Eplontersen for Hereditary Transthyretin Amyloidosis With Polyneuropathy.

Importance: Transthyretin gene silencing is an emerging treatment strategy for hereditary transthyretin (ATTRv) amyloidosis. Objective: To evaluate eplontersen, an investigational ligand-conjugated antisense oligonucleotide, in ATTRv polyneuropathy. Design, Setting, and Participants: NEURO-TTRansform was an open-label, single-group, phase 3 trial conducted at 40 sites across 15 countries (December 2019-April 2023) in 168 adults with Coutinho stage 1 or 2 ATTRv polyneuropathy, Neuropathy Impairment Score 10-130, and a documented TTR variant. Patients treated with placebo from NEURO-TTR (NCT01737398; March 2013-November 2017), an inotersen trial with similar eligibility criteria and end points, served as a historical placebo ("placebo") group. Interventions: Subcutaneous eplontersen (45 mg every 4 weeks; n = 144); a small reference group received subcutaneous inotersen (300 mg weekly; n = 24); subcutaneous placebo weekly (in NEURO-TTR; n = 60). Main Outcomes and Measures: Primary efficacy end points at week 65/66 were changes from baseline in serum transthyretin concentration, modified Neuropathy Impairment Score +7 (mNIS+7) composite score (scoring range, -22.3 to 346.3; higher scores indicate poorer function), and Norfolk Quality of Life Questionnaire-Diabetic Neuropathy (Norfolk QoL-DN) total score (scoring range, -4 to 136; higher scores indicate poorer quality of life). Analyses of efficacy end points were based on a mixed-effects model with repeated measures adjusted by propensity score weights. Results: Among 144 eplontersen-treated patients (mean age, 53.0 years; 69% male), 136 (94.4%) completed week-66 follow-up; among 60 placebo patients (mean age, 59.5 years; 68% male), 52 (86.7%) completed week-66 follow-up. At week 65, adjusted mean percentage reduction in serum transthyretin was -81.7% with eplontersen and -11.2% with placebo (difference, -70.4% [95% CI, -75.2% to -65.7%]; P < .001). Adjusted mean change from baseline to week 66 was lower (better) with eplontersen vs placebo for mNIS+7 composite score (0.3 vs 25.1; difference, -24.8 [95% CI, -31.0 to -18.6; P < .001) and for Norfolk QoL-DN (-5.5 vs 14.2; difference, -19.7 [95% CI, -25.6 to -13.8]; P < .001). Adverse events by week 66 that led to study drug discontinuation occurred in 6 patients (4%) in the eplontersen group vs 2 (3%) in the placebo group. Through week 66, there were 2 deaths in the eplontersen group consistent with known disease-related sequelae (cardiac arrhythmia; intracerebral hemorrhage); there were no deaths in the placebo group. Conclusions and Relevance: In patients with ATTRv polyneuropathy, the eplontersen treatment group demonstrated changes consistent with significantly lowered serum transthyretin concentration, less neuropathy impairment, and better quality of life compared with a historical placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT04136184; EU Clinical Trials Register: EudraCT 2019-001698-10.

[Argentinean Consensus on the Diagnosis and Treatment of Niemann- Pick Disease Type C]. / Consenso argentino sobre diagnóstico y tratamiento de la enfermedad de Niemann-Pick Tipo C.

Niemann-Pick type C (NPC) is a disorder of the lysosomal metabolism due to biallelic pathogenic variants in NPC1 or NPC2. Intracellular deposit of lipids, mainly unesterified cholesterol, gives rise to oxidative damage in several tissues, mainly neurons, spleen and liver. This, in turn, is associated with a myriad of neurological / psychiatric and visceral symptoms, with wide variability in age of presentation, from prenatal / neonatal to adult-onset forms of the disease. The last few years have seen considerable progress in understanding this disease and its management. In this consensus, current approaches to the diagnosis, follow-up and treatment of NPC (including the use of miglustat, the only specific drug approved at the time) are discussed by an Argentinian panel of experts.

