Overwhelming genetic heterogeneity and exhausting molecular diagnostic process in chronic and progressive ataxias: facing it up with an algorithm, a gene, a panel at a time.

Ataxias are one of the most frequent complaints in Neurogenetics units worldwide. Currently, more than 50 subtypes of spinocerebellar ataxias and more than 60 recessive ataxias are recognized. We conducted an 11-year prospective, observational, analytical study in order to estimate the frequency of pediatric and adult genetic ataxias in Argentina, to describe the phenotypes of this cohort and evaluate the diagnostic yield of the algorithm used in our unit. We included 334 ataxic patients. Our diagnostic approach was successful in one-third of the cohort. A final molecular diagnosis was reached in 113 subjects. This rate is significantly higher in the subgroup of patients with a positive family history, where the diagnostic yield increased to 55%. The most prevalent dominant and recessive ataxias in Argentina were SCA-2 (36% of dominant ataxias) and FA (62% of recessive ataxias), respectively. Next generation sequencing-based assays were diagnostic in the 65% of the patients requiring these tests. These results provide relevant epidemiological information, bringing a comprehensive knowledge of the most prevalent subtypes of genetic ataxias and their phenotypes in our territory and laying the groundwork for rationally implementing genetic diagnostic programs for these disorders in our country.

Assessing the non-motor symptoms of Parkinson's disease: MDS-UPDRS and NMS Scale.

BACKGROUND AND PURPOSE: Although Parkinson's disease (PD) is characterized by typical motor manifestations, non-motor symptoms (NMS) are an outstanding part of the disease. At present, several specific instruments for assessment of NMS are available. The objective of our study was to determine the performance of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS): Part I - Non-Motor Aspects of Experiences of Daily Living (nM-EDL) compared with the Non-Motor Symptoms Scale (NMSS). METHODS: To this purpose, 434 consecutive patients with PD were included in an international, observational, cross-sectional study. The association between scores of both scales was determined by the Spearman rank correlation coefficient. Equations for transformation of total score of a scale to the other were constructed from weighted regression models and both, transformed and observed score, contrasted by means of the Lin's Concordance Correlation Coefficient (LCCC) and Bland-Altman plot. RESULTS: As a whole, the prevalence of the NMS according to each scale was quite similar, and most of the correlations between their corresponding components were high (r(S) > 0.60). The total score correlation of the MDS-UPDRS Part I with the NMSS was high (r(S) = 0.81). Concerning the transformed scores, estimated scores only partially approach the observed ones (sharing about 60-64% of the variance) because residual variance increased with increasing magnitudes of the scores, i.e. the most severe patients (Bland-Altman plot; LCCC < 0.60 for severe patients). CONCLUSIONS: (i) MDS-UPDRS Part I (nM-EDL) and NMSS showed a strong convergent validity; (ii) however, transformed scores using the equations from weighted regression models showed that for patients with the most severe NMS they are not concordant.

Relationship between the MDS-UPDRS domains and the health-related quality of life of Parkinson's disease patients.

BACKGROUND AND PURPOSE: The Movement Disorder Society sponsored version of the Unified Parkinson's Disease Rating Scale (MDS-UPDRS) is a comprehensive instrument for assessing Parkinson's disease (PD). The present study was aimed at determining the relationships between MDS-UPDRS components and health-related quality of life (HRQoL) evaluations in PD patients. METHODS: An international, multicenter, cross-sectional study was carried out of 435 PD patients assessed with the MDS-UPDRS, Hoehn and Yahr (HY), Clinical Impression Severity for PD, EQ-5D and PD Questionnaire - eight items (PDQ-8). Spearman's rank correlation coefficients, exploratory factor analysis and multiple linear regression models (dependent variables EQ-5D and PDQ-8) were performed. RESULTS: The participants' age was 66.71 ± 10.32 years (51.5% men). PD duration was 8.52 ± 6.14, and median HY was 2 (range 1-5). The correlation between the EQ-5D index and the MDS-UPDRS ranged from -0.46 (Part IV) to -0.72 (Part II) and for the PDQ-8 index from 0.47 (Part III) to 0.74 (Part II). In multiple regression models with the MDS-UPDRS domains as independent variables, the main determinant for both the EQ-5D index and the PDQ-8 was Part II followed by Part I. After factorial grouping of the cardinal PD manifestations embedded in the MDS-UPDRS Parts III and IV for inclusion into multiple regression models, a factor formed by M-EDL, nM-EDL and fluctuations was the main determinant for both the EQ-5D and PDQ-8 indexes. CONCLUSIONS: The MDS-UPDRS component most tightly related with the HRQoL measures was a combination of motor and non-motor experiences of daily living.

Spontaneous and reflex movements in brain death.

