Cortical gray matter changes in primary blepharospasm: A voxel‐based morphometry study

Previous voxel‐based morphometry studies of patients with primary blepharospasm documented gray matter volumetric differences of the striatum, cerebellum, thalamus, and parietal lobe areas. However, these results were inconsistent across studies, which recruited relatively small samples and did not always provide detailed clinical information on patients with blepharospasm. The objective of this study was to analyze whole‐brain gray matter volume in a larger sample of patients with blepharospasm and to expand on previous works by evaluating whether clinical features of blepharospasm correlate to whole‐brain gray matter changes. Voxel‐based morphometry was performed on 25 patients with primary adult‐onset blepharospasm and 24 healthy subjects (controls) matched for age, sex, and handedness. Clinical data were collected through a standardized interview. Severity of blepharospasm was measured using the Jankovic Rating Scale. Patients with blepharospasm had greater gray matter volume than controls in the right middle frontal gyrus, whereas patients with blepharospasm had smaller gray matter volume than controls in the left postcentral gyrus and left superior temporal gyrus. Spearman correlation analysis with Bonferroni correction failed to show significant correlations between gray matter volume and the explored clinical variables, comprising age at onset, disease duration, blepharospasm severity, presence of an effective geste antagoniste, and dose and duration of botulinum toxin treatment. Patients with blepharospasm exhibited gray matter volume differences exclusively in cortical regions highly relevant to sensory processing and cognitive modulation of motor behavior. Gray matter changes in the primary sensory cortex may represent a common trait of primary dystonias, including blepharospasm. © 2011 Movement Disorder Society     

Cognitive disturbances in primary blepharospasm

The common belief that primary dystonia is a purely motor disorder with no anatomical substrate and no other accompanying neurological dysfunction has recently been challenged. In addition, there is increasing evidence that the basal ganglia besides motor control, plays a role in cognitive functioning. However, no systematic cognitive performance evaluation has been carried out in patients with primary blepharospasm (BS), one of the most common forms of adult dystonia. We evaluated a series of 20 patients with primary BS and a group of 17 controls matched by severity of mood symptoms, age, and sex. BS patients performed significantly worse on the Luria sequencing test, Purdue pegboard test, reciprocal coordination, tactile denomination, and reverse visuospatial span and the differences persisted after correction for age, duration of disease, severity of BS, and degree of depression. The Wisconsin card sorting test showed no statistical difference, but BS patients made more errors and more perseverative answers than expected according to population means, whereas the control group performed poorly but within normal parameters. Our findings suggest broad cortical involvement in focal dystonia that is not correlated with the severity or duration of dystonia. © 2009 Movement Disorder Society     

The TOR1A polymorphism rs1182 and the risk of spread in primary blepharospasm

We studied the influence of the rs1182 polymorphism of the TOR1A gene on the risk of dystonia spread in two representative cohorts of patients presenting with primary blepharospasm (BSP), one from Italy and the other from the United States of America. The relationship between rs1182 polymorphism and spread was estimated by Kaplan‐Meier survival curves and Cox proportional hazard regression models adjusted by age and sex, age of BSP onset. In both series, patients carrying the T allele (G/T or T/T) in the rs1182 polymorphism were more likely to have dystonia spread as compared with the homozygous carriers of the common G allele. The comparable findings obtained in two independent cohorts support a genetic contribution to BSP spread. © 2009 Movement Disorder Society     

Improvement of blepharospasm with Zolpidem.

Zolpidem (ZLP) is an imidazopyridine that binds to GABA receptors. We report on improvement of blepharospasm in 3 patients treated with ZLP. The GABAergic action of this drug on the output structures of the basal ganglia could explain the improvement of blepharospasm in these patients.     

Epidemiology of primary blepharospasm.

