Hospitalization budget impact during the COVID-19 pandemic in Spain.

OBJECTIVES: The aim was to determine the direct impact of the COVID-19 pandemic on Spain's health budget. METHODS: Budget impact analyses based on retrospective data from patients with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) admitted to a Spanish hospital between February 26 and May 21, 2020. Direct medical costs from the perspective of the hospital were calculated. We analyzed diagnostic tests, drugs, medical and nursing care, and isolation ward and ICU stays for three cohorts: patients seen in the emergency room only, hospitalized patients who tested positive for SARS-CoV-2, and patients who tested negative. RESULTS: The impact on the hospital's budget for the 3 months was calculated at €15,633,180, 97.4% of which was related to health care and hospitalization. ICU stays accounted for 5.3% of the total costs. The mean cost per patient was €10,744. The main costs were staffing costs (10,131 to 11,357 €/patient for physicians and 10,274 to 11,215 €/patient for nurses). Scenario analysis showed that the range of hospital expenditure was between €14,693,256 and €16,524,924. The median impact of the pandemic on the Spanish health budget in the sensitivity analysis using bootstrapped individual data was €9357 million (interquartile range [IQR], 9071 to 9689) for the conservative scenario (113,588 hospital admissions and 11,664 ICU admissions) and €10,385 million (IQR, 110,030 to 10,758) for the worst-case scenario (including suspected cases). CONCLUSION: The impact of COVID-19 on the Spanish public health budget (12.3% of total public health expenditure) is greater than multiple sclerosis, cancer and diabetes cost.

Brain Organoids: Expanding Our Understanding of Human Development and Disease.

Stem cell-derived brain organoids replicate important stages of the prenatal human brain development and combined with the induced pluripotent stem cell (iPSC) technology offer an unprecedented model for investigating human neurological diseases including autism and microcephaly. We describe the history and birth of organoids and their application, focusing on cerebral organoids derived from embryonic stem cells and iPSCs. We discuss new insights into organoid-based model of schizophrenia and shed light on challenges and future applications of organoid-based disease model system. This review also suggests hitherto unrevealed potential applications of organoids in combining with new technologies such as nanophotonics/optogenomics for controlling brain development and atomic force microscopy for studying mechanical forces that shape the developing brain.

Toxic dermatitis secondary to treatment with collagenase clostridium histolyticum for Dupuytren´s disease.

OBJECTIVE: Secondary effects and drug reactions relative to collagenase Clostridium histolyticum treatment for Dupuytren's contracture are frequent. In only a few cases these secondary effects are considered serious. The mechanism that produces these effects of production is not well understood. CLINICAL REPORT: We present the case report of a woman with fifth finger interphalangeal joint treatment with generalized skin rash as a complication of collagenase Clostridium histolyticum treatment. DISCUSSION: We discuss treatment, causes and mechanisms of this rare complication from this treatment and review the bibliography about mechanisms for the different types of immunological reactions that may occur after treatment with collagenase Clostridium histolyticum and the possibility of crossed reactions with Clostridiopeptidase A used to treat skin lacerations.

La heterogeneidad del flujo sanguíneo en resonancia magnética, biomarcador para clasificar por grados los astrocitomas cerebrales / The heterogeneity of blood flow on magnetic resonance imaging: a biomarker for grading cerebral astrocytomas

Objetivos: Estudiar si los histogramas de los parámetros cuantitativos de perfusión por RM obtenidos a partir de los volúmenes tumoral y peritumoral permiten clasificar in vivo el grado de los astrocitomas. Material y métodos: Se incluyen 61 pacientes diagnosticados histológicamente de astrocitoma grado II, III o IV, estudiados mediante RM de perfusión T2* con contraste intravenoso, seleccionando manualmente los volúmenes tumoral y peritumoral, cuantificándose vóxel a vóxel diferentes parámetros de perfusión: volumen sanguíneo (VS), flujo sanguíneo (FS), tiempo de tránsito medio (TTM), constante de transferencia (Ktrans), coeficiente de lavado, volumen intersticial y volumen vascular. Para cada volumen se obtuvo el histograma correspondiente con su media, desviación típica y curtosis, estas últimas como medidas de heterogeneidad, comparándose las diferencias por parámetro y grado tumoral. También se calcularon la media y desviación del 10% de los valores máximos. Finalmente se realizó un análisis discriminante multiparamétrico para mejorar la clasificación. Resultados: En el volumen tumoral se obtuvieron diferencias estadísticamente significativas entre los 3 grados tumorales para la media y la desviación de VS, FS y Ktrans, tanto para la distribución completa, como para el 10% máximo. En la región peritumoral no se obtuvieron diferencias significativas para ningún parámetro. El análisis discriminante mejoró ligeramente la clasificación. Conclusiones: La cuantificación de parámetros del volumen total de la región tumoral con VS, FS y Ktrans es útil para establecer el grado de los astrocitomas. La heterogeneidad, representada por la desviación típica del FS, es el parámetro con mayor fiabilidad diagnóstica para separar los tumores de bajo y alto grado (AU)

