Ex-Vivo MRI of the Normal Human Placenta: Structural-Functional Interplay and the Association With Birth Weight.

BACKGROUND: Advanced magnetic resonance imaging (MRI) methods are increasingly being used to assess the human placenta. Yet, the structure-function interplay in normal placentas and their associations with pregnancy risks are not fully understood. PURPOSE: To characterize the normal human placental structure (volume and umbilical cord centricity index (CI)) and function (perfusion) ex-vivo using MRI, to assess their association with birth weight (BW), and identify imaging-markers for placentas at risk for dysfunction. STUDY TYPE: Prospective. POPULATION: Twenty normal term ex-vivo placentas. FIELD STRENGTH/SEQUENCE: 3 T/ T1 and T2 weighted (T1 W, T2 W) turbo spin-echo, three-dimensional susceptibility-weighted image, and time-resolved angiography with interleaved stochastic trajectories (TWIST), during passage of a contrast agent using MRI compatible perfusion system that mimics placental flow. ASSESSMENT: Placental volume and CI were manually extracted from the T1 W images by a fetal-placental MRI scientist (D.L., 7 years of experience). Perfusion maps including bolus arrival-time and full-width at half maximum were calculated from the TWIST data. Mean values, entropy, and asymmetries were calculated from each perfusion map, relating to both the whole placenta and volumes of interest (VOIs) within the umbilical cord and its daughter blood vessels. STATISTICAL TESTS: Pearson correlations with correction for multiple comparisons using false discovery rate were performed between structural and functional parameters, and with BW, with P < 0.05 considered significant. RESULTS: All placentas were successfully perfused and scanned. Significant correlations were found between whole placenta and VOIs perfusion parameters (mean R = 0.76 ± 0.06, range = 0.67-0.89), which were also significantly correlated with CI (mean R = 0.72 ± 0.05, range = 0.65-0.79). BW was correlated with placental volume (R = 0.62), but not with CI (P = 0.40). BW was also correlated with local perfusion asymmetry (R = -0.71). DATA CONCLUSION: Results demonstrate a gradient of placental function, associated with CI and suggest several ex-vivo imaging-markers that might indicate an increased risk for placental dysfunction. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 1.

Automatic Measurement of Fetal Brain Development from Magnetic Resonance Imaging: New Reference Data.

BACKGROUND: Accurate fetal brain volume estimation is of paramount importance in evaluating fetal development. The aim of this study was to develop an automatic method for fetal brain segmentation from magnetic resonance imaging (MRI) data, and to create for the first time a normal volumetric growth chart based on a large cohort. SUBJECTS AND METHODS: A semi-automatic segmentation method based on Seeded Region Growing algorithm was developed and applied to MRI data of 199 typically developed fetuses between 18 and 37 weeks' gestation. The accuracy of the algorithm was tested against a sub-cohort of ground truth manual segmentations. A quadratic regression analysis was used to create normal growth charts. The sensitivity of the method to identify developmental disorders was demonstrated on 9 fetuses with intrauterine growth restriction (IUGR). RESULTS: The developed method showed high correlation with manual segmentation (r2 = 0.9183, p < 0.001) as well as mean volume and volume overlap differences of 4.77 and 18.13%, respectively. New reference data on 199 normal fetuses were created, and all 9 IUGR fetuses were at or below the third percentile of the normal growth chart. DISCUSSION: The proposed method is fast, accurate, reproducible, user independent, applicable with retrospective data, and is suggested for use in routine clinical practice.

Blood pressure values in 8-12 year old children with a history of intrauterine growth retardation.

