Characterizing Secondary and Atypical Parkinsonisms: Defining Features and Clinical Variability

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Dear Authors,

you manuscript entitled "Characterizing Secondary and Atypical Parkinsonisms: Defining features and Clinical Variability" offer a valuable review of the literature about Parkinsonian syndromes. However, it is cruelly lacking  references to associated sleep disorders or sleep-wake circadian rhythms alteration which commonly develop prior to onset of motor symptoms in PD but are also critically experienced in other Parkinsonian syndromes e.g. see https://doi.org/10.1016/b978-0-12-819975-6.00019-4. It is only referred to in Table1 as Hypersomnia. I therefore strongly recommend to include this aspect and expend on the sleep disorder symptomatology for all the different syndromes throughout your review.

Minor comments:

page 3, line 147: It not fully clear when your refer to "attention". Do you men attentional deficits?

page 4, lines 154-155: please rephrase the sentence for clarity and include reference as numbered reference.

page 4, line 178: please precise which "intravenous fluids" are used.

page 5, 3rd paragraph (lines 207-208) could seems somewhat contradictory to the 5th paragraph (lines 221-223): please harmonize the two sentences about using fMRI to distinguish PD from VP.

page 11, line 506: It might be more accurate to replace "treatment" by "symptomatic medical treatment"

page 12, line 569: please include "only" between "necessary" and "related"

page 12, line 578: the term finding seems a little bit exaggerated and could probably be attenuated

 

Author Response

1. Summary

We greatly appreciate your comments and contributions to our work. We know that these were made to improve the final content. In summary, we have made extensive changes to our work, focused on the comments created for us, and strongly emphasized each point. Likewise, we have provided a response on what and where they were modified for each of these comments.

2. Point-by-point response to Comments and Suggestions for Authors

Reviewer 1:

1. Mayor comments: It is cruelly lacking references to associated sleep disorders or sleep-wake circadian rhythms alteration which commonly develop prior to onset of motor symptoms in PD but are also critically experienced in other Parkinsonian syndromes e.g. see https://doi.org/10.1016/b978-0-12-819975-6.00019-4. It is only referred to in Table1 as Hypersomnia. I therefore strongly recommend to include this aspect and expend on the sleep disorder symptomatology for all the different syndromes throughout your review.

Response 1: This comment has been extensively addressed, including detailed information on sleep disorders) in some types of parkinsonism. However, for cases where such information was not included, it is due to a lack of literature reporting these disorders. Below, we outline the types of parkinsonism where information about SD has been added:

• EOP: Additionally, sleep disorders are common in individuals with EOP and occur at similar frequencies as in PD. However, insomnia prevalence is higher in EOP. Before motor symptom onset, 24% of EOP patients experienced sleep disorders, compared to 16% in PD. Post-motor symptom sleep disorders incidence was 5.85 cases per 100 person-years in EOP vs. 4.11 in PD. Specifically, the risk of developing post-motor insomnia was 1.73 times higher in EOP [32].
• VP: Patients with PV not only experience movement disorders but also sleep disturbances [66]. One of the identified symptoms is nocturia and nighttime difficulties associated with getting up to urinate. However, reports indicate that VP exhibits better sleep initiation compared to PD [67].
• Parkinsonism and COVID-19: Additionally, approximately 64% of patients with COVID-19 experience sleep disorders, including increased sleep duration or insomnia [85].
• DLB: Additionally, sleep disorders appear to be more common in DLB compared to Alzheimer's disease. These include rapid eye movement sleep behavior disorder and excessive daytime sleepiness [105].
• MSA: Additionally, various respiratory disorders may occur during sleep, such as obstructive sleep apnea, central apnea (the first symptom of MSA), and nocturnal stridor (a severe condition). Other disorders include rapid eye movement, sleep behavior disorder and excessive daytime sleepiness [105].
• PSP: On the other hand, approximately half of PSP patients experience sleep disturbances, including excessive daytime sleepiness, nighttime insomnia, total sleep reduction, restless legs syndrome, and sleep fragmentation. These disturbances have been interpreted as a factor that increases PSP mortality by up to fourfold [127].
• CBD: Additionally, patients often exhibit insomnia, restless legs syndrome, agrypnia excitata, reversal of the sleep-wake pattern, and periodic limb movements [127].