La enfermedad de Niemann-Pick tipo C (NPC) es un trastorno del metabolismo lisosomal que se debe a la presencia de variantes patogénicas bialélicas en los genes NPC1 o NPC2. El depósito intracelular de lípidos, especialmente colesterol no esterificado, provoca daño oxidativo en diversos tejidos, especialmente neuronas, bazo e hígado. Esto, a su vez, induce la aparición de un conjunto de síntomas neurológicos / psiquiátricos y viscerales, con una amplia variabilidad de edad de aparición, desde formas prenatales / neonatales hasta otras de aparición en la vida adulta. En los últimos años ha habido avances considerables en la comprensión sobre esta enfermedad y su manejo. En el presente consenso un grupo de expertos argentinos abordan los enfoques actuales de diagnóstico, seguimiento y tratamiento de NPC, incluyendo el uso de miglustat como única terapia específica aprobada en la actualidad.

Consenso Argentino sobre Diagnóstico y Tratamiento de la Enfermedad de Niemann-Pick tipo C / Argentinean Consensus on the Diagnosis and Treatment of Niemann-Pick Disease type C

Resumen La enfermedad de Niemann-Pick tipo C (NPC) es un trastorno del metabolismo lisosomal que se debe a la presencia de variantes patogénicas bialélicas en los genes NPC1 o NPC2. El depósito intracelular de lípidos, especialmente colesterol no esterificado, provoca daño oxidativo en diversos tejidos, especialmente neuronas, bazo e hígado. Esto, a su vez, induce la aparición de un conjunto de síntomas neurológicos/psiquiátricos y viscerales, con una amplia variabilidad de edad de apa rición, desde formas prenatales/neonatales hasta otras de aparición en la vida adulta. En los últimos años ha habido avances considerables en la comprensión sobre esta enfermedad y su manejo. En el presente consenso un grupo de expertos argentinos abordan los enfoques actuales de diagnóstico, seguimiento y tratamiento de NPC, incluyendo el uso de miglustat como única terapia específica aprobada en la actualidad.

Abstract Niemann-Pick type C (NPC) is a disorder of the lyso somal metabolism due to biallelic pathogenic variants in NPC1 or NPC2. Intracellular deposit of lipids, mainly unesterified cholesterol, gives rise to oxidative damage in several tissues, mainly neurons, spleen and liver. This, in turn, is associated with a myriad of neurologi cal/psychiatric and visceral symptoms, with wide vari ability in age of presentation, from prenatal/neonatal to adult-onset forms of the disease. The last few years have seen considerable progress in understanding this disease and its management. In this consensus, current approaches to the diagnosis, follow-up and treatment of NPC (including the use of miglustat, the only specific drug approved at the time) are discussed by an Argentin ian panel of experts.

Guía de práctica clínica de tratamiento de la polineuropatía amiloidótica familiar / Practice guideline for the treatment of familial amyloid polyneuropathy

Resumen Esta guía de práctica clínica de tratamiento de la polineuropatía amiloidótica familiar se basa en la mejor evidencia disponible de efectividad clínica. Se generó un listado de preguntas con formato PICO centradas en efectividad y seguridad del tratamiento de polineuropatía amiloidótica familiar. Se realizó la búsqueda en PubMed, Cochrane y Epistemonikos. Los niveles de evidencia y los grados de recomendación se basaron en el sistema GRADE. Las recomendaciones se graduaron según dirección y fuerza y se evaluaron con la herramienta GLIA para su implementación. Resumen de recomendaciones: En pacientes con polineuropatía amiloidótica familiar y neuropatía estadio I y II, se sugiere el tratamiento con inotersen 300 mg subcutáneo semanal o patisirán 0.3 mg/kg endovenoso una vez cada 3 semanas, dado que, probablemente, estabilicen o enlentezcan el avance de la neuropatía y el empeoramiento de la calidad de vida (calidad de la evidencia moderada; fuerza de la recomendación débil). En pacientes con polineruropatía amiloidótica familiar y neuropatía estadio I, se sugiere el tratamiento con tafamidis 20 mg vía oral, una vez por día, ya que podría enlentecer el avance de la neuropatía y el empeoramiento en la calidad de vida (calidad de la evidencia baja; fuerza de la recomendación débil), y aquellos con polineuropatía amiloidótica familiar y neuropatía sintomática y en ausencia de otros tratamientos con eficacia aprobada, se sugiere el tratamiento con diflunisal 250 mg dos veces al día, vía oral, ya que podría evitar la progresión de la neuropatía (calidad de la evidencia baja; fuerza de la recomendación débil).