BACKGROUND: Epidemiological studies have found that intrauterine growth retardation (IUGR) is closely related to hypertension and is associated with a reduced number of nephrons that may be a predisposing factor for the development of hypertension. OBJECTIVES: To determine whether blood pressure levels of children with a history of IUGR are higher than those of children without IUGR. METHODS: Diastolic, systolic and mean arterial blood pressure levels were measured in 64 children aged 8-12 years old with a history of IUGR (mean birth weight 1780 +/- 422 g) and compared with 64 age and gender-matched controls who had a normal birth weight (mean 3134 +/- 594 g). RESULTS: Contrary to previous reports, systolic blood pressure values were significantly lower in the IUGR group compared to the controls (91.6 +/- 11.3 vs. 96.6 +/- 13.9, P = 0.027). There was no difference in diastolic blood pressure values. In the IUGR group, systolic blood pressure correlated significantly with current weight (P < 0.01) and body mass index (P < 0.05), and diastolic blood pressure with weight gain between age 2 and 4 years (P < 0.05). None of the blood pressure values correlated with birth weight. CONCLUSIONS: Children born with IUGR have lower systolic blood pressure levels than matched controls at age 8-12 years. These data indicate that postnatal weight gain in this group has a greater impact on systolic blood pressure than birth weight.

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

INTRODUCTION: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI. METHODS: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T1 weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location; number of bifurcations, generations and vessels diameters. RESULTS: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings. DISCUSSION: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.

Placental vascular tree characterization based on ex-vivo MRI with a potential application for placental insufficiency assessment.

INTRODUCTION: Understanding regarding the whole placental vascular network structure is limited. Our aim was to quantitatively characterize the human placental vascular tree ex-vivo using high-resolution MRI. METHODS: 34 normal placentas were rinsed and injected with a solution of gelatin and contrast agent through the umbilical vessels. A sample of six placentas taken from pregnancies with intrauterine-growth-restriction (IUGR) was used to demonstrate the potential application to cases with placental insufficiency. Structural ex-vivo MR scans of the placenta were performed using high resolution T1 weighted images. A semi-automatic method was developed to segment and characterize the placental vascular architecture: placental volume and cord insertion location, number of bifurcations, generations and vessels diameters. RESULTS: Different vascular patterns were found in placentas with central versus marginal cord-insertion. Based on the placental volume and number of bifurcations we were able to predict birth weight. Furthermore, preliminary results on IUGR sample demonstrated the potential of this method to differentiate between small newborns with suspected IUGR from small normal newborns who reached their full growth potential. Results obtained using the automatic method were validated against manual values demonstrating no significant differences or bias. Histopathology supported the imaging findings. DISCUSSION: This is the first study to quantitatively characterize the human placental vascular architecture using high resolution ex-vivo MRI. Different patterns of vascular architecture may be related to different functioning of the placenta and affect fetal development. This method is simple, relatively fast, provides detailed information of the placental vascular architecture, and may have important clinical applications.

The neurocognitive outcome of mild isolated fetal ventriculomegaly verified by prenatal magnetic resonance imaging.

OBJECTIVE: Neurocognitive outcome of preschool children, prenatal diagnosis of isolated mild ventriculomegaly compared with 2 control groups. STUDY DESIGN: Case-controlled study at the University Hospital of Tel Aviv between October 1999 and December 2002. Study groups consisted of 12 children with bilateral isolated mild ventriculomegaly, and 16 children with unilateral isolated mild ventriculomegaly, mean age 4.4 years, prenatally diagnosed by both ultrasound and fetal magnetic resonanace imaging. Control groups consisted of 16 children with normal prenatal magnetic resonance imaging and 16 regular kindergarten children. A neurodevelopmental examination and the Kaufman Assessment Battery for Children were performed. RESULTS: The neurodevelopmental and Kaufman scores were within normal range in the study groups. No significant differences between the study and control groups for most measures; however, Kaufman achievement score was significantly lower for the bilateral isolated mild ventriculomegaly group (P < .05) compared with the kindergarten children. CONCLUSION: Preschool children with isolated mild ventriculomegaly performed within normal range compared with the controls. Nevertheless, a significant percentage of the children demonstrated developmental difficulties, lower achievement scores, justifying early school years follow-up.

A Long-term, epidemiological survey of outcome and adjustment of children with developmental disabilities.

