Non-motor features of essential tremor with midline distribution.

BACKGROUND: Midline essential tremor (Mid-ET) is a distinctive group of essential tremor (ET) in which tremor affects the neck, jaw, tongue, and/or voice. For long, it has been considered as an ultimate stage of the disease and a marker of its severity. However, recent studies pointed its complexity in terms of non-motor presentation. Thus, we aimed to investigate the non-motor signs (NMS) in Mid-ET. DESIGN: We conducted a cross-sectional study in a tertiary neurology referral center including ET patients classified into two groups based on the presence or not of midline tremor (Mid-ET vs. No-Mid-ET). We assessed NMS using the non-motor severity scale (NMSS), a large battery of cognitive tests, clinical and electrophysiological study of the autonomic nervous system along with the evaluation of sleep disturbances. RESULTS: A total of 163 patients were included: Mid-ET (n = 79) and No-Mid-ET (n = 84) matched in gender and age of onset. Mid-ET patients had higher proportion of late-onset ET (> 60 years old, p = 0.002) and more extrapyramidal signs (p = 0.005). For NMS, Mid-ET was marked with cognitive dysfunction (p = 0.008). The hallmarks of the neuropsychiatric profile of Mid-ET were executive dysfunction (p = 0.004), attention problems (p < 0.000), episodic memory impairment (p = 0.003), and greater depression (p = 0.010). The presence of RBD was a trait of Mid-ET (p = 0.039). In both Mid-ET and No-Mid-ET phenotypes, clinical and neurophysiological dysautonomia correlated with cognitive dysfunction. CONCLUSION: Mid-ET patients had greater cognitive dysfunction, depression, RBD, higher proportion of late-onset ET, and more extrapyramidal signs. Taken all together, these findings could provide a redesigned insight into the underlying physiopathology of Mid-ET indicative of a greater cerebellar dysfunction.

Environmental factors related to multiple sclerosis progression.

Multiple Sclerosis (MS) is a complex neurological disease which prevalence is increasing worldwide. The impact of environmental factors on MS susceptibility has already been defined and highlighted in many previous reports, particularly vitamin D or ultraviolet B light exposure, Epstein-Barr virus (EBV) infection, obesity, and smoking. There is increasing evidence that environmental and lifestyle factors are not only important in triggering MS but are also implicated in MS progression. Low sun exposure and vitamin D deficiency exhibit a strong relationship with disease progression in both animal and human studies. The gestational period seems also to impact long-term disease progression as January's babies had a higher risk of requiring walking assistance than those born in other months. The implication of EBV in neurodegeneration and MS progression was also suggested even though its specific targets and mechanisms are still unclear. Cigarette smoking is correlated with faster clinical progression. The association of obesity and smoking seems to be associated with a faster progression and an increased rate of brain atrophy. Although the effect of air pollution on MS pathogenesis remains not fully understood, exposure to polluted air can stimulate several mechanisms that might contribute to MS severity. People with MS with active disease have an altered microbiota compared to patients in the remission phase. Cardiovascular comorbidities, epilepsy, and depression are also associated with a more severe disability accrual. Knowledge about MS modifiable risk factors of progression need to be incorporated into everyday clinical practice in order to ameliorate disease outcomes.

Clinical and molecular predictors of survival among atypical parkinsonian syndromes in a North African tertiary referral center.

INTRODUCTION: Atypical Parkinsonian Syndromes(APS) are challenging neurodegenerative disorders due to their heterogeneous phenotypic overlaps.So far,there are no validated biomarkers that can accurately predict disease progression,and survival studies were highly different and contradictory. AIM: To investigate clinical and molecular survival factors among Tunisian APS patients. METHODS: A retrospective study included Tunisian APS-patients.Using clinical and molecular parameters,survival was explored by Kaplan-Meier analysis. RESULTS: We included 409-APS patients divided into 166-DLB,112-PSP,81-MSA and 50-CBS.Survival rate was similar in synucleinopathies, while it differed in tauopathies,being shorter in PSP compared to CBS.Median survival in DLB was different according to gender(p = 0.0048),early parkinsonism and cognitive disorders. Among MSA, prognosis was worse in MSA-C-patients(p = 0.012) and those with stridor(p = 0.0049),oculomotor and neuropsychiatric disorders. For tauopathies, survival was shorter in PSP-RS(p = 0.027),cerebellar phenotype, those with tremor and swallowing problems at onset, early parkinsonism and memory impairment. For CBS,prognosis was worse in patients with tremor,swallowing and cognitive problems.Significant differences were noted in terms of survival across APS non-carriers of APOE-ε4(p < 0.001) as well APS patients carriers of MAPT-H1.PSP patients had lower survival rate according to MAPT haplotype carriage. Moreover, the number of copies had an influence as patients with H1/H2-MAPT profile had better prognosis than those with H1/H1. CONCLUSION: This study determined survival rates in APS subgroups,which were comparable across synucleinopathies but shorter in PSP and longer in CBS.It also characterized demographic,phenotypic,and genetic profiles identifying more aggressive forms within APS subgroups.These findings address clinical gaps,aiding counseling for patients and families and guiding clinical management.Furthermore,they could facilitate patient stratification in clinical trials where mortality is an outcome measure.