Objectives: To study whether the histograms of quantitative parameters of perfusion in MRI obtained from tumor volume and peritumor volume make it possible to grade astrocytomas in vivo. Material and methods: We included 61 patients with histological diagnoses of grade II, III, or IV astrocytomas who underwent T2*-weighted perfusion MRI after intravenous contrast agent injection. We manually selected the tumor volume and peritumor volume and quantified the following perfusion parameters on a voxel-by-voxel basis: blood volume (BV), blood flow (BF), mean transit time (TTM), transfer constant (Ktrans), washout coefficient, interstitial volume, and vascular volume. For each volume, we obtained the corresponding histogram with its mean, standard deviation, and kurtosis (using the standard deviation and kurtosis as measures of heterogeneity) and we compared the differences in each parameter between different grades of tumor. We also calculated the mean and standard deviation of the highest 10% of values. Finally, we performed a multiparametric discriminant analysis to improve the classification. Results: For tumor volume, we found statistically significant differences among the three grades of tumor for the means and standard deviations of BV, BF, and Ktrans, both for the entire distribution and for the highest 10% of values. For the peritumor volume, we found no significant differences for any parameters. The discriminant analysis improved the classification slightly. Conclusions: The quantification of the volume parameters of the entire region of the tumor with BV, BF, and Ktrans is useful for grading astrocytomas. The heterogeneity represented by the standard deviation of BF is the most reliable diagnostic parameter for distinguishing between low grade and high grade lesions (AU)

[The heterogeneity of blood flow on magnetic resonance imaging: a biomarker for grading cerebral astrocytomas]. / La heterogeneidad del flujo sanguíneo en resonancia magnética, biomarcador para clasificar por grados los astrocitomas cerebrales.

OBJECTIVES: To study whether the histograms of quantitative parameters of perfusion in MRI obtained from tumor volume and peritumor volume make it possible to grade astrocytomas in vivo. MATERIAL AND METHODS: We included 61 patients with histological diagnoses of grade II, III, or IV astrocytomas who underwent T2*-weighted perfusion MRI after intravenous contrast agent injection. We manually selected the tumor volume and peritumor volume and quantified the following perfusion parameters on a voxel-by-voxel basis: blood volume (BV), blood flow (BF), mean transit time (TTM), transfer constant (K(trans)), washout coefficient, interstitial volume, and vascular volume. For each volume, we obtained the corresponding histogram with its mean, standard deviation, and kurtosis (using the standard deviation and kurtosis as measures of heterogeneity) and we compared the differences in each parameter between different grades of tumor. We also calculated the mean and standard deviation of the highest 10% of values. Finally, we performed a multiparametric discriminant analysis to improve the classification. RESULTS: For tumor volume, we found statistically significant differences among the three grades of tumor for the means and standard deviations of BV, BF, and K(trans), both for the entire distribution and for the highest 10% of values. For the peritumor volume, we found no significant differences for any parameters. The discriminant analysis improved the classification slightly. CONCLUSIONS: The quantification of the volume parameters of the entire region of the tumor with BV, BF, and K(trans) is useful for grading astrocytomas. The heterogeneity represented by the standard deviation of BF is the most reliable diagnostic parameter for distinguishing between low grade and high grade lesions.

[Pharmacoeconomic aspects of oral cytostatic agents]. / Aspectos farmacoeconómicos de los citostáticos orales.