The medical, educational, and psychosocial outcomes of 3224 subjects (age range, 7-33 years; mean age, 20.06 years; SD, 5.74) diagnosed and treated in the Institute for Child Development in Tel Aviv between the years 1975 and 1994 were assessed by a telephone interview. Results indicate that only 9% of the subjects are seriously disabled, and 8% are mentally retarded. Over the years, subjects were referred to the Child Development Center at an increasingly younger age, probably reflecting greater professional and parental awareness of the importance of early intervention. The nature of interventions changed, so that physiotherapy, occupational therapy, and psychological guidance were more often provided. While more children were referred to special education at kindergarten, the percentage of those graduating from regular schools has increased. Most completed 12 years of schooling and successfully acquired full or partial matriculation certificates. As adults, most function independently; fulfill civic obligations, such as their army service; are fully employed; and express satisfaction with their life. These results suggest that children with developmental disabilities who receive early intervention are likely to be functionally independent and to be satisfied with their lives, although they continue to need medical services and require some government support. Further studies are essential to examine the correlation of specific risk factors and early interventions with outcome.

Neurodevelopmental outcome of children with intrauterine growth retardation: a longitudinal, 10-year prospective study.

One hundred twenty-three children with intrauterine growth retardation were prospectively followed from birth to 9 to 10 years of age in order to characterize their specific neurodevelopmental and cognitive difficulties and to identify clinical predictors of such difficulties. Perinatal biometric data and risk factors were collected. Outcome was evaluated at age 9 to 10 by neurodevelopmental, cognitive, and school achievement assessments. Sixty-three children served as controls who were appropriate for gestational age. Significant differences in growth (P < .001), neurodevelopmental scores (P < .001), intelligence quotient (IQ) (P < .0001), and school achievements measured by the Kaufmann Assessment Battery for Children (P < .001) were found between the children with intrauterine growth retardation and controls. Children with intrauterine growth retardation demonstrated a specific profile of neurocognitive difficulties at school age, accounting for lower school achievements. The best perinatal parameter predictive of neurodevelopment and IQ was the Cephalization Index (P < .001). Somatic catch-up growth at age 2 and at age 9 to 10 correlated with favorable outcome at 9 to 10 years of age.

Memory functions of children born with asymmetric intrauterine growth restriction.

OBJECTIVE: Learning difficulties are frequently diagnosed in children born with intrauterine growth restriction (IUGR). Models of various animal species with IUGR were studied and demonstrated specific susceptibility and alterations of the hippocampal formation and its related neural structures. The main purpose was to study memory functions of children born with asymmetric IUGR in a large-scale cohort using a long-term prospective paradigm. METHODS: One hundred and ten infants diagnosed with IUGR were followed-up from birth to 9 years of age. Their performance was compared with a group of 63 children with comparable gestational age and multiple socioeconomic factors. Memory functions (short-term, super- and long-term spans) for different stimuli types (verbal and visual) were evaluated using Visual Auditory Digit Span tasks (VADS), Rey Auditory Verbal Learning Test (Rey-AVLT), and Rey Osterrieth Complex Figure Test (ROCF). RESULTS: Children with IUGR had short-term memory difficulties that hindered both serial verbal processing system and simultaneous processing of high-load visuo-spatial stimuli. The difficulties were not related to prematurity, neonatal complications or growth catch-up, but were augmented by lower maternal education. Recognition skills and benefits from reiteration, typically affected by hippocampal dysfunction, were preserved in both groups. CONCLUSIONS: Memory profile of children born with IUGR is characterized primarily by a short-term memory deficit that does not necessarily comply with a typical hippocampal deficit, but rather may reflect an executive short-term memory deficit characteristic of anterior hippocampal-prefrontal network. Implications for cognitive intervention are discussed.

Role of thrombophilic risk factors in children with non-stroke cerebral palsy.