We review epidemiological data on primary blepharospasm (BSP). There is a large variation in the stated prevalence of BSP, with crude estimates ranging from 16 to 133 per million in different studies. A large proportion of this variability may be the result of differences in physician education on BSP. Age and female gender may increase the risk of developing BSP. The few case-control studies focusing on adult dystonias including BSP showed an increased risk in association with family history of dystonia and/or postural tremor, prior head and face trauma, and prior eye disease (e.g., blepharitis and keratoconjunctivitis), and a decreased risk associated with cigarette smoking. No association was found with age-related medical conditions such as hypertension and diabetes, family history of parkinsonism, and a history of anxiety or depression. Broocks et al. [Am J Psychiatry, 1998;155:555-557] found a significantly higher frequency of obsessive-compulsive symptoms in BSP than hemifacial spasm despite the clinical similarity. Among putative risk factors for BSP, age at onset, female gender, and prior head or face trauma may affect spread of dystonia to adjacent body regions. While limited, the body of epidemiological data support the idea that environmental and familial, possibly genetic, factors may both be important in the etiology of BSP.     

Are nongenetic triggers for dystonia type‐specific? A study exploring scoliosis in blepharospasm

We previously observed that diseases of the anterior ocular segment predispose to primary blepharospasm, but not to other focal dystonias. In this multicenter study, we tested whether prior scoliosis, which increases the risk of developing cervical dystonia, is also a predisposing factor to blepharospasm. The frequency of scoliosis did not differ between blepharospasm patients and controls. This finding supports the hypothesis that environmental risk factors may be specific for a single form of adult-onset dystonia.     

Analysis of blink rate in patients with blepharospasm.

The blink rate (BR) during rest, conversation, and reading was assessed in 50 patients with blepharospasm (BS) and in 150 healthy subjects. BR at rest and during conversation was higher in patients with BS. Moreover, 76% of patients had BR higher at rest than during conversation, whereas in 74% of controls, BR was higher during conversation than at rest. The sensitivity and specificity of two parameters (value of BR at rest and pattern rest-BR higher than conversation-BR) in discriminating patients and controls were computed. The best fit was obtained with a rest-BR above 27 blinks per minute. When the two parameters were combined (rest-BR above 27 blinks per minute together with the pattern rest-BR higher than conversation-BR), we obtained a 92.3% sensitivity and a 82.0% specificity in discriminating between BS patients and controls. These findings indicate that specific features of BR can be associated with BS, suggesting that the analysis of BR might be helpful for the diagnosis of BS in early stages.     

Treatment of essential blepharospasm with quetiapine.

A 69-year-old male with blepharospasm unresponsive to several medications who was successfully treated with quetiapine is described. His symptoms were largely alleviated by low doses, but he experienced sedation, which permitted him to take the medication at bedtime only.     

The phenomenology of the geste antagoniste in primary blepharospasm and cervical dystonia

The geste antagoniste (GA), a relatively common feature of adult‐onset primary dystonia, has been systematically evaluated only in cervical dystonia, but it is still unclear whether its frequency and phenomenology differ among the various forms of focal dystonia. We analysed the frequency, phenomenology, effectiveness, and relationship of the GA with demographic/clinical features of dystonia in a representative clinical series of patients with the two most common forms of adult‐onset primary dystonia, blepharospasm (BSP) and cervical dystonia (CD). Clinical data were gathered using a standardized questionnaire, which showed substantial test‐retest reliability (κ = 0.79, P < 0.00001). The frequency of GA was similar among patients with BSP (42/59, 71.2%) and patients with CD (27/32, 84.4%), and in both groups GA showed similar effectiveness in reducing dystonia. The repertoire of GA was heterogenous in both BSP and CD patients, in whom seven BSP‐related and five CD‐related types of GA were recorded, and a “forcible” type of GA was present in 69% of BSP patients and in 48.1% of CD patients. In our whole patient population, age at dystonia onset was significantly lower among patients reporting a GA compared to those without GA (P = 0.01). GA features shared by BSP and CD predominate over differences, suggesting common mechanisms underlying this phenomenon in the two forms of primary adult‐onset dystonia. © 2010 Movement Disorder Society     

Brain-derived neurotrophic factor and risk for primary adult-onset cranial-cervical dystonia

