Imbalance and gait impairment in Parkinson's disease: discussing postural instability and ataxia.

Gait and balance difficulties pose significant clinical challenges in Parkinson's disease (PD). The impairment of physiological mechanisms responsible for maintaining natural orthostatism plays a central role in the pathophysiology of postural instability observed in PD. In addition to the well-known rigidity and abnormalities in muscles and joints, various brain regions involved in the regulation of posture, balance, and gait, such as the basal ganglia, cerebellum, and brainstem regions like the pontine peduncle nucleus, are affected in individuals with PD. The recognition of the cerebellum's role in PD has been increasingly acknowledged. Cortical areas and their connections are associated with freezing of gait, a type of frontal lobe ataxia commonly observed in PD. Furthermore, impairments in the peripheral nervous system, including those caused by levodopatherapy, can contribute to gait impairment and imbalance in PD patients. Consequently, individuals with PD may exhibit frontal ataxia, sensory ataxia, and even cerebellar ataxia as underlying causes of gait disturbances and imbalance, starting from the early stages of the disease. The complex interplay between dysfunctional brain regions, impaired cortical connections, and peripheral nervous system abnormalities contributes to the multifaceted nature of gait and balance difficulties in PD. Understanding the intricate mechanisms is crucial for the development of effective therapeutic approaches targeting these specific deficits in PD.

Diagnostic Yield of NGS Tests for Hereditary Ataxia: a Systematic Review.

Next-generation sequencing (NGS), comprising targeted panels (TP), exome sequencing (ES), and genome sequencing (GS) became robust clinical tools for diagnosing hereditary ataxia (HA). Determining their diagnostic yield (DY) is crucial for optimal clinical decision-making. We conducted a comprehensive systematic literature review on the DY of NGS tests for HA. We searched PubMed and Embase databases for relevant studies between 2016 and 2022 and manually examined reference lists of relevant reviews. Eligible studies described the DY of NGS tests in patients with ataxia as a significant feature. Data from 33 eligible studies showed a median DY of 43% (IQR = 9.5-100%). The median DY for TP and ES was 46% and 41.9%, respectively. Higher DY was associated with specific phenotype selection, such as episodic ataxia at 68.35% and early and late onset of ataxia at 46.4% and 54.4%. Parental consanguinity had a DY of 52.4% (p = 0.009), and the presumed autosomal recessive (AR) inheritance pattern showed 62.5%. There was a difference between the median DY of studies that performed targeted sequencing (tandem repeat expansion, TRE) screening and those that did not (p = 0.047). A weak inverse correlation was found between DY and the extent of previous genetic investigation (rho = - 0.323; p = 0.065). The most common genes were CACNA1A and SACS. DY was higher for presumed AR inheritance pattern, positive family history, and parental consanguinity. ES appears more advantageous due to the inclusion of rare genes that might be excluded in TP.

Inherited metabolic diseases mimicking hereditary spastic paraplegia (HSP): a chance for treatment.

The syndromic group of hereditary spastic paraplegias has a heterogeneous clinical profile and a broad differential diagnosis, including neurometabolic disorders that are potentially treatable. This group includes 5,10-methylenetetrahydrofolate reductase deficiency, cobalamin C deficiency disease, dopamine responsive dystonia, cerebrotendinous xanthomatosis, biotinidase deficiency, GLUT1 deficiency syndrome, delta-e-pyrroline-carboxylase-synthetase deficiency, hyperonithinemia-hyperammonemia-homocitrullinuria syndrome, arginase deficiency, multiple carboxylase deficiency, and X-linked adrenoleukodystrophy. This review describes these diseases in detail, highlighting the importance of early diagnosis and effective treatment aiming at preserving functionality and quality of life in these patients. For the purpose of this study, we carried a non-systematic review on PUBMED, finding an initial sample of 122 papers; upon refining, 41 articles were found relevant to this review. Subsequently, we added review articles and works with historical relevance, totalizing 76 references. An adequate diagnostic workup in patients presenting with spastic paraplegia phenotype should include screening for these rare conditions, followed by parsimonious ancillary investigation.

The Role of the Cerebellum in Huntington's Disease: a Systematic Review.

