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Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies
Journal of Clinical Neuroscience xxx (2018) xxx–xxx
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Review article
Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies Raffaele Nardone a,b,c,⇑, Francesco Brigo a,d, Viviana Versace e,f, Luca Sebastianelli e,f, Monica Christova g,h, Stefan Golaszewski a,c, Leopold Saltuari e,f,i, Eugen Trinka b,j,k a
Department of Neurology, Franz Tappeiner Hospital, Merano, Italy Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria Karl Landsteiner Institut für Neurorehabilitation und Raumfahrtneurologie, Salzburg, Austria d Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Italy e Department of Neurorehabilitation, Hospital of Vipiteno, Italy f Research Unit for Neurorehabilitation South Tyrol, Bolzano, Italy g Department of Physiology, Medical University of Graz, Austria h Department of Physiotherapy, University of Applied Sciences FH-Joanneum, Austria i Department of Neurology, Hochzirl Hospital, Zirl, Austria j Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria k University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria b c
a r t i c l e
i n f o
Article history: Received 12 May 2018 Accepted 5 October 2018 Available online xxxx Keywords: Corticobasal degeneration Electroencephalography Transcranial magnetic stimulation Motor evoked potentials Sensory evoked potentials Long latency reflexes
a b s t r a c t Background: Several studies have applied electrophysiological techniques to physiologically characterize corticobasal degeneration (CBD). Methods: We performed a systematic literature search of these studies and reviewed all 25 identified articles. Results: Conventional electroencephalography (EEG) is usually normal even in the late stages of disease. Quantitative EEG (qEEG) with spectral analysis revealed mainly lateralized abnormalities, such as an increase of slow wave activity and occasionally the occurrence of sharp waves, and a significant increase of coherence between left parietal-right premotor areas. CBD patients generally have long latency reflexes (LLR) with shorter latencies than in the classic cortical reflex myoclonus observed in progressive myoclonic epilepsy. The somatosensory evoked potentials (SEPs) showed reduced amplitude of the N20– P25 component. These abnormalities may reflect dysfunction of sensory projections to the motor cortex, while the localized parietal cortical damage is thought to be a pivotal factor for the absence of giant SEPs in these patients. Transcranial magnetic stimulation (TMS) revealed asymmetric intracortical disinhibition and asymmetric maps organization; an impaired transcallosal pathways function correlates with the atrophy of the corpus callosum. These findings suggest a pathologic hyperexcitability of the motor cortex, due to a loss of inhibitory input from the sensory cortex. Conclusions: Neurophysiological techniques, in combination with neuroimaging studies, may shed light on the pathophysiological mechanisms of CBD. A better understanding of the disease processes may help clinicians to make a more accurate and early diagnosis. TMS, SEP, LLR, and co-evaluation of EEG and EMG can aid the in differentiation between CBD and other parkinsonism syndromes. Ó 2018 Published by Elsevier Ltd.
1. Introduction Corticobasal degeneration (CBD) is an uncommon neurodegenerative disease, described for the first time by Rebeiz et al. [1], characterized by an asymmetrical parkinsonism affecting one limb, ⇑ Corresponding author at: Department of Neurology, ‘‘F. Tappeiner” Hospital – Merano, Via Rossini, 5 39012 Merano, (BZ), Italy. E-mail address: [email protected] (R. Nardone).
typically an arm. Rigidity is the most common manifestation, followed by bradykinesia, gait disorder characterized by postural instability and falls, tremor, asymmetrical limb dystonia and higher cortical dysfunctions such as apraxia. CBD can be associated with a wide variety of motor, sensory, cognitive and behavioural symptoms [2]. Dementia, progressive nonfluent aphasia, speech apraxia, progressive-supranuclear-palsy-like syndrome and posterior cortical atrophy syndrome are other presentations of CBD [3,4].
https://doi.org/10.1016/j.jocn.2018.10.027 0967-5868/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027
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The symptoms of CBD are often difficult to understand and the patients may have difficulties in describing their experience. Electrophysiological techniques, together with neuroimaging methods, might shed light on the pathophysiological mechanisms of this condition. A better understanding of the disease may help clinicians to make an early diagnosis. Neurophysiological methods could be applied to differentiate this disease from the other parkinsonism syndromes, and thus achieve a more accurate clinical diagnosis. We reviewed and discussed here the electrophysiological studies that have been performed in subjects with CBD.
2. Methods A literature review was conducted using MEDLINE, accessed by Pubmed (1966 – February 2018) and EMBASE (1980 – February 2018) electronic databases. The following medical subject headings (MeSH) and free terms were searched: ‘‘corticobasal degeneration”, ‘‘electroencephalography‘‘, ‘‘EEG”, ‘‘transcranial magnetic stimulation”, ‘‘motor evoked potential”, ‘‘sensory evoked potential”, ‘‘long latency reflex”. Only original articles written in English were considered eligible for inclusion. Review articles were excluded. For the selected titles full-text articles were retrieved, and reference lists of them were searched for additional publications. The principal investigators of the included studies were contacted in those cases in which useful informations were missing or incomplete. Titles and abstracts of the initially identified studies were independently screened in order to determine if they satisfied the selection criteria. The methodological quality of each study and risk of bias was assessed, focusing on blinding. Any disagreement was solved through discussion. This search strategy yielded 25 studies which contributed to this review. A flow-chart (Fig. 1) shows the selection/inclusion process.