Background and purpose:  Adult-onset dystonia may be related, amongst other factors, to abnormal neuronal plasticity in cortical and subcortical structures. Brain-derived neurotrophic factor is a major modulator of synaptic efficiency and neuronal plasticity. Recent works documented that a single nucleotide polymorphism (SNP) of the BDNF gene, the Val66Met SNP, modulates short-term plastic changes within motor cortical circuits. In this study we aimed at exploring the effect of this SNP upon the risk of developing common forms of primary adult-onset dystonia.
Methods:  We explored the influence of the Val66Met SNP of the BDNF gene on the risk of cranial and cervical dystonia in a cohort of 156 Italian patients and 170 age- and gender-matched healthy control subjects drawn from the same population.
Results:  The presence of the rare Met allele was not significantly associated with the diagnosis of dystonia (age- and gender-adjusted odds ratios of 1.22, P  =   0.38). The study had a >90% power to detect a 50% change in the risk of developing cranial-cervical dystonia associated with the presence of the Met allele. Moreover, there was no relationship between Val66Met SNP and age at dystonia onset or type of dystonia.
Conclusion:  Our data do not support the common variant Val66Met of the BDNF gene as an etiologic factor shared by the various forms of primary adult-onset dystonia.     

Diffusion tensor imaging in patients with primary cervical dystonia and in patients with blepharospasm

Diffusion tensor imaging (DTI) analyses the movement of water molecules within the cerebral white matter thus providing information on ultrastructural brain changes. We studied 18 patients with cervical dystonia (CD), 16 with blepharospasm (BSP) and 35 years age-matched healthy controls. DTI data were obtained with a Philips 1.5 Tesla scanner and then processed to obtain maps of fractional anisotropy (FA) and mean diffusivity (MD). Twenty-three square regions of interest of uniform size were positioned on the FA maps and then automatically transferred to the MD maps. FA and MD values in the corpus callosum, left and right putamen, right caudate, left and right pre-frontal cortical area and left supplementary motor area in CD patients differed significantly from those in healthy controls. No significant regional differences were found between patients with BSP and healthy controls. In the CD group, age, duration and severity of dystonia did not correlate with regional FA/MD values, whereas the duration of botulinum toxin treatment correlated significantly with the MD value in the right-pre-frontal cortex. The abnormal DTI findings in patients with CD suggest the presence of brain ultrastructural changes in adult-onset primary CD.     

Focal and segmental primary dystonia in north-western Germany--a clinico-genetic study

OBJECTIVES: To determine the frequency of familial focal and segmental dystonias in a large patient cohort with primary dystonia from north-western Germany. MATERIALS AND METHODS: In this study, 130 patients with focal or segmental dystonia were examined and a family history was obtained. Whenever possible, affected relatives were examined (a total of 789 first-degree relatives). Data on disease duration, age at disease onset and age of the patients were investigated by Student's t-test and a segregation analysis was performed by Weinberg's proband method. RESULTS: Age at onset of disease was significantly later in the blepharospasm group. Only in the writer's cramp group were women outnumbered by men. A positive family history was found in 15 of the 130 index patients (11.5%). None of 102 index patients tested carried the GAG deletion in the DYT1 gene. CONCLUSIONS: In accordance with previous series our study provides evidence that primary focal dystonia may have a genetic etiology, most probably caused by an autosomal dominant trait with reduced penetrance.     

Development of Parkinson's disease in patients with blepharospasm.

The liability to develop parkinsonian symptoms was evaluated in 105 outpatients with idiopathic blepharospasm (IBS; 54 cases) or IBS associated to oromandibular dystonia (Meige's syndrome; 51 cases) mean age 70.3 +/- 9.6 years, and compared with an age- and sex-matched population. Eleven patients developed Parkinson's disease in the blepharospasm group, whereas only 2 of 105 patients were affected in the control group. Our results suggest that patients with IBS either isolated or associated with oromandibular dystonia are more prone to develop parkinsonian symptoms.     

Botulinum toxin in blepharospasm and oromandibular dystonia: comparing different botulinum toxin preparations

Amongst all regions of the body, the craniocervical region is the one most frequently affected by dystonia. Whilst blepharospasm – involuntary bilateral eye closure – is produced by spasmodic contractions of the orbicularis oculi muscles, oromandibular dystonia may cause jaw closure with trismus and bruxism, or involuntary jaw opening or deviation, interfering with speaking and chewing. Both forms of dystonia can be effectively treated with botulinum toxin injection. This article summarizes injection techniques in both forms of dystonia and compares doses, potency and efficacy of different commercially available toxins, including Botox®, Dysport®, Xeomin® and Myobloc®/NeuroBloc®.     