Spontaneous and reflex movements may be found in patients with brain death (BD). The authors prospectively evaluated their frequency using a standardized protocol. Among 38 patients who fulfilled criteria for BD, the authors found 15 (39%) with spontaneous or reflex movements. The most common movement was finger jerks. Undulating toe flexion sign, triple flexion response, Lazarus sign, pronation-extension reflex, and facial myokymia also were seen. These movements may be more common than reported and do not preclude the diagnosis of BD.

The effect of levodopa on the habituation of the acoustic-palpebral reflex in Parkinson's disease.

The aim of the present study was to assess the habituation of the blink responses evoked by repetitive auditory stimuli in patients with Parkinson's disease in different clinical states. We studied 28 parkinsonian patients. Eighteen patients without motor fluctuations were studied off and on levodopa, on two different sessions, one week apart. The remaining 10 parkinsonians had the wearing off phenomenon and were studied while being off their medication and while ON and OFF, as determined clinically, after a single dose of levodopa. Twelve age-matched controls were also studied in a single session. Unilateral auditory 1 kHz, 105 dB stimuli were delivered at a frequency of 0.2 Hz. The number of responses (R) from the orbicularis oculi was registered. R values were significantly smaller in controls and in treated parkinsonians than in untreated patients. R was also significantly smaller when ON than at baseline and when OFF in parkinsonians with the wearing off phenomenon. These results suggest a failure of the inhibition of the acoustic-palpebral reflex in Parkinson's disease. The improvement with levodopa and the similarities between the clinical and the electrophysiological changes suggest a dopaminergic role in the inhibition of this brainstem reflex.

[Hemichorea associated with cerebral toxoplasmosis and AIDS]. / Hemicorea asociada a toxoplasmosis cerebral y SIDA.

Only 12 AIDS cases with hemichorea were reported in the literature. We report the first case of hemichorea associated with AIDS and cerebral toxoplasmosis in our country. A 26-year-old man had 3 episodes of focal seizures on the left side with subsequent loss of consciousness. A few weeks later, he noticed progressive left-sided weakness. Examination revealed a left hemiparesis. MRI of the head showed a round mass in the right frontal lobe and a smaller lesion in the left temporo-occipital area. Laboratory showed positive serum ELISA and Western Blot analysis for HIV antibodies. Serum tests for Toxoplasma showed elevated titers. He was treated with pyrimethamine and sulfadiazine. His weakness improved and he had no further seizures. Two weeks later, choreic movements appeared in the left foot, finally involving the entire left hemibody. A second MRI showed a new small lesion in the right cerebral peduncle. The patient completed 6 weeks of treatment, with further reduction in the size of the lesions. Nevertheless, the left hemichorea persisted. We believe that the hemichorea our patient had was caused by the contralateral peduncular lesion. Lesions involving the subthalamic nucleus or its connections may cause contralateral hemiballismus or hemichorea. In spite of the favorable response to antitoxoplasmic therapy, the hemichorea persisted. The present report illustrates an uncommon neurological complication in AIDS. We believe that a combination of a focal cerebral lesion and the HIV infection caused the movement disorder presented by the patient.

Hemicorea asociada a toxoplasmosis cerebral y SIDA / Hemichorea associated with cerebral toxoplasmosis and AIDS

Se observan complicaciones neurologicas en 40 por ciento de enfermos con SIDA. De estos, en 10 por ciento puede ser la manifestación inicial de la enfermedad. En otro 11 por ciento pueden aparecer trastornos del movimimiento. Comunicamos el primer caso de hemicorea asociada a toxoplasmose cerebral y SIDA en nuestro pais. Hombre de 26 anos, con diagnóstico de SIDA y toxoplasmosis cerebral. Habia comenzado con crisis motoras simples de hemicuerpo izquierdo, con generalización secundaria y luego perdida de fuerza progresiva en dicho hemicuerpo. La RMN de cerebro mostro una lesión frontal derecha y otra temporo-occiptal izquierda, con gran edema perilesional y efecto de masa. Las serologias para HIV y toxoplasmosis fueron positivas. Comenzo tratamiento con sulfadiazina y pirimetamina. Al duodecimo dia aparecieron movimientos involuntários del pie izquierdo, coreicos, que se extendieron mas tarde a todo ese miembro inferior y luego al hemicuerpo. Nueva RMN de cerebro mostro disminución del edema y efecto de masa de las lesiones. Sin embargo, se observó una nueva lesion a nivel peduncular derecho. Movimientos involuntarios en pacientes con toxoplasmosis cerebral la literatura mundial y el primero en nuestro pais de hemicorea asoicada a toxplasmosis y SIDA

[Cerebellar syndrome caused by amiodarone]. / Síndrome cerebeloso por amiodarona.

