Estimation of Ambulation and Survival in Neurodegeneration with Brain Iron Accumulation Disorders.

BACKGROUND: Neurodegeneration with Brain Iron Accumulation (NBIA) disorder is a group of ultra-orphan hereditary diseases with very limited data on its course. OBJECTIVES: To estimate the probability of preserving ambulatory ability and survival in NBIA. METHODS: In this study, the electronic records of the demographic data and clinical assessments of NBIA patients from 2012 to 2023 were reviewed. The objectives of the study and factors impacting them were investigated by Kaplan-Meier and Cox regression methods. RESULTS: One hundred and twenty-two genetically-confirmed NBIA patients consisting of nine subtypes were enrolled. Twenty-four and twenty-five cases were deceased and wheelchair-bound, with a mean disease duration of 11 ± 6.65 and 9.32 ± 5 years. The probability of preserving ambulation and survival was 42.9% in 9 years and 28.2% in 15 years for classical Pantothenate Kinase-Associated Neurodegeneration (PKAN, n = 18), 89.4% in 7 years and 84.7% in 9 years for atypical PKAN (n = 39), 23% in 18 years and 67.8% in 14 years for Mitochondrial Membrane Protein-Associated Neurodegeneration (MPAN, n = 23), 75% in 20 years and 36.5% in 33 years for Kufor Rakeb Syndrome (KRS, n = 17), respectively. The frequencies of rigidity, spasticity, and female gender were significantly higher in deceased cases compared to surviving patients. Spasticity was the only factor associated with death (P value = 0.03). CONCLUSIONS: KRS had the best survival with the most extended ambulation period. The classical PKAN and MPAN cases had similar progression patterns to loss of ambulation ability, while MPAN patients had a slower progression to death. Spasticity was revealed to be the most determining factor for death.

Plasma cytokines profile in patients with Alzheimer's and Parkinson's Disease: a comparative study in terms of inflammation.

BACKGROUND: Neurodegenerative disorders such as Alzheimer's and Parkinson's disease inflict economic and health burdens on societies. Alzheimer's disease (AD), the most prevalent form of dementia, is accompanied by progressive degradation of memory, decision-making, and judgment. Parkinson's disease (PD) is characterized by resting tremor, rigidity, bradykinesia, and loss of balance. Extensive research has pinpointed inflammation as a cause of the onset and progression of both diseases. However, it has not been confirmed which one is more formidable in terms of inflammation. METHODS: To assess the extent of inflammation that is implicated in AD and PD and answer the question of which one is more inflammatory, serum levels of inflammatory biomarkers, including cytokines, chemokines, and prostaglandin E2 (PEG2), were measured in AD and PD patients as well as a healthy group. RESULTS: Our results showed a significant increase in IL-1α, IL-1ß, IL-4, IL-6, IL-10, IL-12p70, IP-10, MCP-1, PEG2, and TNF-α in AD and PD patients compared with the control. Interestingly, IFN-γ did not manifest any significant difference in AD or PD patients compared with the control. CONCLUSION: As a hallmark of our results, it could be inferred that inflammation, as the underlying etiological cause, plays a more crucial role in PD compared with AD. Based on our results, it is proposed that anti-inflammatory remedies would be putatively more effective in PD rather than AD.

Salivary levels of disease-related biomarkers in the early stages of Parkinson's and Alzheimer's disease: A cross-sectional study.

Introduction: Finding a non-invasive and repeatable tool has been recommended to make an accurate diagnosis of Alzheimer's disease (AD) and Parkinson's disease (PD). Methods: 70 volunteers participated in three groups: 24 with mild dementia of AD, 24 in the first and second stages of PD, and 22 healthy controls. After valuing the scores of cognitive tests, the salivary levels of phosphorylated tau (p-tau), total alpha-synuclein (α-syn), and beta-amyloid 1-42 (Aß) proteins have been evaluated. Finally, the cutoff points, receiver operating characteristic (ROC), sensitivity, and specificity have been calculated to find accurate and detectable biomarkers. Results: Findings showed that the salivary level of Aß was higher in both PD (p < 0.01) and AD (p < 0.001) patients than in controls. Moreover, the level of α-syn in both PD and AD patients was similarly lower than in controls (p < 0.05). However, the level of p-tau was only higher in the AD group than in the control (p < 0.01). Salivary Aß 1-42 level at a 60.3 pg/ml cutoff point revealed an excellent performance for diagnosing AD (AUC: 0.81). Conclusion: Evaluation of p-tau, α-syn, and Aß 1-42 levels in the saliva of AD and PD patients could help the early diagnosis. The p-tau level might be valuable for differentiation between AD and PD. Therefore, these hopeful investigations could be done to reduce the usage of invasive diagnostic methods, which alone is a success in alleviating the suffering of AD and PD patients. Moreover, introducing accurate salivary biomarkers according to the pathophysiology of AD and PD should be encouraged.

