerves, several different nerves, symmetrical affection of all nerves, plexus, or root lesions). Furthermore pathological processes may result in either demyelination, axonal degeneration or both. In order to reach an exact diagnosis of any neuropathy electrophysiological studies are crucial to obtain information about these variables. Conventional electrophysiological methods including nerve conduction studies and electromyography used in the study of patients suspected of having a neuropathy and the significance of the findings are discussed in detail and more novel and experimental methods are mentioned. Diagnostic considerations are based on a flow chart classifying neuropathies into eight categories based on mode of onset, distribution, and electrophysiological findings, and the electrophysiological characteristics in each type of neuropathy are discussed.
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http://dx.doi.org/10.1016/B978-0-444-52902-2.00006-0DOI Listing
April 2014

Myopathic EMG findings and type II muscle fiber atrophy in patients with Lambert-Eaton myasthenic syndrome.

Clin Neurophysiol 2013 Sep 3;124(9):1889-92. Epub 2013 May 3.

Department of Clinical Neurophysiology, Rigshospitalet, University of Copenhagen, Denmark.

Objective: Lambert-Eaton myasthenic syndrome (LEMS) is a rare condition, which may mimic myopathy. A few reports have described that EMG in LEMS may show changes compatible with myopathy, and muscle biopsies have been described with type II as well as type I atrophy. The EMG results were, however, based on qualitative EMG examination and the histopathological methods were not always clear. The objective of this study was to investigate if the previous EMG findings could be confirmed with quantitative EMG (QEMG) and to describe muscle histology in LEMS.

Methods: QEMG, nerve conduction studies and muscle biopsy were performed in four consecutive LEMS patients.

Results: QEMG showed significantly decreased mean MUP duration and muscle biopsy showed marked type II fiber atrophy.

Conclusion: EMG and biopsy abnormalities mimicking myopathy may often be found in patients with LEMS.

Significance: LEMS is a debilitating, but treatable disease, which often precedes detection of a malignancy and it is therefore of obvious importance to diagnose these patients with speed and certainty. Hence it is important that neurophysiologists and neurologists are aware that EMG and histological abnormalities mimicking myopathy may be found in LEMS patients so that these findings do not prolong or misdirect the diagnostic process in these patients.
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http://dx.doi.org/10.1016/j.clinph.2013.02.115DOI Listing
September 2013

Non-Hodgkin lymphoma presenting with foot drop.

Clin Neurol Neurosurg 2012 Oct 22;114(8):1201-3. Epub 2012 Mar 22.

Department of Neurology, Copenhagen University Hospital Hillerød, Denmark.

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http://dx.doi.org/10.1016/j.clineuro.2012.02.051DOI Listing
October 2012

[New knowledge of spasticity and its treatment].

Ugeskr Laeger 2012 Feb;174(9):569-73

Center for Rett syndrom, Kennedy Centret, Gammel Landevej 7, 2600 Glostrup, Denmark.

Spasticity is a frequently used diagnosis, and anti-spastic medication is used widespread. In this systematic review article we highlight difficulties in diagnosing spasticity correctly and thus limit the value of the diagnosis in ensuring the best possible treatment. We review recent neuroscience research and conclude that it is necessary to develop better tools for clinical diagnosis of spasticity in order to avoid potential malpractice and to limit treatment with anti-spastic drugs for patients with documented increased reflex-mediated muscle tone as their main annoyance.
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February 2012

Distinguishing active from passive components of ankle plantar flexor stiffness in stroke, spinal cord injury and multiple sclerosis.

Clin Neurophysiol 2010 Nov 10;121(11):1939-51. Epub 2010 May 10.

Department of Physiotherapy, Hvidovre Hospital Kettegård Allé, 2950 Hvidovre, Denmark.

Objective: Spasticity is a common manifestation of lesion of central motor pathways. It is essential for correct anti-spastic treatment that passive and active contributions to increased muscle stiffness are distinguished. Here, we combined biomechanical and electrophysiological evaluation to distinguish the contribution of active reflex mechanisms from passive muscle properties to ankle joint stiffness in 31 healthy, 10 stroke, 30 multiple sclerosis and 16 spinal cord injured participants. The results were compared to routine clinical evaluation of spasticity.

