207. Exploring Fatigue in Parkinson’s Disease: A Comprehensive Literature Review

Article type: Literature Review
Article title: Exploring Fatigue in Parkinson’s Disease: A Comprehensive Literature Review

Journal: Cureus
Year: 2025

Authors: Jamir Pitton Rissardo, Maleesha Jayasinghe, Ahmed Farid Gadelmawla, Masoumeh Rashidi, Fatemeh Rashidi, Hania Moharam, Ola D. Hag Ali, Mohamed Yousif Elamin Yousif, Ibrahim Khalil, Ana Leticia Fornari Caprara, Omesh Prathiraja, Mallak Bahar
E-mail: jamirrissardo@gmail.com

ABSTRACT
Fatigue is one of the most prevalent and debilitating non-motor symptoms of Parkinson’s disease (PD), affecting up to two-thirds of patients and significantly impacting quality of life. This review provides a comprehensive analysis of its complex pathophysiology, prevalence, clinical presentation, assessment methods, and current management strategies. Fatigue in PD is linked to dysfunction in dopaminergic and non-dopaminergic pathways, neuroinflammation, genetic predispositions, and metabolic dysregulation. Reported prevalence rates range from 36% to 60%, highlighting the need for standardized assessment tools and a universally accepted definition. Clinically, fatigue is characterized by an overwhelming and abnormal sense of exhaustion, often preceding motor symptoms by years. Distinguishing it from sleepiness, apathy, and depression is crucial for accurate diagnosis and treatment. Assessment primarily relies on patient-reported scales, such as the Fatigue Severity Scale and the Parkinson’s Disease Fatigue Scale. Management includes both pharmacological and non-pharmacological approaches, with medications like methylphenidate and rasagiline showing potential, alongside physical exercise, cognitive behavioral therapy, and sleep disorder management. Further research is essential to unravel the underlying mechanisms, identify objective biomarkers, and develop more effective, targeted treatments for this burdensome symptom.
Keywords: apathy, behavioral symptoms, chronic fatigue, depression, excessive daytime sleepiness, fatigue, non-motor symptoms, parkinson's disease, secondary fatigue, sleepiness. 

Citation
Pitton Rissardo J, Jayasinghe M, Gadelmawla A, et al. Exploring Fatigue in Parkinson’s Disease: A Comprehensive Literature Review. Cureus 2025;17:e81129. doi:10.7759/cureus.81129.
Table 1. Prevalence of fatigue in Parkinson's disease.

Figure 1. Summary of common scales used to assess fatigue in Parkinson's disease.

Figure 2. Comprehensive management strategies for addressing fatigue in Parkinson’s disease, bifurcated into pharmacological and non-pharmacological categories.

RLS

Restless legs syndrome


- Start w/ gabapentin enacarbil (Horizant) > gabapentin > pregabalin
- IV iron: ferric carboxymaltose >  low molecular weight iron dextran > ferumoxytol > ferrous sulfate
- Others: dipyridamole, extended-release oxycodone
- Devices: Nidra (bl high-frequency peroneal nerve stimulation)
- Against: levodopa, pramipexole, transdermal rotigotine, bupropion, carbamazepine, clonazepam, valerian, valproic acid, cabergoline
> if needs a dopamine agonist, consider Neupro (transdermal rotigotine)
- special situations: 
> ESRD, consider vitamin C
> PLMD: against triazolam, VPA




Tics - General

Tics General

Management
- Behavioral therapy
- Tic App: Neupulse
- Pharmacological
1st: Clonidine versus guanfacine
> theoretically, clonidine had better results
2nd: Topiramate
3rd: Tetrabenazine
> not so much effective
4th: Antipsychotics, especially olanzapine and aripiprazole
> commonly, pts develop tardive DKN

BOTOX - Foot

BOTOX - Foot

Toe flexion (Curling)
Areas of botox:
- plantar surface of the foot (flexor digitorum brevis)

Painful leg and moving toes syndrome

Painful leg and moving toes syndrome

Definition
Movement of toes to compensate returning of pain

Differential
- RLS: not related to isolated toe movements
- Periodic leg movement disorder
- DTN
> not sustained
> usually DYN involving only the leg is observed in young individuals; older individuals had cervical dystonia

Treatment
- pain management

206. A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies

Article type: Literature Review
Article title: A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies

Journal: Clinics and Practice
Year: 2025
Authors: Jamir Pitton Rissardo, Ana Leticia Fornari Caprara
E-mail: jamirrissardo@gmail.com

ABSTRACT
Alpha-synuclein has been associated with neurodegeneration, especially in Parkinson’s disease (PD). This study aimed to review clinical, biochemical, and neuroimaging markers and management of prodromal synucleinopathies. The prodromal state of synucleinopathies can be better understood with PD pathophysiology, and it can be separated into premotor and pre-diagnostic phases. The incidence of PD in patients with prodromal phase symptoms ranges from 0.07 to 14.30, and the most frequently studied pathology is the REM behavioral disorder (RBD). Neuroimaging markers are related to dopamine denervation, brain perfusion changes, gross anatomy changes, and peripheral abnormalities. α-synuclein assays (SAA) in CSF revealed high sensitivity (up to 97%) and high specificity (up to 92%); in the last decade, there was the development of other matrices (blood, skin, and olfactory mucosa) for obtaining quantitative and qualitative α-synuclein. Other biomarkers are neurofilament light chain, DOPA decarboxylase, and multiplexed mass spectrometry assay. Regarding genetic counseling in α-synucleinopathies, it is an important topic in clinical practice to discuss with patients with high-risk individuals and should involve basic principles of autonomy, beneficence, and non-maleficence. Some of the themes that should be reviewed are the involvement of physical activity, diet (including alcohol, coffee, and vitamin supplementation), smoking, sleep, and stress in the pathophysiology of synucleinopathies. The number of trials related to prodromal symptoms is still scarce, and the number of studies evaluating intervention is even lower.
Keywords: alpha-synuclein; synucleinopathies; biofluid; prodromal; RBD; Parkinson’s disease; prevention.
Citation
Rissardo JP, Caprara ALF. A Narrative Review on Biochemical Markers and Emerging Treatments in Prodromal Synucleinopathies. Clin Pract 2025;15(3):65.
Figure 1. Stages of Parkinson’s disease with biomarkers. Dopaminergic loss and noradrenergic denervation can be observed. Also, the Braak staging and Lewy body pathology can be linked to the stages.

Figure 2. Movement Disorder Society research criteria for prodromal multiple system atrophy (MSA) and Parkinson’s disease (PD). Abbreviations: DMS, Diagnostic and Statistical Manual of Mental; OH, orthostatic hypotension; PSP, Progressive Supranuclear Palsy; RBD, REM sleep behavior disorder.

Figure 3. Strategic questions of the Parkinson Progression Marker Initiative (PPMI) study.

Figure 4. WHO Exercise recommendation for adults with living disabilities (including PD).

Table 1. Studies about prodromal Parkinson’s disease symptoms.

Table 2. Neuroimaging and prodromal parkinsonian syndromes.

Table 3. α-Synuclein seeding aggregation assays in prodromal populations.

Table 4. Potential matrices biomarkers of α-synucleinopathies.

Table 5. α-Synuclein in L1CAM-enriched extracellular vesicles (L1EVs) in prodromal populations of patients with REM sleep behavior disorder.

Table 6. Lessons learned from Alzheimer’s disease in disclosing amyloid PET results.

Table 7. Mediterranean and MIND diets and Parkinson’s disease risk.

Table 8. Dairy products and Parkinson’s disease risk.

Table 9. Vitamins and Parkinson’s disease risk.

Table 10. Clinical trials with prodromal synucleinopathies registered in the ClinicalTrials.gov Database.

Table 11. Machine learning models for predicting prodromal Parkinson’s disease.

Stroke - Hypercoagulability work-up

Hypercoagulable panel

Basic
- PTT
- thrombin time
- fibrinogen

Antithrombin III
- antithrombin III activity

Protein C & S
- protein C
- APC resistance (activated protein C resistance)
- protein S

APLS
- hexagonal antibody (hexagonal phase phospholipid neutralization)
- cardiolipin antibody (IgG, IgA, IgM)
- B2-glycoprotein antibody
- DRVVT screen (to detect lupus anticoagulant)
> dilute Russell viper venom

Genetics
- Factor V Leiden mutation
- Factor II (prothrombin) mutation

Others
Less commonly ordered tests
- D-dimer
- lipoprotein (a)
- homocysteine
- factor VIII activity
- MTHFR mutation

Stroke - My Stick Note

Stroke Stick Note
 
Presented in ### on ### with ###.