When validating oral chemotherapy, pharmacists should confirm the suitability and correctness of the prescription, applying the same safety standards as those used for parenteral cytostatic drugs. There are an increasing number of cancers for which orally administered drugs are available, which increases patient satisfaction as these drugs can be taken at home without the need to visit a hospital. As oral cytostatic treatments increase, so does the importance of ensuring optimal treatment compliance. The new oral cytostatic agents are less toxic, reduce indirect costs and imply less loss of time for patients and their families. However, the cost of these agents should be below a threshold acceptable for society. As an aid to decision making, pharmacoeconomic tools should be used.

Análisis nosológico con parámetros de perfusión tisular de RM obtenidos mediante los modelos monocompartimental y farmacocinético en los glioblastomas cerebrales / Nosological analysis of MRI tissue perfusion parameters obtained using the unicompartmental and pharmacokinetic models in cerebral glioblastomas

Objetivos. Clasificar las áreas tumorales en pacientes con astrocitoma de grado IV mediante el cálculo y análisis estadístico de parámetros cuantitativos de perfusión por RM. Material y métodos. Se aplicaron 2 modelos de perfusión por RM, monocompartimental y farmacocinético, en 15 pacientes diagnosticados de astrocitoma grado IV. Con el modelo monocompartimental se cuantificó el volumen sanguíneo cerebral (VSC), el tiempo de tránsito medio (TTM) y el flujo sanguíneo cerebral (FSC). Con el farmacocinético se midió la constante de permeabilidad (Ktrans), el coeficiente de extracción (kep), la fracción de volumen del espacio intersticial (ve), la fracción de volumen vascular (vp), la permeabilidad en primer paso (Kfp) y el volumen vascular en primer paso (vpfp). Para cada parámetro se obtuvieron los histogramas del área tumoral total, peritumoral y sana. El análisis estadístico incluyó un análisis de varianza para cada parámetro y un análisis discriminante. Resultados. Las diferencias más significativas entre las regiones se obtuvieron con el VSC, FSC, Ktrans y vpfp, siendo VSC el que mostró mejores resultados. La mejor función clasificatoria mediante análisis discriminante se obtuvo para una combinación de Ktrans y VSC. El análisis de la forma del histograma evidenció diferencias estadísticamente significativas para la curtosis de Ktrans y kep, así como para la asimetría de VSC, FSC, Ktrans y vpfp. Conclusión. El VSC es el parámetro que aisladamente permitió diferenciar mejor entre área tumoral, peritumoral y sana. La función clasificatoria generada a partir de VSC y Ktrans consiguió mejorar estos resultados haciendo más eficaz la clasificación por áreas (AU)

Objectives. To classify the tumor areas in patients with grade IV astrocytoma by calculating and statistically analyzing quantitative MRI perfusion parameters. Material and methods. We applied two models of MRI perfusion, the unicompartmental and the pharmacokinetic models, in 15 patients diagnosed with grade IV astrocytoma. In the unicompartmental model, we quantified cerebral blood volume (CBV), mean transit time (MTT), and cerebral blood flow (CBF). In the pharmacokinetic model, we measured the permeability constant (Ktrans), the extraction coefficient (kep), the fraction of the volume in the interstitial space (ve), the fraction of the volume in the vessels (vp), the permeability in the first pass (Kfp), and the vascular volume in the first pass (vpfp). For each parameter, histograms were obtained for the total tumor area, for the peritumoral area, and for the healthy tissue. The statistical analysis included an analysis of variance for each parameter and a discriminant analysis. Results. The most significant differences between the regions were obtained with CBV, CBF, Ktrans, and vpfp; of these, CBV had the best results. The best classificatory function on the discriminant analysis was the combination of Ktrans and CBV. The analysis of the shape of the histogram showed statistically significant differences for the kurtosis of Ktrans and kep, as well as for the skewness of CBV, CBF, Ktrans, and vpfp. Conclusion. When parameters are considered individually, CBV is the one that best enables differentiation between tumor, peritumoral, and healthy tissue. The classificatory function generated from CBV and Ktrans results in improved classification by areas (AU)

[Nosological analysis of MRI tissue perfusion parameters obtained using the unicompartmental and pharmacokinetic models in cerebral glioblastomas]. / Análisis nosológico con parámetros de perfusión tisular de RM obtenidos mediante los modelos monocompartimental y farmacocinético en los glioblastomas cerebrales.