Identical twins with progressive kyphoscoliosis and ophthalmoplegia.

The possible differential diagnoses for children presenting with kyphoscoliosis, skeletal deformities and ophthalmoplegia are diverse. We present 11-year-old identical twins with these symptoms, with interesting etiological concern for those practicing in the fields of neurology, pediatrics, spine surgery and related specialties. A new presentation for a rare genetic condition was the final diagnosis for our patients. In this movement disorder round we describe our approach to this clinical constellation and discuss clinical significance of this genetic condition.

Long term follow-up results of deep brain stimulation of the Globus pallidus interna in pediatric patients with DYT1-positive dystonia.

OBJECTIVES: Primary generalized dystonia (PGD) due to heterozygous torsin 1A (TOR1A) gene mutation (DYT1) is a childhood onset dystonia with rapid deterioration of symptoms, leading to severe disability in adolescence. Globus pallidus interna deep brain stimulation (GPi-DBS) has been shown to provide significant improvement in these cases. METHODS: This was a retrospective study of TOR1A mutation positive dystonia patients, conducted at a university hospital from 2006 to 2018. Burke-Fahn-Marsden Dystonia Rating Scale (BFM-DRS) was used to evaluate dystonia severity before and after surgery. Emergence of postsurgical parkinsonian symptoms was evaluated using the Unified Parkinson Disease Rating Scale (UPDRS) part III. Montreal Cognitive Assessment (MOCA) was applied to assess cognitive dysfunction. SPSS version 18 was used for data analysis. RESULTS: Eleven patients entered for analysis with an average age of 22.36 (±3.35) years (range: 18-28). Seven patients (63.6 %) were female. Mean follow-up period was 8.72 (±0.87). Difference between baseline and most recent BFM scores was significant (disability: 10.5 ±4.52 versus 2.09 (±3.20), P: 0.001; severity: 48.45 (±17.88) versus 9.36 (±10.47), P<0.001). The mean MOCA and UPDRS III scores after 7-9 years of DBS were 27.18 (±2.99), and 6.09 (±4.15), respectively. CONCLUSION: Our experience confirms that GPi-DBS in pediatric patients with DYT1 dystonia is overall successful, with significant and long-lasting positive effects on motor and cognitive functions. There was no prominent side effect in long-term follow up.

Impact of anticholinergic drugs withdrawal on motor function in patients with Parkinson's disease.

OBJECTIVES: Physicians have prescribed anticholinergic agents as monotherapy or adjuvant therapy in patients with Parkinson's disease for decades. However, these medications can cause many adverse effects including gait freezing and falling. Herein we assessed the effects of anticholinergic medications on motor function, freezing of gait and falling in a group of patients with PD. PATIENTS AND METHODS: This prospective study evaluated the effect of gradual discontinuation of anticholinergics on motor function in 131 outpatients with Parkinson's disease. We assessed patients' motor function at baseline six and twelve months later using the UPDRS-III. We also evaluated freezing of gait and falling in patients using UPDRS-II part 14 and 13 respectively. The anticholinergics were tapered and gradually discontinued and additional levodopa doses were added as patients needed. RESULTS: 131patients successfully discontinued their anticholinergic medications. Stopping anticholinergics significantly improved the motor symptoms in PD patients as reflected in the change between the mean (±SD) UPDRS-III score of 36.85(±11.5) at the baseline to 32.51(±11.4) and 31.43 (±11.3) after six and twelve months (P < 0.001). The mean (±SD) scores of freezing of gait (FOG)significantly changed from 1.34(±1) to 1.17(±1) and 0.6(±0.7) and for falling down from 0.62(±0.8) to 0.5 (±0.8) and 0.29(±0.5) respectively (p-value of <0.001). CONCLUSION: Our finding demonstrated an improvement in motor function and FOG and falling incidences in PD patients, after discontinuation of anticholinergic drugs. As motor complications adversely affect the quality of life in PD patients, clinicians must be careful with the unnecessary use of anticholinergic drugs in their treatment strategies.