Methods: A computer-controlled robotic device applied stretches to the ankle plantar flexor muscles at different velocities (8-200deg/s; amplitude 6°). The reflex threshold was determined by soleus EMG. Torque and EMG data were normalized to the maximal torque and EMG evoked by supramaximal stimulation of the tibial nerve. Passive resistance (the torque response to stretches) was confirmed to be a good representation of the passive stiffness also at higher velocities when transmission in the tibial nerve was blocked by ischemia.

Results: Passive torque tended to be larger in the neurological than in the healthy participants, but it did not reach statistical significance, except in the stroke group (p<0.05). Following normalization to the maximal stimulus-evoked torque, the passive torque was found to be significantly larger in neurological participants identified with spasticity than in non-spastic participants (p<0.01). There was no significant difference in the reflex threshold between the healthy and the neurological participants. The reflex evoked torque and EMG were significantly larger in all neurological groups than in the healthy group (p<0.001). Twenty three participants with evidence of hypertonia in the plantar flexors (Ashworth score⩾1) showed normal reflex torque without normalization. With normalization this was only the case in 11 participants. Increased reflex mediated stiffness was detected in only 64% participants during clinical examination.

Conclusion: The findings confirm that the clinical diagnosis of spasticity includes changes in both active and passive muscle properties and the two can hardly be distinguished based on routine clinical examination.

Significance: The data suggest that evaluation techniques which are more efficient in distinguishing active and passive contributions to muscle stiffness than routine clinical examination should be considered before anti-spastic treatment is initiated.
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http://dx.doi.org/10.1016/j.clinph.2010.02.167DOI Listing
November 2010

Hereditary spastic paraplegia caused by the PLP1 'rumpshaker mutation'.

J Neurol Neurosurg Psychiatry 2010 Jun 1;81(6):666-72. Epub 2009 Dec 1.

Section of Neurogenetics, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.

Background: Hereditary spastic paraplegia (HSP) is a group of clinically and genetically heterogeneous neurodegenerative disorders characterised by progressive spasticity and weakness in the lower limbs. Mutations in PLP1 on the X chromosome cause spastic paraplegia type 2 (SPG2) or the allelic Pelizaeus-Merzbacher Disease (PMD). The PLP1 protein is a major myelin protein involved in stabilisation and maintenance of the myelin sheath. The function of the protein has been studied in the rumpshaker mouse, which is a model of SPG2/PMD.

Objective: To characterise the phenotype of patients with the 'rumpshaker mutation.'

Patients: A family with HSP caused by the 'rumpshaker mutation.'

Results: The patients showed nystagmus during infancy and had early onset of HSP. They had normal cognition, and cerebral MRI showed relatively unspecific white matter abnormalities on T2 sequences without clear progression. Urinary urgency was reported among the female carriers. MRS of both patients showed increased myo-inositol in the white matter, while decreased N-acetylaspartate was found exclusively in the oldest patient. All evoked potential examinations were compatible with severe central demyelination, while no signs of peripheral demyelination or axonal degeneration were found. (18)F-FDG-PET scans were normal.

Conclusion: The phenotypes of the patients reported here are the mildest described to be caused by the rumpshaker mutation and represent the mildest form among the spectrum of PLP1 related disorders. No definite symptoms in the female carriers could be ascribed to the mutation. These data suggest the pathology to be an underlying dysmyelinating disorder in combination with a central axonal degeneration.
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http://dx.doi.org/10.1136/jnnp.2009.180315DOI Listing
June 2010

Diagnosis of acute neuropathies.

J Neurol 2007 Sep 21;254(9):1151-69. Epub 2007 Sep 21.

Dept. of Clinical Neurophysiology, The Neuroscience Center, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark.

Acute and subacute polyneuropathies present diagnostic challenges since many require prompt initiation of treatment in order to limit axonal degeneration and since an exact and detailed diagnosis is a prerequisite for making the correct choice of treatment. It is for instance of utmost importance to recognize whether the underlying pathological changes are due to demyelination or to axonal degeneration and electrodiagnostic tests can thus in most cases contribute considerably to the securing of an exact diagnosis. The specific and characteristic electrophysiological findings in the different types of acute and subacute neuropathies are discussed, and the various electrophysiological pitfalls and technical problems, which are met in these patients, are mentioned.
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http://dx.doi.org/10.1007/s00415-007-0532-9DOI Listing
September 2007

Post-activation depression of soleus stretch reflexes in healthy and spastic humans.