BACKGROUND: Thrombophilic risk factors play an important role in the pathogenesis of perinatal stroke and resultant cerebral palsy (CP). The association between thrombophilia and CP caused by etiologies other than stroke is undetermined. METHODS: We assessed three genetic thrombophilic markers (mutation of Factor V Leiden [FV G1691A], 677T polymorphism of thermolabile methylenetetrahydrofolate reductase [MTHFR] and G20210A mutation of the prothrombin gene) in 49 pediatric patients with non-stroke CP and compared the findings with 118 apparently healthy controls. CP in the study group was due to periventricular leukomalacia (n=27), intraventricular hemorrhage (n=9), hypoxic ischemic encephalopathy (n=4), prematurity with no apparent complication (n=8) and intrauterine growth retardation (n=1). Twenty-five children had spastic diplegia, 20 had spastic quadriplegia and 4 had spastic hemiplegia. CP was graded as being severe in 26 children (53%). RESULTS: No significant difference in the prevalence of thrombophilic risk factors was found between the study and control groups. Twelve study children (24.5%) had at least one of the three thrombophilic mutations compared with 27 controls (23%). There was no significant difference in the prevalence of each thrombophilic risk factor in the various etiologic groups and in the subgroups of mild/severe CP and the control group. CONCLUSION: These findings support the notion that thrombophilia neither contributes to the occurrence nor affects the clinical outcome and severity of non-stroke CP.

The pregnant spontaneously hypertensive rat as a model of asymmetric intrauterine growth retardation and neurodevelopmental delay.

INTRODUCTION: Hypertension in pregnancy and vascular placental insufficiency are considered common pathogenic factors in human intrauterine growth retardation (IUGR). IUGR neonates experience higher mortality, and the surviving infants have a higher incidence of neurological and intellectual impairment. METHODS: To mimic this condition, we used pregnant spontaneously hypertensive rats (SHR) and performed biometric measurements on Embryonic Day 20, postnatal developmental reflexes, and locomotor activity evaluations. RESULTS: SHR fetuses had significant decreased body weight compared to the Wistar-Kyoto control fetuses (1.51+/-0.02 g vs. 2.05+/-0.01 g, respectively; p<0.0001), and were relatively microcephalic (2.86+/-0.04 cm vs. 3.3+/-0.03 cm, respectively; p<0.0001). Their cephalization index (head circumference/body weight) was increased (1.88+/-0.03 vs. 1.62+/-0.02, respectively; p<0.0001), indicating a "brain-sparing" process. The disproportional ratio indicated that the IUGR type in this model is asymmetric. The SHR pups exhibited a significant (p<0.04) neurodevelopmental delay in the acquisition of neonatal reflexes (righting, negative geotaxis, placing), but they spontaneously caught up with the control pups after approximately 10 days. On Day 30, the SHR pups exhibited significantly increased walking speed and distance and spent less time in quadrant than the controls (p<0.002). CONCLUSION: We speculate that the model of pregnant SHR closely simulate human IUGR caused by hypertension in pregnancy and should enable investigation of mechanisms of hypertension-mediated placenta-vascular injury as well as provide a system for preclinical evaluations of future preventive neuroprotective treatments.

Endocrine profile of children with intrauterine growth retardation.

BACKGROUND: Intrauterine growth retardation (IUGR) is a major cause of short stature in childhood. Most but not all children experience catch-up growth by 2 years of age. METHODS: We investigated the endocrine profile (thyroid function, prolactin, cortisol, C-peptide and insulin-like growth factor-I [IGF-IJ levels) of 57 children with IUGR, aged 2-10 years, and compared it with 30 controls whose birth weight was appropriate-for-gestational-age. RESULTS: The hormonal profile for both groups was similar for thyroid hormones, prolactin, C-peptide and IGF-I. Cortisol levels were significantly lower in the IUGR group compared to controls (p <0,05). When the IUGR group was divided into 'catch-up' growth and 'non-catch-up' subgroups, the latter had significantly lower IGF-I levels (p <0.001). CONCLUSIONS: Lower cortisol levels in children born with IUGR may reflect impaired function of the hypothalamic-pituitary-adrenal axis associated with this condition. The significantly lower IGF-I levels of the 'non-catch-up' subgroup may be involved in their failure to grow.

Facial Expression in Response to Smell and Taste Stimuli in Small and Appropriate for Gestational Age Newborns.

