Movement Disorders in Prionopathies: A Systematic Review
Federico Rodriguez-Porcel,1,2,* Vinícius Boaratti Ciarlariello,3 Alok K. Dwivedi,4 Lilia Lovera,1,2 Gustavo Da Prat,5 Ricardo Lopez-Castellanos,2,6 Ritika Suri,2,7 Holly Laub,2,8 Ruth H. Walker,9,10 Orlando Barsottini,3 José Luiz Pedroso,3 and Alberto J. Espay2 Author information Article notes Copyright and License information PMC Disclaimer Associated Data Supplementary Materials Go to: Abstract Background Movement disorders are frequent features of prionopathies. However, their prevalence and onset remain poorly described.
Methods We performed a systematic review of case reports and case series of pathologically- and genetically confirmed prionopathies. Timing of symptom and movement disorder onset were documented. Continuous variables were compared between two groups using the Wilcoxon rank sum test and between multiple groups using Kruskal–Wallis test. Categorical variables were compared using Fisher’s exact test.
Results A total of 324 cases were included in this analysis. Movement disorders were a common feature at the onset of symptoms in most prionopathies. Gait ataxia was present in more than half of cases in all types of prionopathies. The prevalence of limb ataxia (20%) and myoclonus (24%) was lower in Gerstmann–Sträussler–Scheinker disease compared to other prionopathies (p ≤ 0.004). Myoclonus was common but often a later feature in sporadic Creutzfeldt–Jakob disease (2 months before death). Chorea was uncommon but disproportionately prevalent in variant Creutzfeldt–Jakob disease (30% of cases; p < 0.001). In genetic Creutzfeldt–Jakob disease, E200K PRNP carriers exhibited gait and limb ataxia more often when compared to other mutation carriers.
Discussion Movement disorders are differentially present in the course of the various prionopathies. The movement phenomenology and appearance are associated with the type of prion disease and the PRNP genotype and likely reflect the underlying pattern of neurodegeneration. Reliance on myoclonus as a diagnostic feature of sporadic Creutzfeldt–Jakob disease may delay its recognition given its relatively late appearance in the disease course.
Keywords: Prion, Creutzfeldt–Jakob, Gerstmann–Sträussler–Scheinker, fatal familial insomnia, movement disorders, ataxia, myoclonus
snip...
Discussion In this systematic review, we evaluated the prevalence of movement disorders in prionopathies and their timing of presentation. To our knowledge, this is the first systematic assessment of movement disorders in all human prionopathies. The age of onset was older (over 60) in sCJD and gCJD compared with other prionopathies (under 50). Gait ataxia was the most common movement disorder, noted in more than half of all prionopathies; limb ataxia was, however, uncommon in GSS and FFI (20 and 25%) compared to other prionopathies. Myoclonus was common but appeared later in all prionopathies; chorea was uncommon but disproportionately prevalent in vCJD. In terms of gCJD, E200K PRNP carriers had a shorter disease course, more sleep disturbances, and dysautonomia at onset compared to other gCJD mutation carriers. Not surprisingly, sleep disorders were the most common presentation in FFI.