Abstract. This clinical practice guideline for the treatment of familial amyloid polyneuropathy is based on the best available evi dence of clinical effectiveness. A list of questions was generated with a PICO format focused on the effectiveness and safety of the treatment of familial amyloid polyneuropathy. The search was carried out in PubMed, Cochrane and Epistemonikos. The levels of evidence and grades of recommendation were based on the GRADE system. Recommendations were graded according to their direction and their strength and were evaluated with the GLIA tool for their implementation. In patients with familial amyloid polyneuropathy and stage I and II neuropathy, it is suggested: inotersen 300 mg subcutaneous weekly or patisirán 0.3 mg/kg intravenously once every 3 weeks, since they probably stabilize or slow the progression of neuropathy and worsening quality of life (moderate qual ity of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and stage I neuropathy, treatment with tafamidis 20 mg orally, once a day, is suggested, as it could slow the progression of neuropathy and worsen quality of life (low quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and symptomatic neuropathy and in the absence of other treatments with approved efficacy, treatment with oral diflunisal 250 mg twice daily is suggested, as it could prevent the progres sion of neuropathy (quality evidence low; strength of recommendation weak).

[Practice guideline for the treatment of familial amyloid polyneuropathy]. / Guía de práctica clínica de tratamiento de la polineuropatía amiloidótica familiar.

This clinical practice guideline for the treatment of familial amyloid polyneuropathy is based on the best available evidence of clinical effectiveness. A list of questions was generated with a PICO format focused on the effectiveness and safety of the treatment of familial amyloid polyneuropathy. The search was carried out in PubMed, Cochrane and Epistemonikos. The levels of evidence and grades of recommendation were based on the GRADE system. Recommendations were graded according to their direction and their strength and were evaluated with the GLIA tool for their implementation. In patients with familial amyloid polyneuropathy and stage I and II neuropathy, it is suggested: inotersen 300 mg subcutaneous weekly or patisirán 0.3 mg/kg intravenously once every 3 weeks, since they probably stabilize or slow the progression of neuropathy and worsening quality of life (moderate quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and stage I neuropathy, treatment with tafamidis 20 mg orally, once a day, is suggested, as it could slow the progression of neuropathy and worsen quality of life (low quality of evidence; strength of recommendation weak). In patients with familial amyloid polyneuropathy and symptomatic neuropathy and in the absence of other treatments with approved efficacy, treatment with oral diflunisal 250 mg twice daily is suggested, as it could prevent the progression of neuropathy (quality evidence low; strength of recommendation weak).

Esta guía de práctica clínica de tratamiento de la polineuropatía amiloidótica familiar se basa en la mejor evidencia disponible de efectividad clínica. Se generó un listado de preguntas con formato PICO centradas en efectividad y seguridad del tratamiento de polineuropatía amiloidótica familiar. Se realizó la búsqueda en PubMed, Cochrane y Epistemonikos. Los niveles de evidencia y los grados de recomendación se basaron en el sistema GRADE. Las recomendaciones se graduaron según dirección y fuerza y se evaluaron con la herramienta GLIA para su implementación. Resumen de recomendaciones: En pacientes con polineuropatía amiloidótica familiar y neuropatía estadio I y II, se sugiere el tratamiento con inotersen 300 mg subcutáneo semanal o patisirán 0.3 mg/kg endovenoso una vez cada 3 semanas, dado que, probablemente, estabilicen o enlentezcan el avance de la neuropatía y el empeoramiento de la calidad de vida (calidad de la evidencia moderada; fuerza de la recomendación débil). En pacientes con polineruropatía amiloidótica familiar y neuropatía estadio I, se sugiere el tratamiento con tafamidis 20 mg vía oral, una vez por día, ya que podría enlentecer el avance de la neuropatía y el empeoramiento en la calidad de vida (calidad de la evidencia baja; fuerza de la recomendación débil), y aquellos con polineuropatía amiloidótica familiar y neuropatía sintomática y en ausencia de otros tratamientos con eficacia aprobada, se sugiere el tratamiento con diflunisal 250 mg dos veces al día, vía oral, ya que podría evitar la progresión de la neuropatía (calidad de la evidencia baja; fuerza de la recomendación débil).