Small for gestational age newborns can later suffer from eating difficulties and slow growth. Nutritional preferences can be influenced by changes in sensory perception of smell and taste. To determine whether these could be detected at birth, the authors examined the different recognition pattern of smell and taste in small for gestational age newborns compared to appropriate for gestational age controls, as expressed by gusto-facial and naso-facial reflexes. The authors performed video analysis of facial expressions of 10 small for gestational age and 12 control newborns exposed to various tastes and smells. No difference in the facial recognition patterns for taste or smell was demonstrated between small for gestational age and controls, except for perception of distilled water. Newborns show recognizable patterns of facial expression in response to taste and smell stimuli. Perception of taste and smell in small for gestational age newborns is not different from controls, as measured by the method of facial recognition.

Neonatal general movements: an early predictor for neurodevelopmental outcome in infants with intrauterine growth retardation.

Intrauterine growth retardation plays a significant role in neurodevelopmental outcome. The assessment of general movements during the first 20 weeks is a new method for early detection of brain dysfunction. General movements in 31 infants with asymmetric intrauterine growth retardation and their appropriate for gestational age-matched controls were examined. General movements were scored as normal or abnormal by sequential videotape recordings in the writhing (term to 2 weeks), early fidgety (9-11 weeks), and late fidgety (14-16 weeks) periods. Scores were compared between the groups and correlated with neurodevelopmental outcome at 2 years. The incidence of normal general movements was lower in the intrauterine growth retarded infants than in the controls (P < .001). Significant correlations were found between general movement quality and neurodevelopmental scores in the intrauterine growth retarded group. The fidgety movements were the most sensitive and specific for prediction of neurologic outcome. The general movement assessment can, therefore, serve as an additional tool for examining the neurologic status of the preterm and term intrauterine growth retarded infant.

Significance of microcephaly among children with developmental disabilities.

To assess the clinical impact of microcephaly among children with developmental disabilities, we reviewed the charts of 1393 consecutive patients from birth to 5 years of age referred to our child development center. Comparisons were made between normal and low IQ microcephalic patients and between children with cerebral palsy with and without small head circumference. Microcephaly was detected in 15.4% of patients. Although mental retardation was more common among microcephalic children (P < .001), almost half had normal intelligence. Prematurity (P < .001), perinatal asphyxia (P < .001), small for gestational age (P < .001), respiratory distress syndrome (P < .001), and brain hemorrhage (P < .001) were associated with microcephaly. Hypotonia (P < .001) and spasticity (P < .001) were the most common neurologic findings. Cerebral palsy (P < .001), growth retardation (P < .001), epilepsy (P < .001), and strabismus (P < .001) were the main associated diagnoses found. Mental retardation was significantly more common among microcephalic patients with cerebral palsy than among normocephalic ones (P < .0004). Microcephaly is common among children evaluated for developmental disabilities. Many of these patients have normal or borderline IQ. Of several perinatal conditions associated with later microcephaly, respiratory distress syndrome and intraventricular hemorrhage show the strongest correlation. Mental retardation is not a risk factor for other neurologic complications in microcephalic children. However, in children with cerebral palsy, microcephaly is a risk factor for mental retardation.

Antenatal diagnosis of central nervous system anomalies: can we predict prognosis?

Our technical ability to diagnose fetal anomalies of the central nervous system by ultrasonography and by fetal magnetic resonance imaging far exceeds our current knowledge of their possible neurodevelopmental implications later in life. This limitation often makes obstetric and clinical decisions very difficult. We retrospectively reviewed the ultrasonographic records of 6220 women who had been followed up at two large medical centers between 1994 and 1999. One hundred and sixty (2.6%) women had abnormal fetal central nervous system findings. The neurodevelopmental outcome of these children was assessed by a telephone interview with the parents. Small cerebellar size was the most frequent anomaly, followed by isolated mild ventriculomegaly and isolated choroid plexus pathology. Suboptimal neurodevelopmental outcome was found in 24% of children with isolated ventriculomegaly and in 9% with choroid plexus pathology. In the group of children with a "small cerebellum," suboptimal neurodevelopment was found in 19%. The measurement of transcerebellar diameter in respect to its developmental implication is, to our knowledge, described here for the first time. We believe that cerebellar measurements and their possible neurocognitive implications should be an integral part of future studies.

