Decreased dopamine D receptor binding in essential blepharospasm

Objectives – The purpose of this study was to investigate whether dopamine D₂ receptor binding was altered in the striatum of essential blepharospasm patients. Methods – Striatal dopamine D₂ receptor binding was measured with positron emission tomography and [¹¹C]raclopride. We studied eight drug‐naive patients with bilateral blepharospasm and eight age‐matched normal controls. Results – The uptake indices in the blepharospasm group were significantly reduced by 11.7% in the caudate (P < 0.005), 11.6% in the anterior putamen (P < 0.0001), and 10.3% in the posterior putamen (P < 0.005) relative to the control group. Conclusions – This study indicates decreased dopamine D₂ receptor binding in the entire striatal region of blepharospasm patients. The findings suggest that decreased dopamine D₂ receptor binding might be one of the predisposing factors that leads to the dysfunction of the motor circuit, resulting in the loss of broad inhibition of unwanted movements during an intended movement in blepharospasm patients.     

Saccade responses to dopamine in human MPTP-induced parkinsonism

Depletion of dopamine content in the substantia nigra resulting from 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine (MPTP) toxicity produces parkinsonism. Management of 3 patients with MPTP-induced parkinsonism required drug holidays during which there was a state of dopamine depletion followed by dopamine replacement. We used this opportunity to study the effect of the selective loss of pars compacta dopaminergic cells on vertical and horizontal saccade (fast) eye movements. During the drug holidays, visually guided saccades were hypometric and had long latencies but retained a normal saccade velocity-amplitude relationship. Dopamine agonists or precursors improved the accuracy and reaction times of saccades in all directions, but not their velocity. Two of the three patients also had intermittent blepharospasm during dopamine depletion. During the episodes of blepharospasm, saccade responses became slow eye movements. MPTP causes a dopaminergic-responsive disorder of saccade initiation that is similar to idiopathic parkinsonism. The inhibition of voluntary eyelid opening during MPTP-induced blepharospasm further increases this impairment of fast eye movements and altered saccade velocity, presumably via the pars reticulata of the substantia nigra.     

Assessing the role of DRD5 and DYT1 in two different case-control series with primary blepharospasm.

Primary blepharospasm is a common adult-onset focal dystonia. Polymorphisms of the genes encoding TorsinA (DYT1) and the D5 dopamine receptor (DRD5) have previously been associated with lifetime risk for focal dystonia. We describe here experiments testing common variability within these two genes in two independent cohorts of Italian and North American patients with primary blepharospasm. We have failed to identify a consistent association with disease in the two patient groups examined here; however, analysis of the Italian group reveals an association with the same risk genotype in DYT1 as previously described in an Icelandic population. We have also found global significant DYT1 haplotype differences between patients and controls in the Italian series. These data suggest that further examination is warranted of the role genetic variability at this locus plays in the risk for primary dystonia.     

Ipsilateral blepharospasm and contralateral hemidystonia and parkinsonism in a patient with a unilateral rostral brainstem-thalamic lesion: structural and functional abnormalities studied with CT, MRI, and PET scanning

A patient developed progressive right hemidystonia in childhood. Subsequently, left-sided blepharospasm, slurred and stuttering speech, and right-sided rigidity and bradykinesia, responsive to dopamine agonists, appeared. Investigation with computed tomography and magnetic resonance imaging (MRI) at age 43 years revealed a left-sided calcified rostral brainstem-thalamic lesion of uncertain aetiology. Although no structural lesion was seen in the striatal regions, L-[18F]-fluorodopa uptake was severely diminished in the left striatum but normal on the right. Dopamine receptor binding identified by [11C]-methylspiperone was in the normal range on both sides.     

Blepharospasm in a patient with thymoma and positive anti-acetylcholine receptor antibody]

We report a rare case of a 70-year-old woman diagnosed as having blepharospasm with positive anti-acetylcholine receptor antibody. Blepharospasm developed in November, 2000, and increased in frequency, and worsened toward the evening. She complained of difficulty in her eyelid opening from October, 2002. Neurological examinations revealed blepharospasm and mild ptosis in both eyes. Tensilon test was negative. Waning and waxing were not detected in bilateral orbicularis oculi muscles by Harvey-Masland test. However, anti-acetylcholine receptor antibody was positive and thymoma in the anterior mediastinum was also found by the computed tomography of the chest. After the thymectomy, frequency of blepharospasm decreased. When blepharospasm worsened toward the evening, the co-existence of myasthenia gravis should be borne in mind.     