Exp Brain Res 2008 Feb 12;185(2):189-97. Epub 2007 Oct 12.

Department of Exercise and Sport Science & Department of Neuroscience and Pharmacology, Panum Institute, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.

Reduced depression of transmitter release from Ia afferents following previous activation (post-activation depression) has been suggested to be involved in the pathophysiology of spasticity. However, the effect of this mechanism on the myotatic reflex and its possible contribution to increased reflex excitability in spastic participants has not been tested. To investigate these effects, we examined post-activation depression in Soleus H-reflex responses and in mechanically evoked Soleus stretch reflex responses. Stretch reflex responses were evoked with consecutive dorsiflexion perturbations delivered at different intervals. The magnitude of the stretch reflex and ankle torque response was assessed as a function of the time between perturbations. Soleus stretch reflexes were evoked with constant velocity (175 degrees /s) and amplitude (6 degrees) plantar flexion perturbations. Soleus H-reflexes were evoked by electrical stimulation of the tibial nerve in the popliteal fossa. The stretch reflex and H-reflex responses of 30 spastic participants (with multiple sclerosis or spinal cord injury) were compared with those of 15 healthy participants. In the healthy participants, the magnitude of the soleus stretch reflex and H-reflex decreased as the interval between the stimulus/perturbation was decreased. Similarly, the stretch-evoked torque decreased. In the spastic participants, the post-activation depression of both reflexes and the stretch-evoked torque was significantly smaller than in healthy participants. These findings demonstrate that post-activation depression is an important factor in the evaluation of stretch reflex excitability and muscle stiffness in spasticity, and they strengthen the hypothesis that reduced post-activation depression plays a role in the pathophysiology of spasticity.
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http://dx.doi.org/10.1007/s00221-007-1142-6DOI Listing
February 2008

Stretch reflex regulation in healthy subjects and patients with spasticity.

Neuromodulation 2005 Jan;8(1):49-57

Department of Medical Physiology, University of Copenhagen, Copenhagen; Department of Clinical Neurophysiology, Copenhagen University Hospital (Rigshospitalet), Copenhagen; Center for Sensory-Motor Interaction, Aalborg University, Aalborg, Denmark.

In recent years, part of the muscle resistance in spastic patients has been explained by changes in the elastic properties of muscles. However, the adaptive spinal mechanisms responsible for the exaggeration of stretch reflex activity also contribute to muscle stiffness. The available data suggest that no single spinal mechanism is responsible for the development of spasticity but that failure of different spinal inhibitory mechanisms (reciprocal IA inhibition, presynaptic inhibition, IB inhibition, recurrent inhibition) are involved in different patients depending on the site of lesion and the etiology of the spastic symptoms. A recent finding also shows no sign of exaggerated stretch reflexes in muscles voluntarily activated by the spastic patient in general. This is easily explained by the control of stretch reflex activity in healthy subjects. In healthy subjects, the stretch reflex activity is increased during voluntary muscle contraction in part because of depression of the inhibitory mechanisms that are affected in spasticity. In spastic patients, these inhibitory mechanisms are already depressed at rest and cannot be depressed further in connection with a contraction. In relation to most normal movements, antagonist muscles should remain silent and maximally relaxed. This is ensured by increasing transmission in several spinal inhibitory pathways. In spastic patients, this control is inadequate, and therefore stretch reflexes in antagonist muscles are easily evoked at the beginning of voluntary movements or in the transition from flexor to extensor muscle activity. This problem is contradicted by the fact that antispastic therapy to improve voluntary movements should be directed.
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http://dx.doi.org/10.1111/j.1094-7159.2005.05220.xDOI Listing
January 2005

[Significant newer fields within clinical neurophysiology. The Danish Society of Clinical Neurophysiology].

Ugeskr Laeger 2002 Mar;164(12):1660

Klinisk neurofysiologisk afdeling 3063, H:S Rigshospitalet, DK-2100 Københavan.

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March 2002
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