Huntington's disease (HD) is a rare neurological disorder characterized by progressive motor, cognitive, and psychiatric disturbances. Although striatum degeneration might justify most of the motor symptoms, there is an emerging evidence of involvement of extra-striatal structures, such as the cerebellum. To elucidate the cerebellar involvement and its afferences with motor, psychiatric, and cognitive symptoms in HD. A systematic search in the literature was performed in MEDLINE, LILACS, and Google Scholar databases. The research was broadened to include the screening of reference lists of review articles for additional studies. Studies available in the English language, dating from 1993 through May 2020, were included. Clinical presentation of patients with HD may not be considered as the result of an isolated primary striatal dysfunction. There is evidence that cerebellar involvement is an early event in HD and may occur independently of striatal degeneration. Also, the loss of the compensation role of the cerebellum in HD may be an explanation for the clinical onset of HD. Although more studies are needed to elucidate this association, the current literature supports that the cerebellum may integrate the natural history of neurodegeneration in HD.

Balance and physical functioning in Spinocerebellar ataxias 3 and 10.

OBJECTIVES: Limitations of functional capacity and balance are common features of the natural history of spinocerebellar ataxias (SCA). However, their onset and progression patterns differ according to subtype. The aim of our study was to compare physical functionality and balance parameters in SCA10 and SCA3 patients, correlating with clinical variables. MATERIALS & METHODS: Cross-sectional study evaluating ninety-five SCA patients (60 with SCA3 and 35 with SCA10) with validated scales for functional independence, balance and the severity of signs and symptoms. RESULTS: The groups were similar in terms of age and gender, and results were adjusted for age at symptom onset. The SCA10 patients had better results for balance and functional independence (p < 0.007). They also had lower scores for disease severity (p < 0.0002) and the subitems gait (p < 0.0005), posture (p < 0.0021) and sitting balance (p < 0.0008). Symptom progression in both groups was similar for patients with a disease duration of up to ten years, but there was a more marked decline in SCA3 patients after this period. CONCLUSIONS: We have shown that disease progression as assessed by balance and physical functioning is slower in SCA10 patients than SCA3 patients, particularly after 10 years of disease. These findings are important as they can help to characterize the disease, assisting in the development of new therapies and rehabilitation programs.

Freezing of gait (FOG) in Parkinson's disease patients-the contribution of Garcin and Melaragno.

Raymond Garcin, professor of neurology in Paris, France, and his Brazilian assistant, Professor Roberto Melaragno described in 1948 the phenomenon defined as "bégaiement de la mise en route du mouvement" in patients with Parkinson's disease. This was one of the first descriptions of freezing of gait (FOG) in the world.

Charcot: Buddhist Leanings?

Jean-Martin Charcot, considered the father of modern neurology, had a complex personality featuring well-defined characteristics of introversion, competitiveness, irony, and skepticism. While biographers have described him as Republican, anticlerical, and agnostic, the literature also presents evidence that he came to admire Buddhism toward the end of his life; Charcot's involvement with numerous patients suffering from incurable and insidious neurological diseases may have contributed to this change in attitude.

The Art of Charcot: An Outstanding Caricaturist.

Jean-Martin Charcot is considered the father of modern neurology; alongside his work as a physician, professor, and researcher in this area, he was also artistically gifted with a taste for caricature. This historical note summarizes 8 caricatures by Charcot that exhibit a mixture of humor, satire, irony, and sarcasm.

Volumetric MRI Changes in Spinocerebellar Ataxia (SCA3 and SCA10) Patients.

Spinocerebellar ataxias type 3 (SCA3) and type 10 (SCA10) are the most prevalent in southern Brazil. To analyze the relationships between volumetric MRI changes and clinical and genetic findings in SCA3 and SCA10 patients. All patients in the study had a confirmed genetic diagnosis. Demographic data, ataxia severity (SARA score), and the size of the expanded alleles were evaluated. Nineteen SCA3 and 18 SCA10 patients were selected and compared with a similar number of healthy controls. Patient and control groups underwent the same MRI protocol. The standard FreeSurfer pipeline was used for the morphometric data. Our results show more affected brain structures (volume reductions) in SCA3 patients than in SCA10 patients (15 vs. 5 structures). Volume reductions in brain structures were also greater in the former. The main areas with significant volumetric reductions in the former were the cerebellum, basal ganglia, brain stem, and diencephalon, whereas in the latter, significant volume reductions were observed in the cerebellum and pallidum. While SARA scores and disease duration were more correlated with volume reduction in SCA10, in SCA3, the expansion length (CAGn) correlated positively with cerebellar WM, thalamus, brain stem, and total GM volumes. There was no correlation between expansion length (ATTCTn) and neuroimaging findings in SCA10. Neuroimaging results differed significantly between SCA3 and SCA10 patients and were compatible with the differences in clinical presentation, disease progression, and molecular findings.