3. Neurophysiological findings 3.1. Electroencephalography Conventional electroencephalography (EEG) may be normal when the first clinical symptoms appear, and often remains unchanged as the disease progresses. Nevertheless, an unilateral slowing may be evident in some patients, which may occasionally generalize to the whole cortex as the disease evolves [5,6]. Using a quantitative standard EEG (qEEG) with spectral analysis, the occurrence of several EEG abnormalities (usually enhanced by hyperventilation or intermittent photic stimulation), such as an increase of slow rhythms (delta or theta frequency range) and occasionally the occurrence of sharp waves were found in a study involving six patients [7]. These abnormalities were lateralized in five patients (more often after hyperventilation) and bilateral in one, thus confirming the asymmetrical features of CBD. Moreover, Huang and colleagues showed that the EEG recordings with jerklocked back average do not present any jerk-locked cortical potentials [8]. In another study, five patients with ideomotor apraxia (three of them with CBD) underwent 64-channel EEG recording while performing three tool-use pantomimes with their left hand in a selfpaced manner. Beta band (20–22 Hz) coherence indicates that normal subjects have a dominant left hemispheric network being involved in praxis preparation, which was absent in patients. CBD patients showed a significant increase of coherence between left parietal-right premotor areas [9] (Fig. 2). In a more recent case report no abnormalities were observed on EEG examination, but a more sophisticated analysis showed a focal slow wave activity in the right parietotemporal area [7]. 3.2. Somatosensory evoked potentials In CBD the cortical sensory evoked potentials (SEPs) are not enlarged as in cortical reflex myoclonus, and backaveraged cortical
Fig. 1. Flow-chart showing the selection/inclusion process.
Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027
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Fig. 2. Time-magnitude plot of individual coherence values for patients with corticobasal degeneration (CBD) for each network of interest for all participants relative to movement onset (s). Asterisks (*) indicate significant increases. Reproduced with permission from Wheaton et al., 2008.
potentials do not precede each myoclonic jerk [10–12]. Clinical and imaging evidence suggests that the localized parietal cortical damage is a pivotal factor for the absence of a giant SEP in these patients [13]. The SEPs showed reduced amplitude of the N20– P25 component without giant SEP characteristics. The latencies of the cortical event and of the late responses, as well as the duration and distribution of the discharges share similarities with those of the cortical reflex type of myoclonus. An asymmetric alteration of inhibitory and excitatory balance at the level of cortical neurons leading to a particularly enhanced cortical excitability may additionally play an important role in the generation of myoclonus [11,12]. The loss of the inhibitory input from the somatosensory cortex to the relatively intact motor cortex, which results from the prominent asymmetric parietal atrophy, may give rise to the asymmetric hyperexcitable motor cortex without giant SEP [14,15]. Alternatively, the existence of an alternative hyper-excitable thalamo-cortical pathway should be considered [16]. In a clinical, neuroradiological and neurophysiological study on ten patients with clinically probable CBD, the SEP N30 frontal component was found to be absent bilaterally in four patients, was absent on the left side in one and had increased latency in other three [12]. 3.3. Transcranial magnetic stimulation Monza et al. in their above mentioned study also reported abnormal motor evoked potentials (MEPs) elicited by transcranial
magnetic stimulation (TMS) in four out of 10 patients with probable CBD; three had prolonged central motor conduction time, one of whom also had increased MEP threshold, and one had increased MEP threshold [12]. An alteration in cortical excitability, as evaluated by means of TMS, was also detected in patients with CBD [10]. In fact, motor cortex disinhibition has been clearly demonstrated in CBD by means of TMS applied in several paradigms in different neurophysiological studies [16–18]. By applying single pulse-TMS, Lu and coworkers discovered a relatively higher MEP amplitude and a significantly shorter cortical silent period (SP) in the affected hand of CBD patients [10]. The relatively enlarged MEP could be explained by postulating that an increased number of motoneurons are being recruited by the descending volleys from the motor cortex [10], while the shorter cortical SP may reflect mainly defective inhibitory processes [16]. The results from paired pulse-TMS studies also supported the hypothesis of a reduced intracortical inhibition [8,10,20]. In particular, Frasson and colleagues showed that paired magnetic stimuli delivered at short (inhibitory) interstimulus intervals (ISIs) invariably elicited enlarged MEPs in patients with CBD (Fig. 3). Furthermore, asymmetric corticocortical disinhibition [19,21], as well as asymmetric TMS maps organization [16,22], have been observed in patients with CBD. Another study evaluated the motor function of the transcallosal pathways in patients with CBD has also been evaluated [23]. Ipsilateral SP (iSP) was normal in 3 out of 7 CBD patients. Therefore, it can be assumed that a proportion of CBD patients shows
Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027
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Fig. 4. Ipsilateral silent period (iSP) in patients with CBD. Each recording represents the average of 7 consecutive rectified EMG traces obtained, during maximal voluntary tonic contraction, in the more and less affected opponens pollicis muscle, after TMS (100% of the stimulator output) of the ipsilateral motor cortex. TMS induced an evident inhibition of the ongoing EMG activity in patients 1–4. The iSP was evidently impaired (or absent) in patients 5–7. Note the occurrence of an ipsilateral excitatory response in the more affected side of patient 4. Reproduced with permission from Trompetto et al., 2003.
3.4. Other techniques
Fig. 3. (A) Mean intracortical excitability curves (mean 1 SEM) for the group of healthy control subjects (triangles), patients with CBD (rhombuses) and Parkinson’s disease patients (squares). ISIs are given on the abscissa, the size of conditioned test MEPs as the percentage of the test alone on the ordinate. Horizontal line (100%) indicates the size of test MEPs, lower values indicate intracortical inhibition, and higher values indicate facilitation. Note the intracortical facilitation in the patients with CBD. (B) Intracortical excitability at the ISI of 4 ms in the single patients with CBD (triangles) and patients with PD (circles). The size of conditioned test MEPs as the percentage of the test alone are given on the ordinate. The horizontal dashed line (100%) indicates the mean size ^ 2.5 SD (continuous line). Note that at the 4 ms ISI, all CBD patients had marked intracortical facilitation and all PD patients had responses in the normal range (mean ^ 2.5SD). Reproduced with permission from Frasson et al., 2003.
physiological evidence of impaired transcallosal motor function, which correlates with an atrophy of the corpus callosum on MRI, and is possibly correlated to cognitive disorders (Fig. 4). In another TMS study on patients with various disorders presenting with a parkinsonian syndrome, iSP was abnormal in all the examined five CBD patients [24]. This subgroup was also characterized by a significant atrophy of the corpus callosum as compared with control subjects. Several mechanisms could explain the abnormal motor cortical excitability; the loss of inhibitory neurons in the cortex or thalamus, effects of morphological changes in cortical neurons mainly in the somatosensory cortices, disruption of some neuronal circuits, or the existence of alternative cortical-subcortical pathways [17,25]. Further electrophysiological studies are necessary to better circumstantiate these hypotheses.