As previously reported, patients with GSS had a significantly longer median disease duration (58.5 months) compared to those with other prionopathies.1 Thus, GSS should be considered a chronic, rather than a subacute, progressive disorder. Previous studies suggested that cognitive and behavioral symptoms were more common in sCJD, whereas movement disorders, specifically gait ataxia, were most common as initial features in GSS.1,2 However, in this systematic review, cognitive/behavioral symptoms and movement disorders were similar in frequency at the onset of sCJD, iCJD, and GSS. Cognitive and behavioral changes were markedly more common at onset in vCJD and gCJD compared to other prionopathies. Indeed, the initial manifestation with behavioral abnormalities is a well-known feature of vCJD.3
Cerebellar degeneration is typically considered the neuroanatomical substrate of gait and limb ataxia in the prionopathies. However, ataxia may also be exceptionally contributed to by myelopathy, peripheral neuropathy, or frontal lobe impairment.4,5 Gait ataxia has been reported as common in sCJD and GSS.1,6 Isolated gait ataxia presenting years to decades before the onset of cognitive symptoms has been described as a characteristic feature of the VV2 (ataxic) subtype of sCJD, and in missense mutations causing GSS.7,8 However, while gait ataxia was common in GSS, our results showed limb ataxia was less common compared to other prionopathies. The nature of this discrepancy can be attributed to the degeneration of the spinocerebellar tracts and the posterior horn of the spinal cord as the main driver of symptoms of GSS rather than cerebellar degeneration.9,10 In addition, the presence of gait and limb ataxia early in the disease course may be suggestive of gCJD due to an E200K mutation.11,12 Although not common at presentation, almost all vCJD patients manifest gait ataxia at some point during the disease.3,13
The presence of myoclonus in the context of cognitive impairment is often associated with sCJD, justifying its inclusion in most diagnostic criteria.14–16 In sCJD, spontaneous myoclonus presents as distal and symmetric in the hands, becoming generalized later in the disease. However, asymmetric stimulus-sensitive myoclonus has also been described.17 The latter is reminiscent of a startle response but can be distinguished from it by the presence of habituation.18 Although myoclonus is a common feature in sCJD, it appears in the mid-to-late stages in this and other prionopathies. Myoclonus is rare in GSS.
Other movement disorders were less frequently observed but their presence may help inform the differential diagnosis. Although chorea was rarely reported, almost half of the cases with chorea were associated with vCJD, and thus, this diagnosis should be considered in the differential diagnosis of Huntington disease.3,19 The presence of movement disorders in vCJD has been associated with the degeneration of cholinergic neurons in the caudate and putamen.20 In the sporadic form, although less frequent, the duration of chorea was longer (14 months) than the median duration of the disease (7 months), which may suggest a longer survival in those who present with chorea. Patients with GSS had the longest disease duration overall, but the median duration of chorea was only 2.5 months, suggesting that when present, chorea may represent a late feature.
Finally, gaze palsy is rarely reported but likely to be under-recognized. We found the presence of gaze palsy to be more often associated with sCJD. However, limitations in upgaze and slowness of saccades are often present in vCJD and have been reported as early findings in iCJD.21,22 These abnormalities usually progress to further affect eye movements, leading to ophthalmoparesis.23 Gaze limitations are also described in gCJD and GSS as a later manifestation.23,24 Other oculomotor abnormalities include impaired pursuit and nystagmus.23
The classification of prionopathies is based on the morphology of the PrP and amyloid deposition.25 PrP deposition is often associated with a pattern of neurodegeneration in which certain structures are more predisposed to damage or selectively vulnerable depending on the PrP conformation.26 PrP predominantly affects cerebral cortical structures in sCJD; the anterior and medial nuclei of the thalamus in FFI; the medial and posterior thalamus as well as the striatum, neocortex, and cerebellum in vCJD; and the cerebellum and spinal cord and, to a lesser extent, the neocortex in GSS.8,13,27,28 This selectivity decreases as PrP spreads to other areas toward later phases. These correlations are not precise and there are multiple factors affecting the spread of the prion pathology, which could explain the varied presentation. The most prominent example is sCJD, in which the different phenotypes (e.g., cortical, cerebellar, and thalamic variants) depended on the areas of predominant degeneration.29 The differences in the patterns of neurodegeneration and associated clinical presentations are modulated by the combination of the variability of methionine/valine polymorphism at codon 129 in the PRNP (MV, MM, VV) and the electrophoretic pattern of PrP after exposure of prion protein to proteinase K digestion (classified as 1 or 2) (Table 6).30 While MM1 and MV1 variants are more likely to exhibit rapidly progressive dementia with multisystem neurological disorder, the VV2 (cerebellar) variant accounts for the second most common subtype and it is almost invariably associated with a cerebellar syndrome at the onset, without preceding cognitive changes.5,7 Further understanding of anatomical underpinnings of movement disorders in prionopathies and the factors affecting the selective vulnerability will have an impact on diagnosis, prognosis, and potential treatment.