Amidarone (AMD) is an antiarrhythmic drug with side effects on the nervous system. Cerebellum is seldom involved: We describe the case of a 56 years old male patient with a history of 4 month of cerebellar involvement characterized by gait unsteadiness, ataxia, nistagmus and vertigo. He was on treatment with AMD because of ventricular arrythmia. The cerebellar syndrome progressively disappeared after drug withdrawal and he was symptoms-free 4 months later. Similar symptoms appeared after another one month of automedication with the same drug. Structural lesions, metabolic, nutritional deficiencies or toxics were excluded. Mechanisms of cerebellar toxicity of AMD are yet unknown. The knowledge of the toxic effects of this drug, widely used in our country, would allow its early recognition.

[Schwannomatosis: report of a new case]. / Schwannomatosis: presentacion de un nuevo caso.

Schwannomatosis is a rare disorder, still not quite well defined, seldom described in the literature. In this paper we report the case of male. Patient, 52 years old, who in the last 30 years developed five subcutaneous tumors within his limbs peripheral nerves, which histologically proved to be schwannomas. A brain computed tomography showed a partially calcified tumor in the left temporal lobe which most likely was a meningioma. A thorough clinical examination was unable to find signs of type I or type II neurofibromatosis. The present condition, probably a form of phacomatosis, has to be distinguished from neurofibromatosis and is considered as an independent clinical entity whose origin still awaits further detailed investigations.

Uniones específicas a estradiol y progesterona en meningiomas y neurinomas: correlación clínica y con el edema cerebral / Specific binding of estrogen and progesterone in meningiomas and neurinomas: relation to clinical features and brain edema

El predominio de meningiomas (M) en el sexo femenino, la exacerbación de los sintomas durante el embarazo y el mayor grado de crecimiento de los neurinomas (N) en la edad fértil en mujeres sugieren la posible hormonodependencia de estos tumores. Se estudiaron 16 M, pertenecientes a 7 hombres y 9 mujeres y 5 N de mujeres, obtenidos quirúrgicamente y conservados en nitrógeno líquido. Se determinó en ellos la densidad de receptores (R), de acuerdo a la unión específica a estradiol (E) y progesterona (P), con técnica de Carbón Dextrán. Se consideraron positivos valores mayores a 10 fentomoles de hormona unida por miligramo de proteína citosoluble. Se midió además el grado de edema cerebral de los M en la TAC y se lo expresó como el porcentaje de edema cerebral, en relación al parénquima cerebral no comprometido por edema. Once de 16 M tuvieron R positivos para E y 8 de 16 para P. Tres de 5 N tuvieron R positivos para E y 2 de 5 para P. Si bien un 66,6%de los tumores presentaron R a E y 47,6%R a P, no pudo encontrarse relación entre ellos y la edad , sexo, estado menopáusico de las pacientes ni tipo histológico de los tumores. Tampoco se encontró correlación estadísticamente significativa entre el porcentaje de edema y el nivel de R a E y P en los M evaluados. Nuestros resultados evidencian que un alto porcentaje de M y N presentan R positivos a E y P. Desconocemos el significado funcional de los mismos y la falta de correlación con el grado de edema peritumoral no permite relacionar su presencia con la generación del mismo

Isquemias de territorio carotídeo en trombosis séptica del seno cavernoso / Brain ischemic lesions within the carotid artery territory en cavernous sinus thrombosis

Se presentan dos pacientes con clínica de tromboflebitis del seno cavernoso, quienes desarrollaron complicaciones isquémicas del territorio carotídeo asociado. Uno de ellos presentó embolia de la arteria central de la retina y trombosis carotídea proximal. El segundo mostró un infarto silviano homolateral al proceso infeccioso. El mecanismo iniciador de este inusual tipo de complicación podría ser la arteritis y estenosis focal del segmento intravenoso de la carótida interna, a partir del cual se desencadenarían fenómenos embólicos (distales al estrechamiento) y/o trombóticos (proximales al mismo)

Uniones específicas a estradiol y progesterona en meningiomas y neurinomas: correlación clínica y con el edema cerebral / Specific binding of estrogen and progesterone in meningiomas and neurinomas: relation to clinical features and brain edema

El predominio de meningiomas (M) en el sexo femenino, la exacerbación de los sintomas durante el embarazo y el mayor grado de crecimiento de los neurinomas (N) en la edad fértil en mujeres sugieren la posible hormonodependencia de estos tumores. Se estudiaron 16 M, pertenecientes a 7 hombres y 9 mujeres y 5 N de mujeres, obtenidos quirúrgicamente y conservados en nitrógeno líquido. Se determinó en ellos la densidad de receptores (R), de acuerdo a la unión específica a estradiol (E) y progesterona (P), con técnica de Carbón Dextrán. Se consideraron positivos valores mayores a 10 fentomoles de hormona unida por miligramo de proteína citosoluble. Se midió además el grado de edema cerebral de los M en la TAC y se lo expresó como el porcentaje de edema cerebral, en relación al parénquima cerebral no comprometido por edema. Once de 16 M tuvieron R positivos para E y 8 de 16 para P. Tres de 5 N tuvieron R positivos para E y 2 de 5 para P. Si bien un 66,6%de los tumores presentaron R a E y 47,6%R a P, no pudo encontrarse relación entre ellos y la edad , sexo, estado menopáusico de las pacientes ni tipo histológico de los tumores. Tampoco se encontró correlación estadísticamente significativa entre el porcentaje de edema y el nivel de R a E y P en los M evaluados. Nuestros resultados evidencian que un alto porcentaje de M y N presentan R positivos a E y P. Desconocemos el significado funcional de los mismos y la falta de correlación con el grado de edema peritumoral no permite relacionar su presencia con la generación del mismo