Parkinsonism management issues in a patient with exhausted subthalamic deep brain stimulation battery, stricken by severe acute respiratory syndrome coronavirus 2.

Background: Nowadays, many neurological conditions, including Parkinson's disease (PD), are treated with deep brain stimulation (DBS). Life-threatening consequences can occur from DBS hardware failure or sudden implantable pulse generator (IPG) battery depletion. This issue may potentially worsen in concomitance with medical or infectious conditions, requiring stronger emergency management. Methods: We present here a 58 year-old PD patient with DBS, whose IPG replacement surgery was complicated by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and we report management of this patient along with recommendations for patients with similar situation. Results: As the newly-emerged coronavirus disease 2019 (COVID-19) is now announced to be pandemic, new protocols and specific measures for each individual group of patients with chronic diseases seem obligatory. Regarding our recent experience with a patient suffering from PD, on DBS treatment, who needed hospitalization, we felt useful to share our experience as a recommended protocol for similar patients in the time of current pandemic. Conclusion: Close monitoring of laboratory and clinical signs should be warranted in patients with PD awaiting IPG replacement in order to be prepared in these novel conditions that may precipitate an akinetic crisis/dystonic storm and to prevent life-threatening complications during the current pandemic.

Gait Impairment in Myoclonus-Dystonia (DYT-SGCE).

Background: Myoclonus-dystonia usually presents variable combination of myoclonus and dystonia mainly affecting the neck and arms, but leg involvement, especially as the presenting sign, is not common. Case report: A 29-year-old lady with a heterozygous mutation in Epsilon-sarcoglycan (SGCE) gene is presented with rapid jerks of the right leg interfering with walking. She has also manifested dystonic posture and jerks of the trunk and proximal upper limbs. Discussion: Although it is not typical, leg involvement could be a manifestation of myoclonus-dystonia either at presentation or during disease progression.

Midbrain area for differentiating Parkinson's disease from progressive supranuclear palsy.

OBJECTIVES: We aimed to investigate the values of midbrain area in diagnosing Parkinson's Disease (PD) and progressive supranuclear palsy (PSP) by using transcranial sonography (TCS). Disease duration effect on brain sonographic findings could decrease the accuracy of TCS in PD and PSP patients. We reduced the disease duration effect on sonographic differences found between PD and PSP patients by using multivariate analysis. PATIENTS AND METHODS: Patients with clinical diagnosis of PSP and PD were recruited. We used SonoSite Edge II Ultrasound system to measure midbrain area, diameter of third ventricle and substantia nigra echogenicity. Diagnostic value of each measured area in sonography was estimated regarding its power for diagnosing PD or PSP. Independent sample t-test, Regression analysis and receiver operating characteristic (ROC) curve were performed using SPSS software. RESULTS: Of 35 patients, 18 were PD and 17 PSP cases. The mean midbrain area was 4.86 ± 0.71cm2 in PD patients and 3.61 ± 0.85cm2 in those with PSP (P < 0.005). Regression for reducing the effect of disease duration on midbrain area variances between patients with PD and PSP revealed a significant P value (P < 0.005, Adjusted R2 = 0.36). The sensitivity and specificity of midbrain area in diagnosing PD were 83.3% and 70.6% respectively. The sensitivity of the third ventricle size in diagnosing PSP was 82% although its specificity was 62%. CONCLUSION: Midbrain area in patients with PD was wider than those with PSP that was not affected by disease duration. Midbrain area was the most accurate index for diagnosing PD by TCS although third ventricle size was the most sensitive one for diagnosing PSP.

Tardive Akathisia with Asymmetric and Upper-body Presentation: Report of Two Cases and Literature Review.

Background: Akathisia is an inner urge to move a body area with an objective motor component of restlessness. Tardive akathisia (TA) is usually bilateral with a predominant lower-body presentation. We report two patients with an asymmetrical predominantly upper-body involvement. Case Report: Two young men with history of psychiatric problems and neuroleptic use revealed atypical TA, characterized by asymmetrical and predominantly upper-body involvement. Their main manifestations were rubbing the face, mostly with one hand, accompanied by an inner sensation of restlessness. Discussion: Our patients are proof that TA can present with asymmetrical and upper-body involvement even with normal brain imaging.

Anteromedial GPi deep brain stimulation in Tourette syndrome: The first case series from Iran.