Table 6 Subtypes of Sporadic Creutzfeldt–Jakob Disease
Subtype* (frequency) Age of onset Years (range) Duration Months (range) Presentation Movement disorders Regions predominantly affected MM1/MV1(65%) 68 (31–86) 5 (1–24) Cognitive/behavioral, visual changes Ataxia Myoclonus Neocortex (particularly occipital lobe), subcortical nuclei and cerebellum VV2(20%) 64 (40–83) 6.5 (3–18) Cerebellar dysfunction. Later, cognitive/behavioral changes Gait and limb ataxia Oculomotor abnormalities Cerebellum and subcortical nuclei MV2(10%) 65 (36–83) 17 (4–48) Cognitive/behavioral or motor Ataxia Parkinsonism Myoclonus Cerebellum and subcortical nuclei. Less cortical involvement MM2 (Thalamic)(<5%) 52 (26–71) 16 (8–36) Insomnia, cognitive Ataxia Myoclonus Thalamus and inferior olive MM2 (Cortical)(<5%) 64 (49–77) 16 (9–36) Cognitive, apraxia, aphasia Myoclonus Neocortex VV1(1%) 44 (19–55) 21 (17–42) Cognitive/behavioral Ataxia Parkinsonism Cortex and striatum Open in a separate window *Subtypes are based on the combination of methionine/valine polymorphism at codon 129 in the PRNP (MV, MM, VV) and the electrophoresis pattern of PrP after the exposure of prion protein to proteinase K digestion (classified as 1 or 2). Frequency, age of onset, and duration values for this table were obtained from literature review.
These conclusions have to be tempered by a number of limitations when considering their applicability to clinical practice. First, the selection of cases with genetic or pathological confirmation aimed for a more conservative selection but rendered many reports, mainly of sCJD, ineligible for analysis. This point should be considered when applying our findings to clinical practice, where patients are more often diagnosed based on clinical, imaging, and CSF findings, and only a minority have had an autopsy or genetic testing. Second, the reliance on reported cases invariably leads to a selection bias, as cases reported often need to justify their publication with an element of novelty, raising the concern that the sample is not representative of the whole of prionopathies. The presence of movement disorders is a common reason to publish a case report, which can lead to their overrepresentation, with potential under-representation of iCJD or vCJD. Reassuringly, the age at onset and the duration of the disease in this study are similar to those in prior reports. Third, the nature of case reports publication requires a succinct case presentation highlighting the features of interest for the report, sometimes leaving out details not considered of interest to the publication. This limits the identification of all the elements in the case presentation and may in part explain the absence of documented cognitive or behavioral changes in up to 20% of sCJD reports. However, our sensitivity analyses performed by excluding reports without the mention of cognitive changes or those not published in neurology journals did not affect our results. It should also be noted that most of these case reports were not accompanied by video material, and thus, the phenomenology, which may have been described by non-movement disorders specialists, cannot be confirmed. In addition, we did not include abnormalities not currently classified as movement disorders, such as spasticity and alien hand syndrome, which have also been reported in prionopathies.31 Finally, our study aimed to report the onset of symptoms relative to the time to death. While this measure can help understand the progression of the disease, it may be misleading as the sole marker of disease duration. It should also be noted that this analysis was limited to the onset of symptoms but did not take into account whether the movement disorders remained present until death. In addition, while the analysis of the symptom/disease duration ratio can be helpful to understand the progression of the individual prionopathy, the total duration of each disease needs to be accounted for when translating it to the differential diagnosis of prionopathies. One solution to the limitations of our review, due to the heterogeneity of the reported clinical characteristics, could be a prospective study, with a standardized form to document clinical features as the disease progressed, which could be implemented in any case where the diagnosis is suspected. Despite these limitations, this is the first comprehensive systematic review to evaluate the prevalence and duration of movement disorders in prionopathies, and the results reported can help guide the evaluation of suspected prionopathies.
Conclusion
In conclusion, movement disorders are common in prionopathies, with differential appearance of specific movements in the various disorders. The differences in phenomenology and duration may result from selective neuronal and network vulnerability. A prospective epidemiologic study would be desirable to further refine the clinical variables that may affect the frequency, type, onset, and duration of movement disorders in prionopathies.