The Impact of LRRK2 G2019S on Parkinson's Disease: Clinical Phenotype and Treatment in Tunisian Patients.

OBJECTIVE: LRRK2-G2019S is the most frequent mutation in North African Parkinson's disease (PD) patients. Data on its impact on disease progression and treatment response remain elusive. Therefore, we investigated the clinical features, treatments, and complications of PD in Tunisian patients according to their LRRK2-G2019S profile. METHODS: This longitudinal retrospective study was performed in the Department of Neurology, Razi University Hospital. We included clinically diagnosed PD patients according to the Movement Disorders Society criteria and reviewed their medical records for clinical, treatment, and neuropsychological assessments. All patients were screened for the LRRK2-G2019S mutation using Sanger sequencing. The correlation between LRRK2-G2019S and clinical PD features was evaluated. RESULTS: We included 393 PD patients, 41.5% of whom had LRRK2-G2019S mutations. Patients with mutations were younger (p = 0.017), and female PD patients had a greater mutation frequency (p = 0.008). Mutation carriers exhibited distinct clinical features, with a greater frequency of postural instability gait difficulty forms (adjusted-p < 0.001). During disease progression, carriers showed a faster annual progression in the Unified Parkinson's Disease Rating Scale Section III scores (adjusted-p = 0.009), and significantly higher levodopa equivalent dose values in later stages (1060.81 vs. 877.83 for 6-8 years). Motor complications, such as dyskinesia (adjusted-p < 0.001) and motor fluctuations (31.9% vs. 25.7%, adjusted-p < 0.001), were more prevalent in carriers, particularly in the later stages. LRRK2-G2019S carriers also exhibited a lower prevalence of non-motor symptoms, including episodic memory (adjusted-p < 0.001), attention (adjusted-p < 0.001), and dysexecutive disorders (adjusted-p = 0.038), as well as neuropsychiatric symptoms and dysautonomic signs. CONCLUSION: The present study demonstrated that the variability of the clinical profile among Tunisian PD patients was explained by the incomplete penetrance of LRRK2-G2019S, which increased with age. Further studies using biomarker and disease progression data are necessary to improve PD management.

Psychiatric Symptoms in Stiff-Person Syndrome: A Systematic Review and a Report of Two Cases.

BACKGROUND: The clinical spectrum of stiff-person syndrome (SPS) encompasses a wide range of signs including psychiatric symptoms (PS). OBJECTIVE: Our objective was to provide an overview of the spectrum of PS in SPS through a systematic literature search and 2 illustrative case reports. METHODS: We reported 2 anti-glutamic acid decarboxylase-positive SPS cases that presented with phobic disorder, and we performed a systematic review by following the 2020 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Articles published in PubMed, MEDLINE on Ovid, Embase, and via a manual search before October 20, 2020, were selected by 2 independent reviewers. Original studies, case reports, editorials, commentaries, and letters to the editor reporting cases of SPS with PS were all included. Conference abstracts, reviews and book chapters, unavailable articles, and those not reporting SPS cases or PS were excluded. Quantitative summary data were calculated. RESULTS: In addition to our 2 cases, we identified 237 cases of SPS with PS from 74 additional included publications totaling 239 patients. Anxiety (56%) and depression (45%) were the most common PS in SPS. Mean diagnostic delay was 4.7 years. Among the 3 SPS phenotypes, the classic form was predominant (77%), followed by stiff-limb syndrome (13%) and progressive encephalomyelitis with rigidity and myoclonus (10%). The most frequent etiology of SPS with PS was autoimmune (90%), followed by cryptogenic (7%) and paraneoplastic forms (7%). These patients were mainly treated with immune-mediated therapies and GABAergic drugs. CONCLUSIONS: Our review revealed that the most common PS of SPS are anxiety and depression occurring mostly in autoimmune and classic forms, allowing a clearer understanding of this entity, which may lead to earlier diagnosis and better outcome.