 

2. Minor comments:

1. Page 3, line 147: It not fully clear when your refer to "attention". Do you men attentional deficits?
2. Page 4, lines 154-155: please rephrase the sentence for clarity and include reference as numbered reference.
3. Page 4, line 178: please precise which "intravenous fluids" are used.
4. Page 5, 3rd paragraph (lines 207-208) could seems somewhat contradictory to the 5th paragraph (lines 221-223): please harmonize the two sentences about using fMRI to distinguish PD from VP.
5. Page 11, line 506: It might be more accurate to replace "treatment" by "symptomatic medical treatment"
6. Page 12, line 569: please include "only" between "necessary" and "related"
7. Page 12, line 578: the term finding seems a little bit exaggerated and could probably be attenuated

 

Response 2:

We appreciate these minor revisions to our work, and regarding the comments:

1. We referred to a state of "attention" as such; however, we have decided to omit this term as it does not add significant information to the text: << However, this evaluation must consider factors such as smoking history, concomitant otorhinolaryngological diseases, and cognitive status, as these can affect olfactory assessment [6]. >>
2. These lines, along with the numerical reference, have been rewritten: << Another imaging modality that can differentiate DIP from PD is functional magnetic resonance imaging (fMRI). This technique evaluates factors such as regional homogeneity and the amplitude of low-frequency fluctuations, which provide insights into the intrinsic activity patterns of voxels (the three-dimensional equivalent of a pixel) [36]. >>
3. In the article Parkinsonism-Hyperpyrexia Syndrome and Dyskinesia-Hyperpyrexia Syndrome in Parkinson’s Disease: Two Cases and Literature Review, from which the information was extracted, specific intravenous fluids are not mentioned. However, since the text refers to a hospital context, it could imply crystalloids or colloid solutions.
4. We have reviewed your observation regarding the harmonization of the information described about the use of fMRI to differentiate Parkinson’s disease (PD) from vascular parkinsonism (VP). The confusion arose from the statement that fMRI alone is insufficient to distinguish between these two parkinsonisms, with a combination of fMRI and dopamine transporter studies being more effective. Consequently, we have revised the text to eliminate this ambiguity, focusing exclusively on the dopamine transporter as the key differential method between PD and VP.
5. The term "treatment" has already been changed to "symptomatic medical treatment": << sociodemographic aspects, etiology, diagnosis, and symptomatic medical treatment. >>
6. The word "only" has been added between "necessarily" and "related": << This matches the indication that these syndromes are not necessarily only related to dopamine deficiency [8]. >>
7. The term "discovery" has been replaced with "observation": << A relevant observation in this review is the close relationship between APs and neuroinflammation, as it plays a crucial role in the observed neurodegeneration. >>

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript “Characterizing Secondary and Atypical Parkinsonisms: Defining Features and Clinical Variability” addresses issues that have been scarcely reviewed, so the effort to review and summarize the information available is valuable. However, after reading it carefully I consider that some sections could be improved.

1.        The abstract section presented in this manuscript can be improved. It does not encompass a clear idea of all that is intended to be addressed in this literature review. The abstract should include a summary of the points addressed throughout the review rather than a commentary on the review.

Authors mention that this work aimed to gather the main characteristics of the most well-known secondary and APs, including their definition, predominant symptomatology, sociodemographic aspects, etiology, diagnosis, and treatment.

2.        Table 1 summarizes the predominant symptomatology could be modified to a more reader-friendly format. Additionally, references should be added in an independent column.

3.        Some sociodemographic aspects, particularly in the APs section are not included, it would be interesting for example to include the age range in which these diseases occur since the authors often mention that they have a more agressive progression, faster course, and higher mortality. Data on incidence by gender would also be interesting to know.

4.        Neuroinflammation and microglía are included in this review as a short mention in some of the sections; however, given the scope of the journal it seems that more details should be provided. How or why neuroinflammation in this context can lead to neuronal damage, to better understand why some treatments are targeting this feature? For example, in line 98 authors mention “This occurs because PINK1 and PRKN genes affect mitochondrial control and increase susceptibility to microglia-mediated inflammation” but it is never clear why.

5.        As for DIP section, Al lof them act influencing D2 dopamine receptor signaling? How prolonged does the treatment have to be for this to happen?

6.        As for VIP it is left out as the reports about these cases proved a correlation between the viral infection and the development of parkinson-like symptoms. In most cases it is an untreated infection? Is viral infection, and neuronal damage specific to dopaminergic neurons?

 

7.        Finally, a second table addressing the diagnostic method and existing/possible treatments could help to better visualize the differences between secondary parkisonism and APs.

Author Response

1. Summary

We greatly appreciate your comments and contributions to our work. We know that these were made to improve the final content. In summary, we have made extensive changes to our work, focused on the comments created for us, and strongly emphasized each point. Likewise, we have provided a response on what and where they were modified for each of these comments.

 2. Point-by-point response to Comments and Suggestions for Authors

Reviewer 2:

1. The abstract section presented in this manuscript can be improved. It does not encompass a clear idea of all that is intended to be addressed in this literature review. The abstract should include a summary of the points addressed throughout the review rather than a commentary on the review.

Authors mention that this work aimed to gather the main characteristics of the most well-known secondary and APs, including their definition, predominant symptomatology, sociodemographic aspects, etiology, diagnosis, and treatment.