OBJECTIVES: To classify the tumor areas in patients with grade IV astrocytoma by calculating and statistically analyzing quantitative MRI perfusion parameters. MATERIAL AND METHODS: We applied two models of MRI perfusion, the unicompartmental and the pharmacokinetic models, in 15 patients diagnosed with grade IV astrocytoma. In the unicompartmental model, we quantified cerebral blood volume (CBV), mean transit time (MTT), and cerebral blood flow (CBF). In the pharmacokinetic model, we measured the permeability constant (K(trans)), the extraction coefficient (k(ep)), the fraction of the volume in the interstitial space (v(e)), the fraction of the volume in the vessels (v(p)), the permeability in the first pass (K(fp)), and the vascular volume in the first pass (v(pfp)). For each parameter, histograms were obtained for the total tumor area, for the peritumoral area, and for the healthy tissue. The statistical analysis included an analysis of variance for each parameter and a discriminant analysis. RESULTS: The most significant differences between the regions were obtained with CBV, CBF, K(trans), and v(pfp); of these, CBV had the best results. The best classificatory function on the discriminant analysis was the combination of K(trans) and CBV. The analysis of the shape of the histogram showed statistically significant differences for the kurtosis of K(trans) and k(ep), as well as for the skewness of CBV, CBF, K(trans), and v(pfp). CONCLUSION: When parameters are considered individually, CBV is the one that best enables differentiation between tumor, peritumoral, and healthy tissue. The classificatory function generated from CBV and K(trans) results in improved classification by areas.

[Treating iatrogenic pneumothorax with small-bore chest tube]. / Drenaje de neumotórax iatrogénico con catéter de calibre pequeño.

OBJECTIVE: To evaluate the feasibility of small-bore chest tube placement to treat pneumothorax caused by percutaneous procedures. MATERIAL AND METHODS: Between November 2004 and July 2006 we performed 151 interventional chest procedures (127 biopsies and 24 radiofrequency ablations) in 131 patients (25 women and 106 men; mean age, 63 years, range, 36-83 years). Fine needles (21-25 G) were used in 70 procedures and large core needles (14-20 G) were used in the remaining 81. Pneumothorax occurred in 16 diagnostic procedures (13 of these were treated with small-bore catheter placement) and in two radiofrequency procedures (both cases were treated with small-bore catheter placement). Chest tubes were placed immediately after pneumothorax occurred in all cases because the pneumothorax was greater than 20% or caused symptoms or occurred in patients with emphysema. RESULTS: Chest tubes were successfully placed without incidents in all cases and a Heimlich valve evacuated the air completely. Mean hospital stay was 43 hours (range, 24-72 hours). It was not necessary to place a larger-bore chest tube in any case. CONCLUSION: Small-bore chest tube placement is the treatment of choice for iatrogenic pneumothorax greater than 20% or less than 20% when symptomatic or occurring in patients with emphysema. The procedure is easy, effective, and well tolerated; furthermore, it shortens the hospital stay. The effectiveness of the procedure makes it possible to safely perform percutaneous procedures on patients with emphysema or difficult lesions and to finish an interventional procedure when pneumothorax occurs.

Drenaje de neumotórax iatrogénico con catéter de calibre pequeño / Treating iatrogenic pneumothorax with small-bore chest tube

Objetivo: evaluar la utilidad del drenaje de neumotórax con catéter de calibre pequeño tras la punción de lesiones torácicas. Material y métodos: desde noviembre de 2004 hasta julio de 2006 se realizaron 151 punciones torácicas en 131 pacientes (106 varones y 25 mujeres) con una media de edad de 63 años (36-83 años). Con fines diagnósticos se hicieron 127 punciones y los restantes 24 fueron tratamientos de termocoagulación con radiofrecuencia (RF). Se realizaron 70 punciones con aguja fina (21-25G) y 81 con aguja gruesa (14-20G). En los procedimientos diagnósticos se produjeron 16 neumotórax y se drenaron 13, y en los de RF hubo 2 neumotórax, y se drenaron ambos. El drenaje en todos los casos se realizó inmediatamente después de producirse, porque eran 20 % o presentaban síntomas, o siendo 20 % eran pacientes con enfisema. Resultados: en todos los pacientes pudo colocarse el catéter de drenaje sin incidencias, resolviendo el neumotórax con una válvula de Heimlich. El tiempo máximo de ingreso fue de 72 h, con una media de 43 h. En ningún caso se precisó colocar posteriormente un catéter de mayor calibre. Conclusión: el drenaje de neumotórax con catéter de calibre pequeño tras un procedimiento intervencionista torácico, es la técnica de elección cuando un neumotórax es 20 %, o el paciente está sintomático o tiene enfisema, porque su colocación no es difícil, es resolutivo, bien tolerado y acorta la estancia hospitalaria. Su resolución rápida permite puncionar pacientes con enfisema o lesiones difíciles con mayor seguridad y posibilita finalizar un procedimiento intervencionista si durante su realización se produce el neumotórax (AU)