PMH

NIHSS (scored)
TNK; MT TICI

Stroke work-up
CTH: 
CTA H/N: 
MRI Brain: 
TTE: 
A1c: 
LDL: 
Smoking: 

Etiol

Therap

-----------------------------
Presented in ### on ### with ###.
- as succinct as possible
- only report major weakness
- if non-neuro symptom, describe the main symptom

PMH
- if prior stroke; localize, etiology, and deficits
Example: R MCA stroke (LAA, no deficits)
- focus on antithrombotics and AC, explain why was patient taking AC
Example: apixaban 2/2 Afib

NIHSS
- score, and sections
Example: NIHSS 5 (face, arm, leg, and aphasia)

TNK
- Y/N, reason why not administered

MT
- report TICI

Stroke work-up
CTH
- infarcts (new, chronic) and hemorrhages
- hyperdense MCA

CTA H/N
- LVO? MEVO?
- decreased flow

CTP
- mismatch? Stroke completed?

DSA
- TICI, occlusion, sub-occlusion, thrombus

MRI Brain
- new/old infarct and area
- hemorrhagic transformation?

TTE
- LVEF, PFO, LAD, LVT

A1c
- new

LDL
- only value

Smoking
- packs-year

Etiol
- read stroke etiology

Therap
- ASA, clopdiogrel, ticagrelor load and maintenance
- AC
- statin

205. Neurological Manifestations of Systemic Lupus Erythematosus: A Comprehensive Review

Article type: Literature Review
Article title: Neurological Manifestations of Systemic Lupus Erythematosus: A Comprehensive Review

Journal: Cureus
Year: 2025
Authors: Maleesha Jayasinghe, Fatemeh Rashidi, Ahmed Farid Gadelmawla, Jamir Pitton Rissardo, Masoumeh Rashidi, Christopher C. Elendu, Ana Leticia Fornari Caprara, Ibrahim Khalil, Khalil I. Hmedat, Mohamed Atef, Hania Moharam, Omesh Prathiraja
E-mail: jamirrissardo@gmail.com

ABSTRACT
Neurological involvement in systemic lupus erythematosus (SLE) poses significant challenges, impacting patient morbidity, mortality, and quality of life. This narrative review provides an update on the pathogenesis, clinical presentation, diagnosis, and management of neurological SLE. The multifaceted pathophysiology involves immune-mediated and vascular mechanisms such as autoantibodies, neuroinflammation, complement dysregulation, and genetic factors. Neuropsychiatric SLE (NPSLE) manifests in a variety of ways, including cognitive dysfunction, mood disorders, psychosis, cerebrovascular disease, demyelinating syndromes, and neuropathies. Diagnosing neurological SLE is complicated by nonspecific and fluctuating symptoms, requiring comprehensive neurological examination, neuroimaging, autoantibody profiling, and cerebrospinal fluid analysis. Current management strategies include corticosteroids, immunosuppressive agents, and emerging biologics targeting specific immune pathways. Managing neuropsychiatric symptoms, seizures, and neuropathic pain remains a complex aspect of treatment. This review highlights the importance of early recognition and tailored management approaches to improve patient outcomes in neurological SLE.
Keywords: diagnosis of npsle, lupus erythematosus, neuropsychiatric systemic lupus erythematosus (npsle), sle, systemic lupus erythematosus disease.

Full text available at:

DOI

Citation
Jayasinghe M, Rashidi F, Gadelmawla AF, et al. Neurological Manifestations of Systemic Lupus Erythematosus: A Comprehensive Review. Cureus 2025;17: e79569.
Table 1. Immune-mediated mechanisms in neurological SLE. SLE: systemic lupus erythematosus, aPL: antiphospholipid, NPSLE: neuropsychiatric systemic lupus erythematosus, CNS: central nervous system, MAP-2: microtubule-associated protein 2, AECA: anti-endothelial-cell antibody, β2-GPI: beta-2-glycoprotein I, anti-RP Ab: anti-ribosomal P protein antibodies, aPL Ab: antiphospholipid antibodies, anti-MAP-2 Ab: anti-microtubule-associated protein 2 antibodies, anti-GAPDH Ab: anti-glyceraldehyde-3-phosphate dehydrogenase antibodies, BBB: blood-brain barrier.