Subtypes of Dementia with Lewy Bodies: Clinical Features, Survival, and Apolipoprotein E Effect.

Background: Dementia with Lewy bodies (DLB) is a progressive neurodegenerative disease with various clinical symptoms. Limited data have described the clinical subtypes of DLB. Objective: We aimed to compare clinical subtypes of DLB according to initial symptoms and to study the effect of Apolipoprotein E (APOE) gene in DLB. Methods: We included DLB patients classified into three groups based on initial symptoms: non-motor onset (cognitive and/or psychiatric) (NMO-DLB), motor onset (parkinsonism and/or gait disorders) (MO-DLB), and mixed onset (non-motor and motor symptoms) (MXO-DLB). Clinical and APOE genotype associations and survival were analyzed. Results: A total of 268 patients were included (NMO-DLB = 75%, MXO-DLB = 15.3%, MO-DLB = 9.7%). Visual hallucinations were more frequent (p = 0.025), and attention was less commonly impaired in MXO-DLB (p = 0.047). When adjusting with APOE ɛ4 status (APOE genotype performed in 155 patients), earlier falls and frontal lobe syndrome were more common in MXO-DLB (p = 0.044 and p = 0.023, respectively). The median MMSE decline was 2.1 points/year and the median FAB decline was 1.9 points/year, with no effect of clinical subtypes. Median survival was 6 years. It was similar in DLB subtypes (p = 0.62), but shorter for patients with memory symptoms at onset (p = 0.04) and for males (p = 0.0058). Conclusions: Our study revealed a few differences between DLB clinical subtypes. APOE ɛ4 appears to be associated with earlier falls and a higher prevalence of frontal syndrome in MXO-DLB. However, DLB clinical subtypes did not impact on survival. Nevertheless, survival analysis identified other poor prognosis factors, notably inaugural memory impairment and male gender.

Determinants of cognitive impairment in multiple system atrophy: Clinical and genetic study.

INTRODUCTION: Classically, cognitive impairment (CI) was not considered as a paramount feature of multiple system atrophy(MSA) in both parkinsonian(MSA-P) and cerebellar(MSA-C) motor-subtypes. Yet, growing evidence indicates currently the commonness of such deficits among MSA patients in different populations. Our aim was to evaluate the cognitive profile of MSA Tunisian patients and to analyze the underlying clinical and genetic determinants. METHODS: In a retrospective cross-sectional study, clinically-diagnosed MSA patients were included. All subjects underwent clinical and neuropsychological assessments to characterize their cognitive profile. The associations with their APOE genotype status were analyzed. Determinant of CI were specified. RESULTS: We included 71 MSA patients. Female gender(sex-ratio = 0.65) and MSA-P subtype(73%) were predominant. Mean age of disease onset was 59.1years. CI was found in 85.7% of patients(dementia in 12.7% and Mild cognitive impairment(MCI) in 73% of patients mainly of multiple-domain amnestic type(37.3%)). Mean MMSE score was lower among MSA-P compared to MSA-C(23.52 vs. 26.47;p = 0.027). Higher postural instability gait disorder(PIGD) and MDS-UPDRS-III scores were noted in demented MSA patients(p = 0.019;p = 0.015 respectively). The main altered cognitive domain was attention(64.8%). Executive functions and mood disorders were more affected in MSA-P(p = 0.029,p = 0.035 respectively). Clinical and neurophysiological study of dysautonomia revealed no differences across cognitive subtypes. APOE genotyping was performed in 51 MSA patients with available blood samples. Those carrying APOEε4 had 1.32 fold higher risk to develop CI, with lower MMSE score(p = 0.0001). Attention and language were significantly altered by adjusting the p value to APOEɛ4 carriers(p = 0.046 and p = 0.044 respectively). Executive dysfunction was more pronounced among MSA-PAPOEε4 carriers(p = 0.010). CONCLUSION: In this study, the main determinants of CI in Tunisian MSA patients were MSA-P motor-subtype, mainly of PIGD-phenotype, disease duration and APOEε4 carrying status, defining a more altered cognitive phenotype. This effect mainly concerned executive, attention and language functions, all found to be more impaired in APOEε4 carriers with variable degrees across MSA motor-subtypes.