Abnormalities on magnetoencephalography [26] as well as an exaggerated electromyographic-electromyographic (EMG-EMG) coherence [27], have also been reported in CBD patients. Patients with CBD and myoclonus generally have long latency reflexes (LLR) with shorter latencies than in the classic cortical reflex myoclonus encountered, for example, in progressive myoclonic epilepsy [16,28–30]. In the study of Monza et al. [12] all six patients with myoclonus had enhanced LLRs at rest, with abnormally increased amplitude during motor activation; latencies were generally shorter than in classic cortical reflex myoclonus. All patients with myoclonus showed clear facilitation of LLRs in the myoclonic arm (present at rest as well as during voluntary activation), indicated by an increased amplitude with reduction of the short latency reflexes/ LLR amplitude ratio (Fig. 5). 4. Discussion EEG studies yielded contradictory findings in CBD. In some studies [10,29,31,32] no significant modification of brain electrical activity has been reported. Conversely, in another study [6], spectral properties of the EEG were always found to be altered, and the abnormalities were markedly enhanced by activation procedures such as hyperventilation. The location of the neurophysiological abnormalities detected using qEEG was in agreement with MRI, SPECT, and neuropsychological tests. Of particular interest is the correlation between the slowing of EEG activity and the decrease of N-acetyl-aspartate in this degenerative disease. The marked correlation between the EEG findings and magnetic resonance spectroscopy in this asymmetrical disease when it becomes secondarily generalized forms a strong argument for an integrated concept of the brain pathology based on electrophysiology (classically) and neurochemistry. The pronounced decrease in this neuronal marker in the parietal regions, as well as the intense modification of the neuronal dynamics detected by qEEG, suggest significant and extended cortical degeneration.
Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027
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Fig. 5. Long loop responses during voluntary activation. a After response M, two late responses (SLR > LLR) are evident in a healthy control. B Note inversion of amplitude (SLR < LLR) in patient 4. Reproduced with permission from Monza et al., 2012.
There are some possible explanations for these discrepancies between studies. The patients may have been studied at different stages of the disease, and thus the comparability between the samples is limited. On the other hand, spectral analysis is more sensitive than standard visual inspection for detecting anomalies, but a true statistical analysis of the spectra has been not regularly applied. Thus, the results of e.g. Vion-Dury and colleagues [6] were evaluated qualitatively, despite spectral analysis is a method of qEEG. However, the study of Wheaton et al. [9] implemented the state of the art of qEEG and reported network disturbances in the beta frequency range for the left hemisphere. The pattern of neuronal loss or damage in CBD is probably different in topography, extent, and intensity from that found in Parkinson’s disease (PD). This could explain the extreme variability of the magnetic resonance spectroscopy results observed in PD in agreement with the neurophysiological features [33]. Moreover, the asymmetrical qEEG pattern observed contrasts with the find-
ings in PD, in which the EEG is often described as normal initially, becoming abnormal (with diffuse slowing) only in the most advanced cases, particularly in patients with marked akinesia [34]. One EEG study aimed at evaluating whether patients use the intact, non-dominant right hemisphere networks in cognitive motor control [35]. An interesting finding was that coherence increases involve the non-lesioned homologous cortex, thus indicating that the undamaged right hemisphere parietal and/or frontal areas assist in planning praxis in these pathologies. The results of Wheaton and coworkers suggest that coherent networks are interhemispherically distributed, extending to the non-dominant right hemisphere in patients performing praxis. Whether this potential neuronal mechanism is permanent is unclear, as the right hemisphere may not be optimal for lasting recovery [35]. Further analyses of other patients with ideomotor apraxia, including longitudinal studies of recovery, are required to assess the duration of network changes.
Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027
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It has been proposed that the reduced amplitude of the N30 SEP component is partly due to impairment of the complex pathway that includes the basal ganglia, supplementary motor area and precentral motor area [36,37]. Likewise, the frontal response abnormalities may be explained by dysfunction of the main sensory pathway projecting from the ventrolateral thalamic nuclei to the frontal cortex (including the supplementary motor area), and of the cortico-cortical sensory projections from the primary sensory area to the primary motor area [38–41]. On the other hand, it should be noted that the focal reflex myoclonus in CBD does not show the electrophysiological characteristics which were documented in patients with typical cortical reflex myoclonus [40,41]. Therefore, the absence of giant SEP might be determined by the ongoing cortical atrophy initially affecting the parietal lobe. Action myoclonus in CBD is likely to represent the result of the pathologic hyperexcitability of the motor cortex, based on a loss of inhibitory input from the sensory cortex. It has been hypothesized that myoclonus in CBD is mediated by a pathway whose afferent branch reaches the motor cortex (area 4) by way of a direct monosynaptic thalamocortical connection [16]. This hypothesis is supported by the lack of giant SEPs in CDB patients, and also for the reduced LLR latency. In fact, patients with CBD and myoclonus generally have LLRs with shorter latencies than in the classic cortical reflex myoclonus encountered, for example, in progressive myoclonic epilepsy [16,28–30]. The origin of LLR responses is debated but most evidence points to a transcortical rather than multisynaptic spinal origin. LLR facilitation could be the expression of increased cortical excitability, which is also the favoured explanation for the myoclonus in the absence of giant SEP or EEG jerk-related alterations. The relatively enlarged MEP observed in CBD patients may be explained by postulating that more a motoneurons are being recruited by the descending volleys from the motor cortex [14]. The shorter cortical SP may reflect the defective central inhibitory processes elicited by TMS. Conversely, the inhibitory loops segmentally activated by the muscle twitch may play a minor role, if any. These MEP findings are similar to those reported in patients with PD [14]. Because this corresponds to the more affected hand in both patients, it may indicate that the relatively intact motor cortex, compared with the more severely involved parietal cortex contralateral to the affected limb, is in a hyperactive state. The role of this hyperactive motor cortex could for the production of reflex myoclonus is not understood in detail, but a plausible explanation might be that the loss of the inhibitory input from the somatosensory cortex to the motor cortex [14], as a result of the prominent parietal lesion, gives rise to the hyperexcitable motor cortex without giant SEP. An alternative explanation might be the existence of an alternative thalamocortical pathway [16]. An enhanced excitability, or reduced inhibition, was observed for the motor area of the hemisphere contralateral to the alien hand limb in CBD. The delay of the ipsilateral responses is compatible with a disinhibited transcallosal input [22]. Therefore, TMS findings suggest that the unusual clinical manifestations of CBD might partly arise from motor cortex disinhibition. Paired magnetic stimulation could thus represent a useful diagnostic tool particularly in the early stages of the disease. Notably, the results of ipsilateral intracortical inhibition with paired TMS reflect the excitability of inhibitory interneurons in the motor cortex and that, unlike the outputs from somatosensory systems or cerebellum outputs from the basal ganglia, markedly affect this inhibition [20]. Moreover, dysfunction of the corticospinal tract or spinal motoneurons does not affect results obtained by the paired magnetic stimulation technique when the control responses are generated by I-waves (i.e. descending volleys) are produced by transsynaptic activation of the corticospinal tract neurons.
It can also be hypothesized that the facilitation found in CBD originates from decreased inhibition within the motor cortex [22]. Nonetheless, the substantially higher motor threshold in patients with CBD and the failure of TMS at maximum stimulator output to elicit MEPs in one patient could be related to the progressive course of CBD that may involve motor cortical excitatory and inhibitory interneurons as well as cortical and subcortical neurons [42–47]. Indeed, cortical MEPs cannot be elicited even at the maximal level of stimulator output in some patients with CBD [21,22]. This finding might also depend on the brain regions predominantly affected by CBD when patients come for examination. ISP measurements may represent another useful clinical neurophysiologic test in differential diagnosis of patients with parkinsonian syndromes. ISP reflects as a functional parameter a disturbance of transcallosally mediated cortical inhibitory circuitry [24], and available data suggest an impairment of callosal integrity in patients with CBD. In conclusion, the reviewed studies illustrate that CBD is a unique clinical entity characterized by action myoclonus, which probably result from the pathologic hyperexcitability of the motor cortex, based on a loss of inhibitory input from the sensory cortex. TMS, SEPs, LLR, and correlations between results on EEG and EMG can reduce the difficulty of diagnosing CBD, or provide further support for the CBD diagnosis. Acknowledgements None. Author Disclosure Statement None of the authors have potential conflicts of interest to be disclosed. References [1] Rebeiz JJ, Kolodny EH, Richardson Jr EP. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 1967;92:23–6. [2] Santacruz P, Torner L, Cruz-Sànchez F, Lomena F, Catafau A, Blesa R. Corticobasal degeneration syndrome: a case of Lewy body variant of Alzheimer’s disease. Int J Geriatr Psychiatry 1996;11:59–564. [3] Mahapatra RK, Edwards MJ, Schott JM, Bhatia K. Corticobasal degeneration. Lancet Neurol 2004;3(12):736–43. [4] Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 2003;54:S15–9. [5] Ozsancak C, Auzou P, Hannequin D. La dégéné rescence corticobasale. Rev Neurol 1999;155:1007–20. [6] Vion-Dury J, Rochefort N, Michotey P, Planche D, Ceccaldi M. Proton magnetic resonance neurospectroscopy and EEG cartography in corticobasal degeneration: correlations with neuropsychological signs. J Neurol Neurosurg Psychiatry 2004;75(9):1352–5. [7] Mastrolilli F, Benvenga A, Di Biase L, Giambattistelli F, Trotta L, Salomone G, et al. An unusual cause of dementia: essential diagnostic elements of corticobasal degeneration-a case report and review of the literature. Int J Alzheimers Dis 2011;2011:536141. [8] Huang KJ, Lu MK, Kao A, Tsai CH. Clinical, imaging and electrophysiological studies of corticobasal degeneration. Acta Neurol Taiwan 2007;16(1):13–21. [9] Wheaton LA, Bohlhalter S, Nolte G, Shibasaki H, Hattori N, Fridman E, et al. Cortico-cortical networks in patients with ideomotor apraxia as revealed by EEG coherence analysis. Neurosci Lett 2009;433(2):87–92. [10] Lu CS, Ikeda A, Terada K, Mima T, Nagamine T, Fukuyama H, et al. Electrophysiological studies of early stage corticobasal degeneration. Mov Disord 1998;13(1):140–6. [11] Thompson PD. Myoclomis in corticobasal degeneration. Clin Neurosci 1996;3 (4):203–8. [12] Monza D, Ciano C, Scaioli V, Soliveri P, Carella F, Avanzini G, et al. Neurophysiological features in relation to clinical signs in clinically diagnosed corticobasal degeneration. Neurol Sci 2003;24(1):16–23. [13] Brunt ER, van Weerden TW, Pruim J, Lakke JW. Unique myoclonic pattern in corticobasal degeneration. Mov Disord 1995;10(2):132–42.