Table 2. Diagnostic tests for neurological SLE. SLE: systemic lupus erythematosus, CNS: central nervous system, MRI: magnetic resonance imaging, CT: computed tomography, PET: positron emission tomography, CSF: cerebrospinal fluid, WM: white matter, SPECT: single-photon emission computed tomography, apL: antiphospholipid, NMO: neuromyelitis optica, NPSLE: neuropsychiatric systemic lupus erythematosus, MS: multiple sclerosis.

Table 3. Management of neuropsychiatric manifestations in SLE. SLE: systemic lupus erythematosus, DNA: deoxyribonucleic acid, IV: intravenous, CNS: central nervous system, NPSLE: neuropsychiatric systemic lupus erythematosus, IL-2: interleukin-2, GI: gastrointestinal, TPE: therapeutic plasma exchange, IVIG: intravenous immunoglobulin.

Figure 1. Pathophysiology, clinical manifestations, and treatment of NPSLE. NPSLE: neuropsychiatric systemic lupus erythematosus.

204. Transient myoclonic state or transient myoclonic state with asterixis: A systematic review

Article type: Literature Review
Article title: Transient myoclonic state or transient myoclonic state with asterixis: A systematic review

Journal: Medicine International
Year: 2025
Authors: Jamir Pitton Rissardo, Nilofar Murtaza Vora, Nirali Seth, Sanobar Shariff, Ana Letícia Fornari Caprara

ABSTRACT
Transient myoclonic state (TMS) is a rare type of myoclonic jerks occurring predominantly in the upper extremities involving the head and commonly associated with asterixis. The present study performed a systematic review of published articles on this condition. For this purpose, six databases were searched by two reviewers to identify reports on TMS published online until November, 2024. A total of 17 reports containing 78 cases were found. Almost all the reports were from Japan, apart from one case reported in the USA. The mean age of the patients was 75.67 years (standard deviation, 5.8 years) and the median age was 75 years (range, 54 to 84 years). Sex was reported in 74 reports, and 60.8% of the patients were males. A precipitating factor, such as an infectious disease or the introduction of a new medication was observed in 24 cases (30.7%). All individuals achieved full recovery; however, 53 patients (67.9%) required benzodiazepine therapy, while the remaining individuals improved spontaneously. In summary, the present systematic review demonstrates that TMS is a rare condition, and is mainly encountered in Japan by unknown factors. There are likely genetic and environmental factors involved in its development; however, no specific geolocation related to the occurrence of TMS in Japan was found. It has a benign course and usually improves with the prescription of benzodiazepines. Management strategies include ensuring adequate multidisciplinary care coordination, as well as educating patients and their families about TMS. Future studies are required to describe the cases of TMS, including videos of the phenomenology. It is also recommended to perform whole genome sequencing analysis in patients with TMS..
Keywords: transient myoclonic state; myoclonus; transient myoclonic state with asterixis; transient co‑occurrence of myoclonus; asterixis.

Full text available at:

DOI

Citation
Rissardo J, Vora NM, Seth N, Shariff S, Fornari Caprara AL. Transient myoclonic state or transient myoclonic state with asterixis: A systematic review. Med Int 5: 29, 2025. https://doi.org/10.3892/mi.2025.228.
Figure 1. Flowchart of the study screening process for the present systematic review.

Figure 2. Geographical distribution in Japan of the cases reported in the literature of transient myoclonic state. The case described in the study by Sethi (21) was not included as it was outside Japan. In addition, there were insufficient data from the study by Tsuchiyama et al (23) to provide the geographical localization. The locations are indicated by numbers on the map and refer to the following studies: 1, Mizutani et al (2); 2, Hashimoto et al (1); 3, Negoro et al (12); 4, Fujihara et al (13); 5, Hirata et al (14); 6, Iijima et al (15); 7, Yamamoto (16); 8, Kohono et al (17); 9, Okuma et al (18); 10, Kawakami (19); 11, Hitomi et al (20); 12, Hiraga et al (7); 13, Doden et al (3); 14, Umemura et al (22); 15, Harada et al (8).

Table I. Free text and medical subject heading search terms used in the US National Library of Medicine.

Table II. Quality evaluation of case reports by the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Case Reports.

Table III. Literature review of reports of transient myoclonic state.

Table IV. Transient myoclonic state features (as indicated in the manuscript).
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