Valor pronóstico del ecocardiograma con strain bidimensional por Speckle Tracking en pacientes con amiloidosis asociada a transtiretina / Prognosis value of the echocardiogram with bidimensional strain by speckle tracking in patients with amyloidosis associated with transthyretin

[RESUMEN]: La amiloidosis cardíaca asociada a transtiretina (ATTR) es una cardiomiopatía infiltrativa caracterizada por el depósito de fibrillas en el miocardio, asociada a un mal pronóstico, incluye dos subtipos: hereditaria (ATTRh) y natural. La mutación Val30Met es la más frecuente a nivel mundial. El diagnóstico es desafiante, se basa en un alto grado de sospecha clínica, una combinación de técnicas de imagen y en algunos casos una biopsia endomiocárdica. Las nuevas técnicas ecocardiográficas han aportado avances en el diagnóstico gracias a su mejor sensibilidad en comparación con parámetros clásicos. OBJETIVO: Evaluar si el deterioro del strain (deformación) longitudinal global (SLG) del ventrículo izquierdo (VI) evaluada por ecocardiografía en pacientes con ATTRh Val30Met, se asocia a eventos cardiovasculares adversos. METODOLOGÍA: Estudio prospectivo de Cohorte. Se evaluaron en total 53 pacientes con amiloidosis tratados en el Hospital "El Cruce" de Florencio Varela desde junio de 2014 y se incluyeron 26 pacientes con la mutación Val30Met, entre marzo y noviembre del 2019 que cumplían con los criterios de inclusión. RESULTADOS: Se observaron eventos (requerimiento de marcapaso, desarrollo de insuficiencia cardíaca y muerte) en el 53.8 % de los pacientes, de los cuales 71,4 % eran hombres (OR: 0,30 (IC95: 0,05-1,54), p=0.13). De los 5 pacientes con amiloidosis de inicio tardío (>60 años) el 100 % presentó eventos (p 0,03). En el análisis univariado, las variables que mostraron asociación con eventos fueron: edad de inicio de los síntomas (p= <0.001), edad de diagnóstico (p=0.004), inicio temprano (p= 0.02), bajo peso (p= 0.004), disnea (p= <0.001), presencia de HVI (p=0.005), disfunción diastólica (p=0.007), dilatación de la AI (p=0.003) y el SLG promedio (p= 0.003). CONCLUSIONES: La FEY (fracción de eyección) del VI se mantiene normal hasta etapas avanzadas, por lo que se considera inadecuada para la correcta valoración de estos pacientes siendo necesarios métodos alternativos que aumenten la sensibilidad en el período preclínico. El punto de corte de SLG-14.4 ± 4.5% discriminó la evolución a eventos cardiovasculares adversos.

[ABSTRACT]: Transthyretin-associated cardiac amyloidosis (ATTR) is an infi ltrative cardiomyopathy characterized by the deposition of fi brils in the myocardium, associated with a poor prognosis, it includes two subtypes: hereditary (hATTR) and natural. The Val30Met mutation is the most frequent worldwide. The diagnosis is challenging, based on a high degree of clinical suspicion, a combination of imaging techniques, and in some cases an endomyocardial biopsy. The new echocardiographic techniques have brought advances in diagnosis thanks to their better sensitivity compared to classical parameters. OBJECTIVE: To assess whether the deterioration of the global longitudinal strain (deformation) of the left ventricle (LV) evaluated by echocardiography in patients with hATTR Val30Met is associated with adverse cardiovascular events. METHODS: Prospective cohort study. A total of 53 patients with amyloidosis treated at the Hospital "El Cruce" in Florencio Varela since June 2014 were evaluated, 26 patients with the Val30Met mutation were included, between March and November 2019, who met the inclusion criteria. RESULTS: Of the 5 patients with late-onset amyloidosis (> 60 years), 100% had events (p 0.03). Events (requirement for a pacemaker, development of heart failure and death) were observed in 53.8% of the patients, of which 71.4% were men (OR: 0.30 (CI95: 0.05-1.54), p = 0.13). In the univariate analysis, the variables that showed an association with events were: age of onset of symptoms (p = <0.001), age of diagnosis (p = 0.004), early onset (p = 0.02), underweight (p = 0.004), dyspnea (p = <0.001), presence of LVH (p = 0.005), diastolic dysfunction (p = 0.007), LA dilation (p = 0.003) and mean GLS (p = 0.003). CONCLUSIONS: The LV EF (ejection fraction) remains normal until advanced stages, which is why it is considered inadequate for the correct evaluation of these patients, and alternative methods are necessary to increase sensitivity in the preclinical period. The cut-off point of GLS-14.4 ± 4.5% discriminated the evolution to adverse cardiovascular events.