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Review article
Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies Raffaele Nardone a,b,c,⇑, Francesco Brigo a,d, Viviana Versace e,f, Luca Sebastianelli e,f, Monica Christova g,h, Stefan Golaszewski a,c, Leopold Saltuari e,f,i, Eugen Trinka b,j,k a
Department of Neurology, Franz Tappeiner Hospital, Merano, Italy Department of Neurology, Christian Doppler Klinik, Paracelsus Medical University, Salzburg, Austria Karl Landsteiner Institut für Neurorehabilitation und Raumfahrtneurologie, Salzburg, Austria d Department of Neuroscience, Biomedicine and Movement Science, University of Verona, Italy e Department of Neurorehabilitation, Hospital of Vipiteno, Italy f Research Unit for Neurorehabilitation South Tyrol, Bolzano, Italy g Department of Physiology, Medical University of Graz, Austria h Department of Physiotherapy, University of Applied Sciences FH-Joanneum, Austria i Department of Neurology, Hochzirl Hospital, Zirl, Austria j Centre for Cognitive Neurosciences Salzburg, Salzburg, Austria k University for Medical Informatics and Health Technology, UMIT, Hall in Tirol, Austria b c
a r t i c l e
i n f o
Article history: Received 12 May 2018 Accepted 5 October 2018 Available online xxxx Keywords: Corticobasal degeneration Electroencephalography Transcranial magnetic stimulation Motor evoked potentials Sensory evoked potentials Long latency reflexes
a b s t r a c t Background: Several studies have applied electrophysiological techniques to physiologically characterize corticobasal degeneration (CBD). Methods: We performed a systematic literature search of these studies and reviewed all 25 identified articles. Results: Conventional electroencephalography (EEG) is usually normal even in the late stages of disease. Quantitative EEG (qEEG) with spectral analysis revealed mainly lateralized abnormalities, such as an increase of slow wave activity and occasionally the occurrence of sharp waves, and a significant increase of coherence between left parietal-right premotor areas. CBD patients generally have long latency reflexes (LLR) with shorter latencies than in the classic cortical reflex myoclonus observed in progressive myoclonic epilepsy. The somatosensory evoked potentials (SEPs) showed reduced amplitude of the N20– P25 component. These abnormalities may reflect dysfunction of sensory projections to the motor cortex, while the localized parietal cortical damage is thought to be a pivotal factor for the absence of giant SEPs in these patients. Transcranial magnetic stimulation (TMS) revealed asymmetric intracortical disinhibition and asymmetric maps organization; an impaired transcallosal pathways function correlates with the atrophy of the corpus callosum. These findings suggest a pathologic hyperexcitability of the motor cortex, due to a loss of inhibitory input from the sensory cortex. Conclusions: Neurophysiological techniques, in combination with neuroimaging studies, may shed light on the pathophysiological mechanisms of CBD. A better understanding of the disease processes may help clinicians to make a more accurate and early diagnosis. TMS, SEP, LLR, and co-evaluation of EEG and EMG can aid the in differentiation between CBD and other parkinsonism syndromes. Ó 2018 Published by Elsevier Ltd.
1. Introduction Corticobasal degeneration (CBD) is an uncommon neurodegenerative disease, described for the first time by Rebeiz et al. [1], characterized by an asymmetrical parkinsonism affecting one limb, ⇑ Corresponding author at: Department of Neurology, ‘‘F. Tappeiner” Hospital – Merano, Via Rossini, 5 39012 Merano, (BZ), Italy. E-mail address: [email protected] (R. Nardone).
typically an arm. Rigidity is the most common manifestation, followed by bradykinesia, gait disorder characterized by postural instability and falls, tremor, asymmetrical limb dystonia and higher cortical dysfunctions such as apraxia. CBD can be associated with a wide variety of motor, sensory, cognitive and behavioural symptoms [2]. Dementia, progressive nonfluent aphasia, speech apraxia, progressive-supranuclear-palsy-like syndrome and posterior cortical atrophy syndrome are other presentations of CBD [3,4].
https://doi.org/10.1016/j.jocn.2018.10.027 0967-5868/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027
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The symptoms of CBD are often difficult to understand and the patients may have difficulties in describing their experience. Electrophysiological techniques, together with neuroimaging methods, might shed light on the pathophysiological mechanisms of this condition. A better understanding of the disease may help clinicians to make an early diagnosis. Neurophysiological methods could be applied to differentiate this disease from the other parkinsonism syndromes, and thus achieve a more accurate clinical diagnosis. We reviewed and discussed here the electrophysiological studies that have been performed in subjects with CBD.
2. Methods A literature review was conducted using MEDLINE, accessed by Pubmed (1966 – February 2018) and EMBASE (1980 – February 2018) electronic databases. The following medical subject headings (MeSH) and free terms were searched: ‘‘corticobasal degeneration”, ‘‘electroencephalography‘‘, ‘‘EEG”, ‘‘transcranial magnetic stimulation”, ‘‘motor evoked potential”, ‘‘sensory evoked potential”, ‘‘long latency reflex”. Only original articles written in English were considered eligible for inclusion. Review articles were excluded. For the selected titles full-text articles were retrieved, and reference lists of them were searched for additional publications. The principal investigators of the included studies were contacted in those cases in which useful informations were missing or incomplete. Titles and abstracts of the initially identified studies were independently screened in order to determine if they satisfied the selection criteria. The methodological quality of each study and risk of bias was assessed, focusing on blinding. Any disagreement was solved through discussion. This search strategy yielded 25 studies which contributed to this review. A flow-chart (Fig. 1) shows the selection/inclusion process.