Stroke in Djibouti.

Background: Stroke is a neurological emergency affecting both developed and developing countries. In Djibouti, stroke is the fourth leading cause of death. Our objective was to describe the demographic, clinical, paraclinical profile of stroke in Djibouti and identify the possible underlying risk factors. Methods: We conducted a cross-sectional multicentre study carried out over a period of 6 months in the medical services of the Soudano-Djibouti military hospital, the General Peltier hospital and the emergency department of the National fund for social security health centre. Results: A total of seventy patients were included. The mean age was 59.61 years with a male predominance (sex ratio: 2.5) and a statistically significant female-related difference beyond the age of 60 years (p <10-3). Cardiovascular risk factors were mainly hypertension (73%), khat chewing (64%) and tobacco use (50%). Khat chewing and tobacco use were associated with a younger age of occurrence of stroke (p=0.020 and p=0.004, respectively). Diabetes mellitus and hypercholesterolemia were found respectively in 30% and 19% of cases, and were more associated with ischemic stroke. Coronary disease (11%), heart failure (3%) and obesity (4%) (significantly associated with the female gender; p= 0,021) were less common. Motor deficits (94%) were the most common clinical manifestations, followed by sensory deficits (51%) and alteration of consciousness (37%). Stroke was ischemic in 61.5% of patients. The most affected territory in ischemic stroke was the territory of the middle cerebral artery, and capsulo-thalamic involvement in haemorrhagic stroke which was significantly associated with the alteration of consciousness(p=0,003). Discussion: Stroke had primarily modifiable risk factors in Djiboutian patients dominated by high blood pressure, tobacco use and khat chewing especially in the male population under the age of 60 years. These findings could have implications on future preventive measures and a better approach to public health policy.

Heart rate variability and sympathetic skin response for the assessment of autonomic dysfunction in leucine-rich repeat kinase 2 associated Parkinson's disease.

OBJECTIVES: We aimed to assess and compare autonomic function in Parkinson's disease (PD) associated with the leucine-rich repeat kinase (LRRK2) G2019S mutation (LRRK2-PD) and non-LRRK2 PD, by the study of heart rate variability (HRV) and sympathetic skin responses (SSR). METHODS: In a cross-sectional three-year study, fifty LRRK2-PD and fifty clinically matched non-LRRK2 PD patients were included. Cardiac parasympathetic functions were assessed using heart rate variation to deep breathing (HR-DB), to the Valsalva maneuver (HR-V) and to standing (HR-S) and the sympathetic autonomic system by sympathetic skin responses (SSR). RESULTS: Neurophysiological, parasympathetic and sympathetic dysautonomia were found in 78%, 69% and 37% of all PD patients respectively. Rates of dysautonomia in the LRRK2-PD and non-LRRK2 PD patient subgroups were 76% vs 80% (p = 0.405) for neurophysiological, 62% vs 76% (p = 0.123) for parasympathetic and 38% vs 36% (p = 0.500) for sympathetic dysautonomia. HR-S was the most frequently altered parameter in both groups, and was significantly associated with the tremor-dominant (TD) motor phenotype of PD in the total cohort (p = 0.004) and in LRRK2-PD (p = 0.015). In LRRK2-PD patients, female gender was associated with parasympathetic dysfunction (p = 0.024), and with altered HR-DB (p = 0.022). Early-onset parkinsonism was also significantly associated with preserved neurophysiological autonomic functions (p = 0.044) in LRRK2-PD. In non-LRRK2 PD patients, male gender was associated with early parasympathetic (p = 0.043) and sympathetic dysfunction (p = 0.007). CONCLUSION: Our study showed a roughly similar neurophysiological autonomic profile in non-LRRK2 PD and LRRK2-PD. The latter had some peculiarities with more marked parasympathetic dysfunction and more altered HR-DB in females, more altered HR-S in the TD-motor phenotype, and preserved autonomic functions in early-onset parkinsonism. These preliminary findings would require further investigations on larger genetically homogeneous cohorts to explore the multiple facets of autonomic dysfunction in PD.