Resistencia a la heparina en pacientes con síndrome respiratorio agudo grave coronavirus tipo 2: a propósito de un caso / Heparin resistance in patients with severe acute respiratory syndrome coronavirus type 2: a case report

[RESUMEN]: Los pacientes con Covid 19 causado por el virus del síndrome respiratorio agudo severo coronavirus 2 (SARS-CoV-2) desarrollan coagulopatía sobre todo en los casos graves, lo que conlleva un alto riesgo de presentar eventos trombóticos. En estos pacientes, el uso de terapia anticoagulante con heparina no fraccionada (HNF) resulta en ocasiones de difícil manejo. Como sabemos, su utilización debe controlarse mediante el tiempo de tromboplastina parcial activada (APTT), con un valor referencial de 1.5 a 2.5 del valor basal. Debido a la respuesta inflamatoria severa provocada por SARS-CoV-2 hay un aumento en la síntesis de fibrinógeno y/o Factor VIII (FVIII), que puede producir la ausencia de prolongación del APTT a pesar de dosis altas de HNF, fenómeno conocido como resistencia bioquímica a la heparina. Además, en pacientes con Covid 19 se ha descrito disminución de los valores de antitrombina (AT), aunque dentro del rango hemostático, respecto a un grupo control. Se describirá el caso de un paciente internado en nuestra institución, con diagnóstico de Covid 19 grave y resistencia bioquímica a la heparina, lo que resultó en un difícil manejo de la anticoagulación.

[ABSTRACT]: Patients with Covid 19, caused by the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) can develop a coagulopathic state, mostly in severe cases, with a high risk of thrombotic complications. In these patients, the use of anticoagulant therapy with unfractioned heparin (UFH) can be challenging. UFH must be controlled by the activated partial thromboplastin time (aPTT), with a referetial value of 1.5 ­ 2.0 times the baseline value. SARS-CoV-2 produces a severe infl ammatory response which causes an elevation in fi brinogen and Factor VIII (FVIII) liver synthesis. This can interfere with the aPTT, not being able to raise it to therapeutically desired ranges in spite of high doses of UFH, a phenomenon known as heparin laboratory resistance. In Covid 19 patients, a lower level of antithrombin (AT) synthesis with respect to a control group has also been described, although witihn the hemostatic range. We will describe a case report from our hospital, with a diagnosis of severe Covid 19 and heparin laboratory resistance, which led to diffi culties in the anticoagulation therapy management.

Weight Loss in Parkinson's Disease: The Relationship with Motor Symptoms and Disease Progression.

OBJECTIVES: To determine the prevalence of weight loss (WL) in PD patients, its relationship to the severity of motor manifestations and appetite changes. METHODS: 144 PD patients and 120 controls were evaluated in a single session. All subjects were asked about changes in body weight and appetite. PD patients were examined with the UPDRS-III and the Hoehn and Yahr (HY) scales. Subscores of tremor, bradykinesia /rigidity, and non-dopaminergic symptoms (NDS) were analyzed individually. Multivariable logistic regression analysis was used to determine an association between WL and PD motor manifestations. RESULTS: 48.6 % of PD patients presented WL compared to 20.8 % of controls (p < 0.001). Weight losers were significantly older and had longer disease duration, higher scores in HY stages, UPDRS-III, and NDS-subscore. Multivariable logistic regression analysis demonstrated that WL was associated with NDS-subscore (p= 0.002; OR: 1.33) and older age (p= 0.037; OR: 1.05). Appetite in PD cases losing weight was unchanged (35.7 %), decreased (31.4 %), or even increased (32.9). CONCLUSIONS: Our results showed that WL occurs in almost half of PD patients and it is largely the consequence of disease progression rather than involuntary movements or a decrease in food intake.

Erdheim-Chester disease: atypical presentation of a rare disease.

We report the clinical case of an adult patient referred to our hospital because of trismus due to a tumour in the right infratemporal and pterygomaxillary fossa. He referred hyporexia, weight loss and right trigeminal neuralgia. On physical examination, he had trismus and diplopia. On neuroimaging, the tumour invaded the central nervous system affecting the right temporal lobe and orbit, and the sellar region. Tumour biopsy revealed foamy histiocytes and isolated giant multinuclear cells immunoreactive to CD68 and negative to CD1a and S100. A diagnosis of Erdheim-Chester disease was made. Non-evidence of large bone involvement was found in neither plain radiographs nor Technetium 99 m bone scintigraphy. BRAFV600E mutation analysis was negative. Because of raised intracranial pressure, a debulking surgery of the intracranial histiocytic process was performed. The patient improved his symptoms and remains clinically stable after 12 months of treatment with pegylated interferon-α-2a 180 µg/weekly.