3. Neurophysiological findings 3.1. Electroencephalography Conventional electroencephalography (EEG) may be normal when the first clinical symptoms appear, and often remains unchanged as the disease progresses. Nevertheless, an unilateral slowing may be evident in some patients, which may occasionally generalize to the whole cortex as the disease evolves [5,6]. Using a quantitative standard EEG (qEEG) with spectral analysis, the occurrence of several EEG abnormalities (usually enhanced by hyperventilation or intermittent photic stimulation), such as an increase of slow rhythms (delta or theta frequency range) and occasionally the occurrence of sharp waves were found in a study involving six patients [7]. These abnormalities were lateralized in five patients (more often after hyperventilation) and bilateral in one, thus confirming the asymmetrical features of CBD. Moreover, Huang and colleagues showed that the EEG recordings with jerklocked back average do not present any jerk-locked cortical potentials [8]. In another study, five patients with ideomotor apraxia (three of them with CBD) underwent 64-channel EEG recording while performing three tool-use pantomimes with their left hand in a selfpaced manner. Beta band (20–22 Hz) coherence indicates that normal subjects have a dominant left hemispheric network being involved in praxis preparation, which was absent in patients. CBD patients showed a significant increase of coherence between left parietal-right premotor areas [9] (Fig. 2). In a more recent case report no abnormalities were observed on EEG examination, but a more sophisticated analysis showed a focal slow wave activity in the right parietotemporal area [7]. 3.2. Somatosensory evoked potentials In CBD the cortical sensory evoked potentials (SEPs) are not enlarged as in cortical reflex myoclonus, and backaveraged cortical
Fig. 1. Flow-chart showing the selection/inclusion process.
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Fig. 2. Time-magnitude plot of individual coherence values for patients with corticobasal degeneration (CBD) for each network of interest for all participants relative to movement onset (s). Asterisks (*) indicate significant increases. Reproduced with permission from Wheaton et al., 2008.
potentials do not precede each myoclonic jerk [10–12]. Clinical and imaging evidence suggests that the localized parietal cortical damage is a pivotal factor for the absence of a giant SEP in these patients [13]. The SEPs showed reduced amplitude of the N20– P25 component without giant SEP characteristics. The latencies of the cortical event and of the late responses, as well as the duration and distribution of the discharges share similarities with those of the cortical reflex type of myoclonus. An asymmetric alteration of inhibitory and excitatory balance at the level of cortical neurons leading to a particularly enhanced cortical excitability may additionally play an important role in the generation of myoclonus [11,12]. The loss of the inhibitory input from the somatosensory cortex to the relatively intact motor cortex, which results from the prominent asymmetric parietal atrophy, may give rise to the asymmetric hyperexcitable motor cortex without giant SEP [14,15]. Alternatively, the existence of an alternative hyper-excitable thalamo-cortical pathway should be considered [16]. In a clinical, neuroradiological and neurophysiological study on ten patients with clinically probable CBD, the SEP N30 frontal component was found to be absent bilaterally in four patients, was absent on the left side in one and had increased latency in other three [12]. 3.3. Transcranial magnetic stimulation Monza et al. in their above mentioned study also reported abnormal motor evoked potentials (MEPs) elicited by transcranial
magnetic stimulation (TMS) in four out of 10 patients with probable CBD; three had prolonged central motor conduction time, one of whom also had increased MEP threshold, and one had increased MEP threshold [12]. An alteration in cortical excitability, as evaluated by means of TMS, was also detected in patients with CBD [10]. In fact, motor cortex disinhibition has been clearly demonstrated in CBD by means of TMS applied in several paradigms in different neurophysiological studies [16–18]. By applying single pulse-TMS, Lu and coworkers discovered a relatively higher MEP amplitude and a significantly shorter cortical silent period (SP) in the affected hand of CBD patients [10]. The relatively enlarged MEP could be explained by postulating that an increased number of motoneurons are being recruited by the descending volleys from the motor cortex [10], while the shorter cortical SP may reflect mainly defective inhibitory processes [16]. The results from paired pulse-TMS studies also supported the hypothesis of a reduced intracortical inhibition [8,10,20]. In particular, Frasson and colleagues showed that paired magnetic stimuli delivered at short (inhibitory) interstimulus intervals (ISIs) invariably elicited enlarged MEPs in patients with CBD (Fig. 3). Furthermore, asymmetric corticocortical disinhibition [19,21], as well as asymmetric TMS maps organization [16,22], have been observed in patients with CBD. Another study evaluated the motor function of the transcallosal pathways in patients with CBD has also been evaluated [23]. Ipsilateral SP (iSP) was normal in 3 out of 7 CBD patients. Therefore, it can be assumed that a proportion of CBD patients shows
Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027
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Fig. 4. Ipsilateral silent period (iSP) in patients with CBD. Each recording represents the average of 7 consecutive rectified EMG traces obtained, during maximal voluntary tonic contraction, in the more and less affected opponens pollicis muscle, after TMS (100% of the stimulator output) of the ipsilateral motor cortex. TMS induced an evident inhibition of the ongoing EMG activity in patients 1–4. The iSP was evidently impaired (or absent) in patients 5–7. Note the occurrence of an ipsilateral excitatory response in the more affected side of patient 4. Reproduced with permission from Trompetto et al., 2003.
3.4. Other techniques
Fig. 3. (A) Mean intracortical excitability curves (mean 1 SEM) for the group of healthy control subjects (triangles), patients with CBD (rhombuses) and Parkinson’s disease patients (squares). ISIs are given on the abscissa, the size of conditioned test MEPs as the percentage of the test alone on the ordinate. Horizontal line (100%) indicates the size of test MEPs, lower values indicate intracortical inhibition, and higher values indicate facilitation. Note the intracortical facilitation in the patients with CBD. (B) Intracortical excitability at the ISI of 4 ms in the single patients with CBD (triangles) and patients with PD (circles). The size of conditioned test MEPs as the percentage of the test alone are given on the ordinate. The horizontal dashed line (100%) indicates the mean size ^ 2.5 SD (continuous line). Note that at the 4 ms ISI, all CBD patients had marked intracortical facilitation and all PD patients had responses in the normal range (mean ^ 2.5SD). Reproduced with permission from Frasson et al., 2003.
physiological evidence of impaired transcallosal motor function, which correlates with an atrophy of the corpus callosum on MRI, and is possibly correlated to cognitive disorders (Fig. 4). In another TMS study on patients with various disorders presenting with a parkinsonian syndrome, iSP was abnormal in all the examined five CBD patients [24]. This subgroup was also characterized by a significant atrophy of the corpus callosum as compared with control subjects. Several mechanisms could explain the abnormal motor cortical excitability; the loss of inhibitory neurons in the cortex or thalamus, effects of morphological changes in cortical neurons mainly in the somatosensory cortices, disruption of some neuronal circuits, or the existence of alternative cortical-subcortical pathways [17,25]. Further electrophysiological studies are necessary to better circumstantiate these hypotheses.