Response 1: Thank you very much; we are deeply grateful for your precise reviews. We have revised our abstract for better comprehension of the topic:

<<Abstract: Parkinsonism is a clinical syndrome characterized by akinesia/bradykinesia, muscle rigidity, resting tremor, and postural instability. This group includes Parkinson's disease, also known as neurodegenerative parkinsonian syndrome. The classification of atypical parkinsonisms emerged due to sporadic parkinsonisms that do not share the exact etiology of Parkinson's disease. Moreover, parkinsonisms arising from causes other than neurodegeneration are categorized as secondary parkinsonisms. Considering the diverse etiologies that can lead to parkinsonism, it is crucial to understand its symptomatology and relationship with the basal ganglia (including damage to the nigrostriatal pathway, neuroinflammation, and neuronal injury). Only with this understanding will it be possible to propose appropriate treatments for each variant of parkinsonism.>>

2. Table 1 summarizes the predominant symptomatology could be modified to a more reader-friendly format. Additionally, references should be added in an independent column.

Response 2: The table has been updated to include current information, and a row with references to the observed symptomatology for each type of parkinsonism has been added. Additionally, it has been relocated and renumbered (now referred to as Table 2).

3. Some sociodemographic aspects, particularly in the APs section are not included, it would be interesting for example to include the age range in which these diseases occur since the authors often mention that they have a more agressive progression, faster course, and higher mortality. Data on incidence by gender would also be interesting to know.

Response: We have supplemented the sociodemographic information for atypical parkinsonisms, providing further detail on incidence rates between men and women. Additionally, in response to your comment on age ranges, this information has been included for the subtypes of atypical parkinsonisms that previously lacked such details. Furthermore, the average life expectancy after diagnosis has been added to standardize the information regarding the aggressive progression of these disorders.

4. Neuroinflammation and microglía are included in this review as a short mention in some of the sections; however, given the scope of the journal it seems that more details should be provided. How or why neuroinflammation in this context can lead to neuronal damage, to better understand why some treatments are targeting this feature? For example, in line 98 authors mention “This occurs because PINK1 and PRKN genes affect mitochondrial control and increase susceptibility to microglia-mediated inflammation” but it is never clear why.

Response 4: The potential implications of glia are summarized in the introduction, primarily highlighting these genes and the alterations in proinflammatory factors. Therefore, improving the introduction and the sections where this is mentioned could strengthen certain points.

5. As for DIP section, Al lof them act influencing D2 dopamine receptor signaling? How prolonged does the treatment have to be for this to happen?

Response 5: The text in the DIP section was modified to include this information: <<However, not all drugs capable of inducing DIP directly affect D2 dopaminergic receptors. For instance, flunarizine and cinnarizine impair dopaminergic function by interfering with the storage and release of dopamine. Additionally, other medications such as selective serotonin reuptake inhibitor (SSRI) antidepressants are associated with a reduction in dopamine levels within the striatum. Furthermore, certain drugs, including calcium channel blockers and some antiepileptics, operate through indirect mechanisms or pathways unrelated to direct dopaminergic signaling [48,49].

The onset of DIP symptoms also varies depending on the type of medication and the method of administration. Peripheral dopamine antagonists typically exhibit a rapid onset of symptoms within 0.1 to 1 week, followed by benzodiazepines (0.5 to 1 week), typical and atypical antipsychotics (0.7 to 3.3 weeks), and benzamides (4 to 5 weeks). In contrast, medications such as antiepileptics and tricyclic antidepressants tend to have a delayed onset, ranging from 9 to 28 weeks, with some cases reported to develop symptoms after two years or more. Drugs that directly block D2 receptors generally cause symptoms more rapidly, whereas those that affect indirect systems, such as the GABAergic or serotonergic pathways, exhibit a longer latency before symptom onset [49]. Additionally, it has been observed that patients with DIP exhibit a limited response to levodopa, a diagnostic marker that helps distinguish this disorder from PD [6].>>

6. As for VIP it is left out as the reports about these cases proved a correlation between the viral infection and the development of parkinson-like symptoms. In most cases it is an untreated infection? Is viral infection, and neuronal damage specific to dopaminergic neurons?

Response 6: Thank you very much for your observations. We have modified our text as follows...

<<Moreover, antiretroviral drugs, such as protease inhibitors, may worsen neuronal damage [77,78]. This specific type of PEV occurs in severely immunosuppressed patients with a thymic CD4 T-cell count below 40 cells/mm³ [79].>>

[...]

<<In reported cases, dengue-associated PEV has appeared after the acute phase of the viral infection, even when medical care was administered [80], and following cases of dengue encephalitis developed post-infection [81].>>

7. Finally, a second table addressing the diagnostic method and existing/possible treatments could help to better visualize the differences between secondary parkisonism and APs.

Response 7: We consider this comment to be highly enriching for our work. As a result, we have created a table that displays the main diagnostic techniques and treatments for each type of parkinsonism, now included as Table 1.