Objective: to evaluate the feasibility of small-bore chest tube placement to treat pneumothorax caused by percutaneous procedures. Material and methods: between November 2004 and July 2006 we performed 151 interventional chest procedures (127 biopsies and 24 radiofrequency ablations) in 131 patients (25 women and 106 men; mean age, 63 years, range, 36-83 years). Fine needles (21-25 G) were used in 70 procedures and large core needles (14-20G) were used in the remaining 81. Pneumothorax occurred in 16 diagnostic procedures (13 of these were treated with small-bore catheter placement) and in two radiofrequency procedures (both cases were treated with small-bore catheter placement). Chest tubes were placed immediately after pneumothorax occurred in all cases because the pneumothorax was greater than 20 % or caused symptoms or occurred in patients with emphysema. Results: chest tubes were successfully placed without incidents in all cases and a Heimlich valve evacuated the air completely. Mean hospital stay was 43 hours (range, 24-72 hours). It was not necessary to place a larger-bore chest tube in any case. Conclusion: small-bore chest tube placement is the treatment of choice for iatrogenic pneumothorax greater than 20 % or less than 20 % when symptomatic or occurring in patients with emphysema. The procedure is easy, effective, and well tolerated; furthermore, it shortens the hospital stay. The effectiveness of the procedure makes it possible to safely perform percutaneous procedures on patients with emphysema or difficult lesions and to finish an interventional procedure when pneumothorax occurs (AU)

Evaluación de la arteriopatía de los miembros inferiores por tomografía computarizada multidetector comparada con la angiografía por sustracción digital / The evaluation of lower limb arteriopathy by multidetector computed tomography compared with digital subtraction angiography

Objetivos. Evaluar la eficacia diagnóstica de la angiografía por tomografía computarizada multidetector (ATCM) en la arteriopatía de miembros inferiores (MMII), comparándola con angiografía por sustracción digital (ASD). Material y métodos. Se estudiaron 24 pacientes con arteriopatía de MMII. Se realizaron ATCM (4 detectores) y ADS realizando doble lectura entre las dos técnicas. Los territorios vasculares se dividieron para facilitar el análisis. Se calcularon sensibilidad (S), especificidad (E), prevalencia, valor predictivo positivo y negativo (VPP, VPN) y concordancia (test de Kappa). En arterias de tercera porción se estudió el rendimiento diagnóstico del ATCM realizando una curva ROC. Resultados. El estudio ATCM para la evaluación de la patología arterial mostró: una S menor en el estudio de la arteria ilíaca primitiva y arteria ilíaca interna (S: 0,65 y 0,71) con E de 0,94 y de 1; en los demás territorios vasculares obtuvimos S próximas a 1, disminuyendo algo la E. La concordancia fue muy alta (kappa entre 0,62 y 1) en todos los territorios estudiados. La ATCM mostró más longitud de vaso que la ASD. En la tercera porción el mejor rendimiento diagnóstico (ROC) se obtuvo en la lectura de vasos patológicos. Conclusión. La ATCM presentó alta fiabilidad en el estudio de la arteriopatía de MMII, con alta concordancia respecto a la ASD. En vasos tortuosos la ATCM visualiza mal las lesiones, en cambio en vasos rectos y en tercera porción el estudio con ATCM visualiza más segmentos vasculares