The Melted Statue of Charcot: The Nazi Occupation of Paris During World War II.

The authors describe the construction of a statue in honor of Professor Charcot, the father of modern neurology, in Paris in 1898, 5 years after his death. The Nazi invaders destroyed the statue, which was erected near the entrance to the Salpêtrière hospital with the support of his disciples and the international neurological community, in 1942 during World War II. An international campaign is now needed to rebuild the statue of this great neurologist.

Different Cerebellar Ataxia Phenotypes Associated with Mutations of the PNPLA6 Gene in Brazilian Patients with Recessive Ataxias.

Autosomal recessive cerebellar ataxias (ARCAs) represent a heterogeneous group of inherited disorders. The association of early-onset cerebellar ataxia with hypogonadotropic hypogonadism is related to two syndromes, known as Gordon Holmes syndrome (GHS-ataxia and pyramidal signs with hypogonadotropic hypogonadism) and Boucher-Neuhäuser syndrome (BNS-ataxia with chorioretinal dystrophy). Mutations in the PNPLA6 gene have been identified as the cause of hereditary spastic paraplegia and complex forms of ataxia associated with retinal and endocrine manifestations. We reported two Brazilian patients with sporadic, progressive cerebellar ataxia, associated with hypogonadotropic hypogonadism, in whom the GHS and BNS were confirmed by the demonstration of compound heterozygote mutations in the PNPLA6 gene. Genetic analysis of the patient 1 revealed compound heterozygous mutations, one allele in exon 34 and the other allele in exon 29. Genetic exam of the patient 2 also demonstrated compound heterozygous mutations. Three were novel mutations. The missense mutation c.3373G> A, found in the BNS patient, was previously related to Oliver-McFarlane syndrome. These different mutations in this gene suggest a complex phenotype associated disease spectrum.

Broken dynasty: how Jean Batiste Charcot relinquished his father's neurological empire to conquer the seven seas.

The authors review the relationship between Jean-Martin Charcot, the most celebrate Professor of Neurology of the XIX century, and his son, Jean-Baptiste Charcot, former a physician and neurologist and after Professor Charcot's death, a worldwide famous maritime explorer, the "Commander Charcot."

The prominent role of Charcot and the French neurological tradition in Latin America.

The establishment of neurology schools in Latin America during the late-nineteenth and early-twentieth centuries profoundly influenced the French neurology school. In the latter half of the nineteenth century, the neurology department at the Salpêtrière Hospital in Paris held a preeminent position as the global hub of neurology. Professor Jean-Martin Charcot, widely acclaimed as the father of modern neurology, was the most revered neurology professor of the nineteenth century. Many physicians from diverse countries across South America (notably Argentina, Uruguay, Peru, Brazil, and Colombia), the Caribbean (Cuba), and Mexico pursued specialized training in neurology under Charcot's tutelage, and even after his passing in 1893, they continued their training with his numerous disciples. As a result, nearly two centuries after the birth of Charcot, his enduring contributions to the field of neurology remain vibrantly influential, particularly in Latin America.

Ramsay Hunt syndrome: New impressions in the era of molecular genetics.

More frequent use of next-generation sequencing led to a paradigm shift in assessing heredodegenerative diseases. This is particularly notable in progressive myoclonus epilepsy (PME) and progressive myoclonus ataxia (PMA) where a group of disorders linked to novel genetic mutations has now been added to these phenotypical realms. Despite the historical value of Ramsay Hunt's contribution defining the syndrome later known as PMA, recent genetic developments have made this eponym obsolete and a new definition and classification of PMA and PME seem necessary. A rational possibility is to adopt the wider term progressive myoclonus ataxia and epilepsy syndrome (PMAES), which can be subdivided into its main subtypes, PME and PMA, whenever clinical data is sufficient to make that distinction.