Sleep-wake patterns in children with intrauterine growth retardation.

The purpose of this study was to characterize the sleep patterns of children with intrauterine growth retardation, known to be at risk for neurodevelopmental disorders, and seek a possible correlation with behavior, concentration, and attention problems. The sleep patterns of 26 children with intrauterine growth retardation aged 4 to 7 years were compared with those of 47 control children using activity monitors (actigraphs). In addition, data were collected from the parents regarding sleep habits, behavior, concentration, and attention. Children with intrauterine growth retardation aged 4 to 7 years were found to have a tendency toward poorer quality of sleep than their matched controls. This inclination was statistically significant only for one sleep measure, the true sleep time. A tendency toward increased fragmentation of sleep, prolonged waking, and decreased sleep efficiency, although not statistically significant in this study, was demonstrated. Our results showed that 58% of the children with intrauterine growth retardation, compared with 40% of the children in the control group, could be defined as "poor sleepers" (sleep efficiency lower than 90% or three or more waking episodes per night). This disturbed sleep profile is probably an integral part of the neurodevelopmental profile typical of these at-risk children. No significant correlations were found between sleep quality and behavior, concentration, and attention problems.

Congenital muscular dystrophy in Israeli families.

Twelve patients from 11 Israeli families with congenital muscular dystrophy were evaluated between 1991 and 2001. There were six males and six females, of whom six were merosin negative and six were merosin positive. Serum creatine kinase levels were highly elevated in the merosin-negative group. Four of the children were cognitively normal but nonambulant. Two had unusual clinical findings of severe cognitive and motor developmental dysfunction. Four infants in the merosin-positive group who had normal serum creatine kinase levels had early-onset severe motor weakness and died within the first year of life owing to ventilatory insufficiency. The other two were ambulant and had normal cognitive development and elevated serum creatine kinase levels. Noteworthy, two of the six children with merosin-negative congenital muscular dystrophy had cognitive impairment, and four of the six children with merosin-positive congenital muscular dystrophy had a severe form of the disease with ventilatory insufficiency and death during infancy.

Myoclonic seizures as a main manifestation of Epstein-Barr virus infection.

A 15-year-old girl with clinical and serologic evidence of active Epstein-Barr virus infection presented with a new onset of myoclonic jerks, confirmed on electroencephalogram (EEG) by generalized polyspike-and-wave epileptiform activity. Family history for juvenile myoclonic epilepsy was negative, and brain magnetic resonance imaging was normal. The myoclonic jerks resolved spontaneously after 5 days, with gradual normalization of the EEG during the ensuing month and since then no resumption over the last 2 years. Previous reports have already linked Epstein-Barr virus infection to opsoclonus-myoclonus syndrome and hypsarrhythmia, but to the best of our knowledge, this is the first presentation of epileptic myoclonic jerks associated with acute Epstein-Barr virus infection. We suggest that acute myoclonic seizures with a transiently abnormal EEG and benign course can be associated with acute Epstein-Barr virus infection.

Parameters for predicting favorable responses to botulinum toxin in children with cerebral palsy.

We sought markers for predicting a favorable outcome of botulinum toxin A injected to the lower-extremity muscles of 26 children with hemiplegic or diplegic cerebral palsy. Clinical assessment preceding and 1 month following injection included gross motor function measure, a modified Ashworth scale, and evaluation of range of motion of knee extension and ankle dorsiflexion. Response to treatment was classified based on a parent questionnaire. The 19 children (73%) considered by their parents as being good responders were compared to the 7 (27%) considered as being poor responders. In the good responders, the preinjection Ashworth scale (spasticity) was significantly higher (P < .05) and gross motor function measure scores (function) were lower (P < .05). Sixty-eight percent of the good responders were nonindependent walkers compared to 14% of the poor responders (P < .05). There were no differences in age, type of cerebral palsy, and dose of injection. An Ashworth scale indicating increased muscle tone, lower gross motor function measure scores, and nonindependent ambulatory status were predictive for a favorable response to botulinum toxin A injections and can guide patient selection and expectations of treatment outcome.