Holmes tremor: Clinical description, lesion localization, and treatment in a series of 29 cases.

OBJECTIVE: To describe the clinical features, etiology, findings from neuroimaging, and treatment results in a series of 29 patients with Holmes tremor (HT). METHODS: A retrospective study was performed based on review of medical records and videos of patients with HT diagnosis. RESULTS: A total of 16 women and 13 men were included. The mean age at the moment of CNS insult was 33.9 ± 20.1 years (range 8-76 years). The most common causes were vascular (48.3%), ischemic, or hemorrhagic. Traumatic brain injury only represented 17.24%; other causes represented 34.5%. The median latency from lesion to tremor onset was 2 months (range 7 days-228 months). The most common symptoms/signs associated with HT were hemiparesis (62%), ataxia (51.7%), hypoesthesia (27.58%), dystonia (24.1%), cranial nerve involvement (24.1%), and dysarthria (24.1%). Other symptoms/signs were vertical gaze disorders (6.8%), bradykinesia/rigidity (6.8%), myoclonus (3.4%), and seizures (3.4%). Most of the patients had lesions involving more than one area. MRI showed lesions in thalamus or midbrain or cerebellum in 82.7% of the patients. Levodopa treatment was effective in 13 out of 24 treated patients (54.16%) and in 3 patients unilateral thalamotomy provided excellent results. CONCLUSIONS: The most common causes of HT in our series were vascular lesions. The most common lesion topography was mesencephalic, thalamic, or both. Treatment with levodopa and thalamic stereotactic lesional surgery seems to be effective.

[Sensory neuronopathy. Its recognition and early treatment]. / Neuronopatía sensitiva. Su reconocimiento y tratamiento temprano.

Sensory neuronopathies or ganglionopathies, or dorsal root ganglion disorders, represent a subgroup of peripheral nervous system diseases, frequently associated with dysinmune or neoplastic disorders and with toxic agents. A degeneration of both central and peripheral sensory proyections is present. Patients typically show early ataxia, loss of deep tendon reflexes and positive sensory symptoms present both in proximal and distal sites of the body. We retrospectively studied 10 cases with a final diagnosis of sensory neuronopathy. Sensory neuropathy was the presenting symptom and the course was subacute in all cases. Paresthesias in upper limbs were a predominant manifestation (100%). Other manifestations included: hypoesthesia (10/10), gait ataxia (8/10), autonomic symptoms (3/10) and perioral paresthesias (3/10). Electrophysiology showed sensory axonal neuronal pattern, with normal motor responses. Final diagnosis was acquired sensory neuronopathy in all patients, associated with Sjögren's syndrome in 2, with lupus erythematosus in 1, with rheumatoid arthritis in 1, with a cancer in 2 (paraneoplastic) and idiopathic in 4. In paraneoplastic cases, the tumor was small cell lung cancer in 1 (with positive anti-Hu antibodies), and epidermoid lung cancer in the other. Eight patients were treated with immunotherapy, high dose intravenous methylprednisolone and/or intravenous immunoglobulin; with poor response in 4 cases, neurologic improvement in 5, and without any change in 1 patient. The present work shows the typical clinical and electrophysiological pattern of subacute sensory neuronopathy, and the relevance of early treatment.

Neuronopatía sensitiva: Su reconocimiento y tratamiento temprano / Sensory neuronopathy. Its recognition and early treatment