Comparing loss of balance and functional capacity among patients with SCA2, SCA3 and SCA10.

BACKGROUND: Spinocerebellar ataxia (SCA) presents different rates of functional decline depending on the type of ataxia. OBJECTIVE: To compare the progression of disability, imbalance and severity of ataxia in patients with the three most common types of SCA in southern Brazil. METHODS: 126 patients (31-SCA2, 58-SCA3 and 37-SCA10) were stratified into four groups based on disease duration. Progression rates were calculated in each group for ataxia severity (SARA), functioning (FIM-ADL and Lawton-IADL), and balance (Berg Balance Scale). RESULTS: Differences across groups in terms of disease severity revealed a linear pattern of decline in SCA3, with a faster rate over time (p = 0.039) compared to SCA2 and SCA10. The pattern was nonlinear for SCA2 and SCA10, with a twofold faster rate in patients with up to seven years of disease compared to all other periods in SCA10 (p < 0.001) and to the longer follow up period in SCA2 (p = 0.049). Differences across groups regarding worsening of balance scores was significantly faster in SCA3 compared to SCA10 (p = 0.028) and SCA2 (p = 0.028). The rate of loss of independence of ADLs tended to diminish over time in the three types of ataxia and was faster in SCA3. Similarly, the rate for loss of independence (IADLs) was faster in SCA3 compared to SCA2 (p = 0.057) and significantly faster compared to SCA10 (p = 0.028). CONCLUSION: The present findings suggest that the progression of the disease (severity/functioning/balance) varies according to the SCA subtype and the period in disease course. Progression is more linear and aggressive in patients with SCA3.

Would Francisco Soca have been the first to relate toe phenomenon as pyramidal disorders?

INTRODUCTION: The Uruguayan physician Francisco Soca, who specialized in neurology in Jean-Martin Charcot's clinic, defended a thesis at the Paris Faculty of Medicine in 1888 on Friedreich's ataxia in eleven patients. In this work he described the presence of toe phenomenon. OBJECTIVE: This historical note presents a toe sign described by the Soca eight years before Babinski's classic description. DISCUSSION: In the late 1800s Soca completed a specialization in neurology at the service run by Charcot in Paris. He defended an important thesis in 1888 assessing data from 11 Friedreich's ataxia. In his thesis, Soca also described the toe phenomenon and the presence of structural changes in the feet of these patients that were not described in the Friedreich study published in 1863. CONCLUSION: The Soca's thesis contained the description of toe extension associated with pyramidal tract lesions, eight years later described and further immortalized as Babinski's sign. Therefore, Soca had already publicized this sign as being representative of a pyramidal dysfunction before Babinski or any other neurologist.

Follow-Up of Advanced Parkinson's Disease Patients after Clinical or Surgical Emergencies: A Practical Approach.

BACKGROUND: Patients with advanced stage Parkinson's disease (PD) typically present with a myriad of motor and nonmotor symptoms in addition to comorbidities and, as a consequence, polypharmacy. OBJECTIVE: To analyze a series of cases of advanced PD in which a clinical or surgical emergency played a trigger role in the irreversible progression of landmarks of the course of the disease. METHODS: Data were collected during a 13-month observational period of a cohort of 230 PD patients, in 751 medical appointments. We included a total of 13 (5.65% of the total number) patients with advanced PD defined by Hoehn & Yahr (H&Y) stage ≥3 who presented with various clinical and surgical complications which, with the contribution of drug interventions, led to significant worsening of patients' overall clinical condition. RESULTS: Hip fractures and infections were the most common complications identified. As part of this scenario, most patients presented with delirium, often requiring treatment with dopamine receptor blocking agents and/or had dopaminergic treatment withdrawn. Upon reassessment after 3 months, all patients remained bed or wheel chair bound (H&Y 5) and presented significant worsening of their UPDRS part III score of at least 10 points (mean 51.5 ± 3.3; paired t-test two-tailed p < 0.0001 compared to baseline). The mean dose of levodopa at baseline was 907.7 ± 149.8 mg (600-1200) and significantly higher (paired t-test two-tailed p < 0.0001) on follow-up, 1061.5 ± 175.8 mg (700-1300). CONCLUSION: Clinical and surgical emergencies are major determinants for a progression of PD to more advanced stages.