Abnormalities on magnetoencephalography [26] as well as an exaggerated electromyographic-electromyographic (EMG-EMG) coherence [27], have also been reported in CBD patients. Patients with CBD and myoclonus generally have long latency reflexes (LLR) with shorter latencies than in the classic cortical reflex myoclonus encountered, for example, in progressive myoclonic epilepsy [16,28–30]. In the study of Monza et al. [12] all six patients with myoclonus had enhanced LLRs at rest, with abnormally increased amplitude during motor activation; latencies were generally shorter than in classic cortical reflex myoclonus. All patients with myoclonus showed clear facilitation of LLRs in the myoclonic arm (present at rest as well as during voluntary activation), indicated by an increased amplitude with reduction of the short latency reflexes/ LLR amplitude ratio (Fig. 5). 4. Discussion EEG studies yielded contradictory findings in CBD. In some studies [10,29,31,32] no significant modification of brain electrical activity has been reported. Conversely, in another study [6], spectral properties of the EEG were always found to be altered, and the abnormalities were markedly enhanced by activation procedures such as hyperventilation. The location of the neurophysiological abnormalities detected using qEEG was in agreement with MRI, SPECT, and neuropsychological tests. Of particular interest is the correlation between the slowing of EEG activity and the decrease of N-acetyl-aspartate in this degenerative disease. The marked correlation between the EEG findings and magnetic resonance spectroscopy in this asymmetrical disease when it becomes secondarily generalized forms a strong argument for an integrated concept of the brain pathology based on electrophysiology (classically) and neurochemistry. The pronounced decrease in this neuronal marker in the parietal regions, as well as the intense modification of the neuronal dynamics detected by qEEG, suggest significant and extended cortical degeneration.
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Fig. 5. Long loop responses during voluntary activation. a After response M, two late responses (SLR > LLR) are evident in a healthy control. B Note inversion of amplitude (SLR < LLR) in patient 4. Reproduced with permission from Monza et al., 2012.
There are some possible explanations for these discrepancies between studies. The patients may have been studied at different stages of the disease, and thus the comparability between the samples is limited. On the other hand, spectral analysis is more sensitive than standard visual inspection for detecting anomalies, but a true statistical analysis of the spectra has been not regularly applied. Thus, the results of e.g. Vion-Dury and colleagues [6] were evaluated qualitatively, despite spectral analysis is a method of qEEG. However, the study of Wheaton et al. [9] implemented the state of the art of qEEG and reported network disturbances in the beta frequency range for the left hemisphere. The pattern of neuronal loss or damage in CBD is probably different in topography, extent, and intensity from that found in Parkinson’s disease (PD). This could explain the extreme variability of the magnetic resonance spectroscopy results observed in PD in agreement with the neurophysiological features [33]. Moreover, the asymmetrical qEEG pattern observed contrasts with the find-
ings in PD, in which the EEG is often described as normal initially, becoming abnormal (with diffuse slowing) only in the most advanced cases, particularly in patients with marked akinesia [34]. One EEG study aimed at evaluating whether patients use the intact, non-dominant right hemisphere networks in cognitive motor control [35]. An interesting finding was that coherence increases involve the non-lesioned homologous cortex, thus indicating that the undamaged right hemisphere parietal and/or frontal areas assist in planning praxis in these pathologies. The results of Wheaton and coworkers suggest that coherent networks are interhemispherically distributed, extending to the non-dominant right hemisphere in patients performing praxis. Whether this potential neuronal mechanism is permanent is unclear, as the right hemisphere may not be optimal for lasting recovery [35]. Further analyses of other patients with ideomotor apraxia, including longitudinal studies of recovery, are required to assess the duration of network changes.
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It has been proposed that the reduced amplitude of the N30 SEP component is partly due to impairment of the complex pathway that includes the basal ganglia, supplementary motor area and precentral motor area [36,37]. Likewise, the frontal response abnormalities may be explained by dysfunction of the main sensory pathway projecting from the ventrolateral thalamic nuclei to the frontal cortex (including the supplementary motor area), and of the cortico-cortical sensory projections from the primary sensory area to the primary motor area [38–41]. On the other hand, it should be noted that the focal reflex myoclonus in CBD does not show the electrophysiological characteristics which were documented in patients with typical cortical reflex myoclonus [40,41]. Therefore, the absence of giant SEP might be determined by the ongoing cortical atrophy initially affecting the parietal lobe. Action myoclonus in CBD is likely to represent the result of the pathologic hyperexcitability of the motor cortex, based on a loss of inhibitory input from the sensory cortex. It has been hypothesized that myoclonus in CBD is mediated by a pathway whose afferent branch reaches the motor cortex (area 4) by way of a direct monosynaptic thalamocortical connection [16]. This hypothesis is supported by the lack of giant SEPs in CDB patients, and also for the reduced LLR latency. In fact, patients with CBD and myoclonus generally have LLRs with shorter latencies than in the classic cortical reflex myoclonus encountered, for example, in progressive myoclonic epilepsy [16,28–30]. The origin of LLR responses is debated but most evidence points to a transcortical rather than multisynaptic spinal origin. LLR facilitation could be the expression of increased cortical excitability, which is also the favoured explanation for the myoclonus in the absence of giant SEP or EEG jerk-related alterations. The relatively enlarged MEP observed in CBD patients may be explained by postulating that more a motoneurons are being recruited by the descending volleys from the motor cortex [14]. The shorter cortical SP may reflect the defective central inhibitory processes elicited by TMS. Conversely, the inhibitory loops segmentally activated by the muscle twitch may play a minor role, if any. These MEP findings are similar to those reported in patients with PD [14]. Because this corresponds to the more affected hand in both patients, it may indicate that the relatively intact motor cortex, compared with the more severely involved parietal cortex contralateral to the affected limb, is in a hyperactive state. The role of this hyperactive motor cortex could for the production of reflex myoclonus is not understood in detail, but a plausible explanation might be that the loss of the inhibitory input from the somatosensory cortex to the motor cortex [14], as a result of the prominent parietal lesion, gives rise to the hyperexcitable motor cortex without giant SEP. An alternative explanation might be the existence of an alternative thalamocortical pathway [16]. An enhanced excitability, or reduced inhibition, was observed for the motor area of the hemisphere contralateral to the alien hand limb in CBD. The delay of the ipsilateral responses is compatible with a disinhibited transcallosal input [22]. Therefore, TMS findings suggest that the unusual clinical manifestations of CBD might partly arise from motor cortex disinhibition. Paired magnetic stimulation could thus represent a useful diagnostic tool particularly in the early stages of the disease. Notably, the results of ipsilateral intracortical inhibition with paired TMS reflect the excitability of inhibitory interneurons in the motor cortex and that, unlike the outputs from somatosensory systems or cerebellum outputs from the basal ganglia, markedly affect this inhibition [20]. Moreover, dysfunction of the corticospinal tract or spinal motoneurons does not affect results obtained by the paired magnetic stimulation technique when the control responses are generated by I-waves (i.e. descending volleys) are produced by transsynaptic activation of the corticospinal tract neurons.