Las neuronopatías o ganglionopatías sensitivas, o enfermedades del ganglio dorsal, representan un subgrupo de enfermedades del sistema nervioso periférico, frecuentemente asociadas a trastornos disinmunes o paraneoplásicos, y a agentes tóxicos. Los pacientes típicamente presentan ataxia temprana, pérdida de los reflejos osteotendinosos y síntomas sensitivos positivos, presentes tanto en partes proximales como distales del cuerpo. Estudiamos retrospectivamente 10 casos con un diagnóstico final de neuronopatía sensitiva. El síntoma de presentación fue el de una neuropatía sensitiva de curso subagudo en todos los casos, con parestesias en el 100% de los casos. Otras manifestaciones fueron: hipoestesia (10/10), ataxia de la marcha (8/10), síntomas autonómicos (3/10) y parestesias periorales (3/10). La electrofisiología mostró un patrón de compromiso sensitivo axonal, con respuestas motoras normales. El diagnóstico final fue neuronopatía sensitiva adquirida en todos, asociada a síndrome de Sjögren en dos, a lupus eritematoso en uno, a artritis reumatoidea en uno, a cáncer en dos (paraneoplásica) e idiopática en cuatro. En los casos paraneoplásicos, los tumores fueron un carcinoma de pulmón de células pequeñas (con anticuerpos anti-Hu positivos) y un carcinoma epidermoide de pulmón. Ocho pacientes fueron tratados con inmunoterapia, con altas dosis de metilprednisolona endovenosa y/o con inmunoglobulina endovenosa; con pobre respuesta en cuatro casos, mejoría neurológica en cinco, y sin cambios en uno. El presente trabajo muestra el patrón clinico y electrofisiológico de las neuronopatías sensitivas subagudas, y la relevancia de un tratamiento temprano.

Sensory neuronopathies or ganglionopathies, or dorsal root ganglion disorders, represent a subgroup of peripheral nervous system diseases, frequently associated with dysinmune or neoplastic disorders and with toxic agents. A degeneration of both central and peripheral sensory proyections is present. Patients typically show early ataxia, loss of deep tendon reflexes and positive sensory symptoms present both in proximal and distal sites of the body. We retrospectively studied 10 cases with a final diagnosis of sensory neuronopathy. Sensory neuropathy was the presenting symptom and the course was subacute in all cases. Paresthesias in upper limbs were a predominant manifestation (100%). Other manifestations included: hypoesthesia (10/10), gait ataxia (8/10), autonomic symptoms (3/10) and perioral paresthesias (3/10). Electrophysiology showed sensory axonal neuronal pattern, with normal motor responses. Final diagnosis was acquired sensory neuronopathy in all patients, associated with Sjögren’s syndrome in 2, with lupus erythematosus in 1, with rheumatoid arthritis in 1, with a cancer in 2 (paraneoplastic) and idiopathic in 4. In paraneoplastic cases, the tumor was small cell lung cancer in 1 (with positive anti-Hu antibodies), and epidermoid lung cancer in the other. Eight patients were treated with immunotherapy, high dose intravenous methylprednisolone and/or intravenous immunoglobulin; with poor response in 4 cases, neurologic improvement in 5, and without any change in 1 patient. The present work shows the typical clinical and electrophysiological pattern of subacute sensory neuronopathy, and the relevance of early treatment.

Gastrointestinal manifestations in Parkinson's disease: prevalence and occurrence before motor symptoms.

To assess the prevalence of gastrointestinal symptoms (GIS) in Parkinson's disease (PD) compared to control subjects and their timing of appearance in relationship to the onset of motor symptoms. There is a rostrocaudal gradient of alpha-synuclein (α-SYN) neuropathology in the enteric nervous system at early stages of PD with higher burden in the upper than the lower gut. However, only constipation has been recognized as a premotor gastrointestinal manifestation of PD. 129 PD patients and 120 controls underwent a structured questionnaire to assess the presence of GIS and, in PD patients, the time of their appearance respect to the onset of motor manifestations. GIS significantly more prevalent in PD patients were dry mouth, drooling, dysphagia, constipation and defecatory dysfunction. Constipation and defecatory dysfunction preceded motor manifestations. Whereas gastroparesis symptoms preceded motor manifestations, their prevalence was not significantly different from controls. Despite evidence of a higher α-SYN burden in the upper gut, only constipation and defecatory dysfunction were prominent premotor GIS of PD.

Dry mouth: an overlooked autonomic symptom of Parkinson's disease.

There is involvement of salivary glands by α-synuclein pathology in PD. However, the prevalence of dry mouth has not been systematically assessed in these patients. We studied 97 PD patients and 86 controls using a structured questionnaire. Dry mouth was reported by 60.8% of PD patients and 27.9% of controls (p < 0.0001). Dry mouth and drooling coexisted in 30% of cases. Only 12% of patients had reported dry mouth to their physicians. Dry mouth is a frequent but underreported symptom and may be an early manifestation of autonomic involvement in PD.