Isquemias de territorio carotídeo en trombosis séptica del seno cavernoso / Brain ischemic lesions within the carotid artery territory en cavernous sinus thrombosis

Se presentan dos pacientes con clínica de tromboflebitis del seno cavernoso, quienes desarrollaron complicaciones isquémicas del territorio carotídeo asociado. Uno de ellos presentó embolia de la arteria central de la retina y trombosis carotídea proximal. El segundo mostró un infarto silviano homolateral al proceso infeccioso. El mecanismo iniciador de este inusual tipo de complicación podría ser la arteritis y estenosis focal del segmento intravenoso de la carótida interna, a partir del cual se desencadenarían fenómenos embólicos (distales al estrechamiento) y/o trombóticos (proximales al mismo)

Habituación del reflejo acústico-palpebral en la enfermedad de Parkinson / Habituation of the acoustic-blink reflex in Parkinsons disease

La oclusión palpebral ante un estímulo auditivo sorpresivo es una respuesta refleja [RAP] polisináptica de integración mesencefálica que tiende a desaparecer frente a estímulos repetidos. Este reflejo transcurre a través del núcleo coclear, cuerpo trapezoide, collículo inferior y sus conexiones, y está sujeto a influencias supramesencefálicas. En el estudio presente, se evaluaron electrofisiológicamente 6 individuos normales y 6 pacientes con enfermedad de Parkinson de edades similares. Se aplicaron estímulos tonales registrándose la actividad refleja en el orbicular de los párpados. Se midieron latencia [L], duración [D], amplitud [A] y fases [F] de las respuestas reflejas obtenidas por aplicación de estímulos auditivos a intervalos randomizados, y luego de un período de reposo, se midió el número de respuestas obtenidas [R] aplicando los estímulos a una frecuencia fija de 0,2 Hz. No se observaron diferencias significativas en L,D,A y F, viéndose en cambio, un mayor número de R en los enfermos de Parkinson. Esta observación sugiere una alteración en la habituación a los estímulos auditivos posiblemente debida a fallas en la inhibición de este reflejo por compromiso de estructuras supramesencefálicas

Habituación del reflejo acústico-palpebral en la enfermedad de Parkinson / Habituation of the acoustic-blink reflex in Parkinson's disease

La oclusión palpebral ante un estímulo auditivo sorpresivo es una respuesta refleja [RAP] polisináptica de integración mesencefálica que tiende a desaparecer frente a estímulos repetidos. Este reflejo transcurre a través del núcleo coclear, cuerpo trapezoide, collículo inferior y sus conexiones, y está sujeto a influencias supramesencefálicas. En el estudio presente, se evaluaron electrofisiológicamente 6 individuos normales y 6 pacientes con enfermedad de Parkinson de edades similares. Se aplicaron estímulos tonales registrándose la actividad refleja en el orbicular de los párpados. Se midieron latencia [L], duración [D], amplitud [A] y fases [F] de las respuestas reflejas obtenidas por aplicación de estímulos auditivos a intervalos randomizados, y luego de un período de reposo, se midió el número de respuestas obtenidas [R] aplicando los estímulos a una frecuencia fija de 0,2 Hz. No se observaron diferencias significativas en L,D,A y F, viéndose en cambio, un mayor número de R en los enfermos de Parkinson. Esta observación sugiere una alteración en la habituación a los estímulos auditivos posiblemente debida a fallas en la inhibición de este reflejo por compromiso de estructuras supramesencefálicas

Type 2 neurofibromatosis with Lisch nodules.

We describe a patient who, throughout a period of 6 years, had several cranial tumors in different locations. Bilateral acoustic neuromas, frontal meningiomas and a brain stem schwannoma were found on clinical and CT scan examinations and were histologically confirmed after surgery. These findings were associated with cutaneous neurofibromas and large café au lait spots suggesting the diagnosis of neurofibromatosis (NF) type 2. However, the presence of Lisch nodules, which characterizes NF-1, makes this patient rather unique. Clinical findings in the patient's relatives suggested the existence of NF-1 within the family. That is, the patient combines features of both types of NF.