Objectives. To evaluate the diagnostic efficacy of multidetector computed tomography angiography (MDCTA) in lower limb arteriopathy (LLA) by comparing it with digital subtraction angiography (DSA). Material and methods. Twenty-four patients with LLA were studied. All patients underwent MDCTA (four detectors) and DSA, with double reading between the two techniques. Vascular territories were divided to facilitate analysis. Sensitivity (S), specificity (Sp), prevalence, positive and negative predictive values (PPV, PNV), and concordance (Kappa test) were evaluated. In third-portion arteries, the diagnostic performance of MDCTA was evaluated using an ROC curve. Results. MDCTA study to evaluate arterial pathology showed: Lower sensitivity in the study of the internal iliac artery (S: 0.65 and 0.71) with Sp 0.94 and 1. In the other vascular territories, S approached 1, with a slight decrease in Sp. Concordance with DSA was very high (kappa between 0.62 and 1) in all of the territories studied. MDCTA showed greater vessel longitude than DSA. In the third portion, the best diagnostic performance (ROC) was obtained in the reading of pathological vessels. Conclusion. MDCTA was highly reliable in the study of LLA, with high concordance with DSA. In tortuous vessels, MDCTA depicted the lesions poorly; however, in straight vessels and third-portion vessels, MDCTA showed more vascular segments

[The evaluation of lower limb arteriopathy by multidetector computed tomography compared with digital subtraction angiography]. / Evaluación de la arteriopatía de los miembros inferiores por tomografía computarizada multidetector comparada con la angiografía por sustracción digital.

OBJECTIVE: To evaluate the diagnostic efficacy of multidetector computed tomography angiography (MDCTA) in lower limb arteriopathy (LLA) by comparing it with digital subtraction angiography (DSA). MATERIAL AND METHODS: Twenty-four patients with LLA were studied. All patients underwent MDCTA (four detectors) and DSA, with double reading between the two techniques. Vascular territories were divided to facilitate analysis. Sensitivity (S), specificity (Sp), prevalence, positive and negative predictive values (PPV, PNV), and concordance (Kappa test) were evaluated. In third-portion arteries, the diagnostic performance of MDCTA was evaluated using an ROC curve. RESULTS: MDCTA study to evaluate arterial pathology showed: Lower sensitivity in the study of the internal iliac artery (S: 0.65 and 0.71) with Sp 0.94 and 1. In the other vascular territories, S approached 1, with a slight decrease in Sp. Concordance with DSA was very high (kappa between 0.62 and 1) in all of the territories studied. MDCTA showed greater vessel longitude than DSA. In the third portion, the best diagnostic performance (ROC) was obtained in the reading of pathological vessels. CONCLUSION: MDCTA was highly reliable in the study of LLA, with high concordance with DSA. In tortuous vessels, MDCTA depicted the lesions poorly; however, in straight vessels and third-portion vessels, MDCTA showed more vascular segments.

Chilaiditi syndrome associated with transverse colon volvulus: first report in a paediatric patient and review of the literature.

A hepatodiaphragmatic interposition of the colon, known as Chilaiditi's sign, is usually discovered by chance during the study of another event, given that its presentation is normally asymptomatic. When this finding is accompanied by clinical symptoms, either intermittent or persistent, it is known as Chilaiditi syndrome. It may be associated with intestinal obstruction due to twisting. The association of Chilaiditi syndrome and transverse colon volvulus is exceptional. To date only three cases have been reported, all in adult males. Among the common predisposing factors were anatomical alterations of the intestine such as elongation of the colon and a history of prior abdominal surgery. The clinical symptoms were due to the intestinal obstruction. We present the first description in the paediatric population of an association of transverse colon volvulus and Chilaiditi syndrome whose predisposing factors, clinical symptoms and treatment differed from those reported in the non-paediatric cases published to date.

[Multiple sclerosis or Lyme disease? a diagnosis problem of exclusion]. / Esclerosis múltiple o enfermedad de Lyme? Un problema diagnóstico de exclusión.

There is no diagnostic biological marker in multiple sclerosis. Thus, its diagnosis is based on clinical criteria. These criteria can also be found in other conditions. Lyme disease is currently among them. In a late period of the disease demyelinating involvement of central nervous system can develop, and multiple sclerosis can be erroneously diagnosed. We have evaluated a series of 55 patients with a definite diagnosis of multiple sclerosis, and we have found evidence of infection by the causative organism of Lyme disease in three. We describe the three patients and we discuss the relationship between both conditions. We conclude that it is important to consider Lyme disease as a diagnostic possibility in patients with neurological disease of unknown etiology such as multiple sclerosis.