Clinical features of patients with blepharospasm: a report of 240 patients

Background and purpose: To characterize patients with benign essential blepharospasm (BEB) by diagnosis, environmental risk factors, and family history. Methods: Two hundred and forty patients with BEB were evaluated through a clinical examination and questionnaire. The questionnaire reviewed personal medical history, demographic factors, risk factors for the development of blepharospasm and family history of dystonia and other neurological conditions. Results: Benign essential blepharospasm was more commonly found in women (2.8:1) and 93% of the patients were Caucasian. Fifty percent had pure BEB, 31% had BEB/Meige’s syndrome, and 4% had BEB and eyelid opening apraxia (+/− Meige’s syndrome). A minority of patients reported preceding photophobia (25%) or other eye conditions (22%). The majority were non‐smokers, had no exposure to anti‐emetic or antipsychotic agents, had a normal birth history, and had no history of head trauma. Seventy‐two percent did report a stressful event immediately prior to the development of symptoms. Treatments reported included botulinum toxin (BoNT), oral medications, surgical procedures, and acupuncture. Thirty‐two percent of patients reported a family history of focal dystonia, and BEB was the most commonly reported. Conclusion: This study confirms previous reports of usual age, sex, caffeine and tobacco use, and family history in patients with blepharospasm. New findings include a report on occupation, lower reports of preceding eye conditions and photophobia, and higher reported stressful events. Further, this study shows a change in treatment with an increase in BoNT use and decrease in surgical procedures.     

Relative risk of spread of symptoms among the focal onset primary dystonias.

Adult-onset primary torsion dystonia (PTD) may spread to multiple body parts, but the relative risk of spread by site of onset of dystonia has not been well characterized. We retrospectively identified 602 patients with PTD out of 1,500 dystonia patients in our electronic database and extracted age at onset, site of onset, family history, and spread. Survival analyses were performed for groups based on site of onset, and hazard ratios compared relative risk of spread across groups. Patients with adult-onset blepharospasm were more likely to spread (31% past the head) than those with dystonia starting in the neck (9%), larynx (12%), or upper extremities (16%). Hazard ratios proved that the blepharospasm group had the greatest relative risk of spread. The rate of spread after onset varied significantly between the different groups. Most spread occurred in the first 1 to 2 years after onset of blepharospasm, whereas the risk of spread was relatively constant over time in cervical and laryngeal dystonia. Different sites of onset of PTD confer different risks of spread, important for clinical prognosis. Different risks of spread may provide clues about underlying pathogenesis of adult-onset primary dystonias.     

The prevalence of primary dystonia: A systematic review and meta‐analysis

Dystonia is a hyperkinetic movement disorder characterized by sustained muscle contractions that produce repetitive movements and abnormal postures. Specific information on the prevalence of dystonia has been difficult to establish because the existing epidemiological studies of the condition have adopted different methodologies for case ascertainment, resulting in widely differing reported prevalence. Medline and Embase databases were searched using terms specific to dystonia for studies of incidence, prevalence, and epidemiology. All population‐based studies reporting an incidence and/or prevalence of primary dystonia were included. Sixteen original studies were included in our systematic review. Fifteen studies reported the prevalence of dystonia, including 12 service‐based and three population‐based studies. We performed a meta‐analysis on the results of the service‐based studies, and were able to combine data on the prevalence of several dystonia subtypes. From these studies, we calculated an overall prevalence of primary dystonia of 16.43 per 100,000 (95% confidence interval [CI]: 12.09–22.32). The prevalence of dystonia reported in the three population‐based studies appears higher than that reported in the service‐based studies. Only 1 of the 16 studies reported an incidence of cervical dystonia. This corresponded to a corrected incidence estimate of 1.07 per 100,000 person‐years (95% CI: 0.86–1.32). Despite numerous studies on the epidemiology of dystonia, attempting to determine an accurate prevalence of the condition for health services planning remains a significant challenge. Given the methodological limitations of the existing studies, our own prevalence estimate of primary dystonia likely underestimates the true prevalence of the condition. © 2012 Movement Disorder Society