It can also be hypothesized that the facilitation found in CBD originates from decreased inhibition within the motor cortex [22]. Nonetheless, the substantially higher motor threshold in patients with CBD and the failure of TMS at maximum stimulator output to elicit MEPs in one patient could be related to the progressive course of CBD that may involve motor cortical excitatory and inhibitory interneurons as well as cortical and subcortical neurons [42–47]. Indeed, cortical MEPs cannot be elicited even at the maximal level of stimulator output in some patients with CBD [21,22]. This finding might also depend on the brain regions predominantly affected by CBD when patients come for examination. ISP measurements may represent another useful clinical neurophysiologic test in differential diagnosis of patients with parkinsonian syndromes. ISP reflects as a functional parameter a disturbance of transcallosally mediated cortical inhibitory circuitry [24], and available data suggest an impairment of callosal integrity in patients with CBD. In conclusion, the reviewed studies illustrate that CBD is a unique clinical entity characterized by action myoclonus, which probably result from the pathologic hyperexcitability of the motor cortex, based on a loss of inhibitory input from the sensory cortex. TMS, SEPs, LLR, and correlations between results on EEG and EMG can reduce the difficulty of diagnosing CBD, or provide further support for the CBD diagnosis. Acknowledgements None. Author Disclosure Statement None of the authors have potential conflicts of interest to be disclosed. References [1] Rebeiz JJ, Kolodny EH, Richardson Jr EP. Corticodentatonigral degeneration with neuronal achromasia: a progressive disorder of late adult life. Trans Am Neurol Assoc 1967;92:23–6. [2] Santacruz P, Torner L, Cruz-Sànchez F, Lomena F, Catafau A, Blesa R. Corticobasal degeneration syndrome: a case of Lewy body variant of Alzheimer’s disease. Int J Geriatr Psychiatry 1996;11:59–564. [3] Mahapatra RK, Edwards MJ, Schott JM, Bhatia K. Corticobasal degeneration. Lancet Neurol 2004;3(12):736–43. [4] Boeve BF, Lang AE, Litvan I. Corticobasal degeneration and its relationship to progressive supranuclear palsy and frontotemporal dementia. Ann Neurol 2003;54:S15–9. [5] Ozsancak C, Auzou P, Hannequin D. La dégéné rescence corticobasale. Rev Neurol 1999;155:1007–20. [6] Vion-Dury J, Rochefort N, Michotey P, Planche D, Ceccaldi M. Proton magnetic resonance neurospectroscopy and EEG cartography in corticobasal degeneration: correlations with neuropsychological signs. J Neurol Neurosurg Psychiatry 2004;75(9):1352–5. [7] Mastrolilli F, Benvenga A, Di Biase L, Giambattistelli F, Trotta L, Salomone G, et al. An unusual cause of dementia: essential diagnostic elements of corticobasal degeneration-a case report and review of the literature. Int J Alzheimers Dis 2011;2011:536141. [8] Huang KJ, Lu MK, Kao A, Tsai CH. Clinical, imaging and electrophysiological studies of corticobasal degeneration. Acta Neurol Taiwan 2007;16(1):13–21. [9] Wheaton LA, Bohlhalter S, Nolte G, Shibasaki H, Hattori N, Fridman E, et al. Cortico-cortical networks in patients with ideomotor apraxia as revealed by EEG coherence analysis. Neurosci Lett 2009;433(2):87–92. [10] Lu CS, Ikeda A, Terada K, Mima T, Nagamine T, Fukuyama H, et al. Electrophysiological studies of early stage corticobasal degeneration. Mov Disord 1998;13(1):140–6. [11] Thompson PD. Myoclomis in corticobasal degeneration. Clin Neurosci 1996;3 (4):203–8. [12] Monza D, Ciano C, Scaioli V, Soliveri P, Carella F, Avanzini G, et al. Neurophysiological features in relation to clinical signs in clinically diagnosed corticobasal degeneration. Neurol Sci 2003;24(1):16–23. [13] Brunt ER, van Weerden TW, Pruim J, Lakke JW. Unique myoclonic pattern in corticobasal degeneration. Mov Disord 1995;10(2):132–42.
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Please cite this article in press as: Nardone R et al. Pathophysiology of corticobasal degeneration: Insights from neurophysiological studies. J Clin Neurosci (2018), https://doi.org/10.1016/j.jocn.2018.10.027