OBJECTIVES: Tourette syndrome (TS) is a neuropsychiatric disorder characterized by childhood onset motor and phonic tics. In refractory cases, deep brain stimulation (DBS) with different targets including anteromedial Globus pallidus (AM-GPi) looks promising. PATIENTS AND METHODS: Patients with TS diagnosed according to DSM-IV TR criteria with severe medication-recalcitrant disease referred to our DBS clinic, were recruited for this study. They underwent bilateral AM-GPi DBS with Model 3389, Medtronic electrodes. Patients were assessed using Yale Global Tic Severity Scale (YGTSS) and Gilles de la Touretts syndrome-quality of life (GTS-QOL) questionnaire before and one year after DBS. RESULTS: Six patients (four men and two women) with severe medication-recalcitrant TS, mean age of 26.33 ±â€¯7.25 years fulfilled the follow up visits. All patients revealed significant improvement in tics severity one year after surgery. Based on YGTSS, total tic severity score decreased from 75.66 ±â€¯16.54 to 28.33 ±â€¯13.95, P-value:0.005. Quality of life improved significantly after DBS (26.66 ±â€¯20.65 before and 70.00 ±â€¯17.88 one year after surgery, P-value:0.02). CONCLUSIONS: Results of our study in accordance to previous ones suggest AM-GPi DBS as an effective and well-tolerated therapeutic modality for patients with medication refractory TS.

Mutations in C19orf12 and intronic repeat expansions in C9orf72 not observed in Iranian Parkinson's disease patients.

Various neurodegenerative disorders share some clinical features that sometimes renders differential diagnosis challenging. Genetic-based classification also has limitations as mutations in the same gene are sometimes associated with different clinically based diagnoses. In this light, we screened the C19orf12 neurodegeneration with brain iron accumulation (NBIA) causing gene and the C9orf72 intronic expansion mutation that is cause of amyotrophic lateral sclerosis in 186 Iranian Parkinson's disease (PD) patients. C19orf12 has previously been screened in PD patients in only one study, and to the best of our knowledge neither gene has ever been screened in a PD cohort from a Middle East population. The study was justified because mutations in C19orf12 had previously been shown to be common in Iranian neurodegeneration with brain iron accumulation patients and all the patients with mutations in this gene had exhibited Parkinsonism features. The C9orf72 intronic expansion mutation was screened because the mother of an Iranian amyotrophic lateral sclerosis patient with the expansion who had been diagnosed with PD also harbored the expansion. The screenings did not identify disease causing variations in either of the genes among the PD patients screened.

RIT2 Polymorphisms: Is There a Differential Association?

Neurological disorders include a wide variety of mostly multifactorial diseases related to the development, survival, and function of the neuron cells. Single-nucleotide polymorphisms (SNPs) have been extensively studied in neurological disorders, and in a number of instances have been reproducibly linked to disease as risk factors. The RIT2 gene has been recently shown to be associated with a number of neurological disorders, such as Parkinson's disease (PD) and autism. In the study reported here, we investigated the association of the rs12456492 and rs16976358 SNPs of the RIT2 gene with PD, essential tremor (ET), autism, schizophrenia (SCZ), and bipolar disorder (BPD; total of 2290 patients), and 1000 controls, by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. Significant association was observed between rs12456492 and two disorders, PD and ET, whereas rs16976358 was found to be associated with autism, SCZ, and BPD. Our findings are indicative of differential association between the RIT2 SNPs and different neurological disorders.

Tremor-Dominant Pantothenate Kinase-associated Neurodegeneration.

Neurodegeneration with brain iron accumulation (NBIA) includes a rare and heterogeneous group of disorders characterized by iron deposition in the basal ganglia. Pantothenate kinase-associated neurodegeneration (PKAN) is the most common NBIA and has 2 main presentations: typical and atypical, the latter rarely presents with tremor. Our reported patients underwent full neurologic examination, standard brain magnetic imaging, and genetic testing for PKAN. Three patients who had "tremor-dominant" PKAN with a relatively benign course were reported, including 1 with dystonic tremor and 2 with parkinsonian tremor. All 3 patients had homozygous mutations in the PANK2 gene and typical eye of the tiger sign on brain imaging. PKAN (and NBIA in general) may be a potential cause of tremor, thus emphasizing the need to consider this diagnosis even in patients with a clinical diagnosis of essential, dystonic, or parkinsonian tremor.