The control of blepharospasm by essential fatty acids

Dopamine depletion induced by administration of Ro4-1284 produces a condition of rapid and repeated eye blinking in rats. This condition mimics the human disorder, blepharospasm, which often accompanies parkinsonism and other dopamine deficiency disorders. When given a 3-week course of a compound (SR-3) developed from a specific ratio of two free polyunsaturated fatty acids - linoleic acid and alpha-linolenic acid - the eye blinking rate following administration of Ro4-1284 is reduced to saline and no drug control levels. These results suggest a favorable prospect for essential fatty acids in general, and SR-3 in particular, to provide an improved therapeutic option for the clinical management of benign essential blepharospasm.     

Meige disease: striatal dopaminergic preponderance.

A dopamine agonist (apomorphine) and a cholinomimetic drug (physostigmine) were administered to five patients with blepharospasm and oromandibular dystonia (Meige disease). The effects of haloperidol and levodopa were also assessed. Apomorphine lessened and physostigmine aggravated the facial dyskinesias in all patients, while placebo injections had no consistent effect. Levodopa did not modify the symptoms, but haloperidol attentuated the facial dystonia. Dysfunction of the basal ganglia, characterized by a state of striatal dopamine preponderance, probably underlies the dystonic spasms in Meige disease. The prominent cholinergic enhancement of facial dyskinesias may distinguish this disorder pharmacologically from tardive dyskinesia, a differentiation which has practical therapeutic implications.     

Late-onset Hallervorden-Spatz disease presenting as familial parkinsonism

We studied a 68-year-old man who died after 13 years of progressive dementia, rigidity, bradykinesia, mild tremor, stooped posture, slow and shuffling gait, dystonia, blepharospasm, apraxia of eyelid opening, anarthria, aphonia, and incontinence. At autopsy, he had generalized brain atrophy with large deposits of iron pigment in the globus pallidus, caudate, and substantia nigra. Axonal spheroids were found in the globus pallidus, substantia nigra, medulla, and spinal cord. The neurochemical analysis of the brain revealed marked loss of dopamine in the nigral-striatal areas, with relative preservation of dopamine in the limbic areas. This is the oldest case of familial Hallervorden-Spatz disease reported and the first with neurochemical analysis of the brain.     

Bell's palsy-induced blepharospasm relieved by passive eyelid closure and responsive to apomorphine.

OBJECTIVE: We describe the case of a woman with Bell's Palsy-induced blepharospasm (BPIB) of the right eye that appeared simultaneously with a complete left facial nerve palsy. The involuntary spasm was relieved by passive lowering of the upper eyelid on the paretic side. METHODS: The recovery curve of the blink reflex was evaluated on the non-paretic side in baseline conditions, after subcutaneous apomorphine and placebo administration and 8 months later, at recovery from the palsy. RESULTS: We found increased recovery of the test-R2 responses at short interstimulus intervals at baseline, which was normalised by apomorphine but not by placebo. At recovery the blink reflex R2 recovery curve returned to normal. CONCLUSIONS: This report demonstrates for the first time a response of BPIB to a dopamine agonist. SIGNIFICANCE: Our findings are in agreement with an animal model of blepharospasm that suggests a combined role of weakness of the orbicularis oculi muscle and a dysfunction of the dopaminergic system in the pathogenesis of this disorder.     

Blepharospasm associated with multiple system atrophy: a case report and review of the literature

Although blepharospasm has been occasionally associated with parkinsonism, it has rarely been reported in patients with multiple system atrophy (MSA). We report a 65-year-old woman with MSA who developed blepharospasm seven years after onset, rendering her functionally blind. Clinical course and the findings of magnetic resonance imaging indicated cerebellar type MSA. The blink reflex studies showed prolonged R2 response and enhanced recovery cycle, indicating an increased excitability of the brainstem interneurons. These results suggest that pathophysiology of blepharospasm in MSA is similar to that of essential blepharospasm. Recognition of blepharospasm in MSA patients is important, as blepharospasm is a treatable feature in this otherwise intractable disorder.     

Blepharospasm 40 years later

Forty years ago, C.D. Marsden proposed that blepharospasm should be considered a form of adult‐onset focal dystonia. In the present paper, we provide a comprehensive overview of the findings regarding blepharospasm reported in the past 40 years. Although prolonged spasms of the orbicularis oculi muscles remain the clinical hallmark of blepharospasm, patients with blepharospasm may be characterized by various types of involuntary activation of periocular muscles. In addition to motor features, blepharospasm patients may also have nonmotor manifestations, including psychiatric, mild cognitive, and sensory disturbances. The various motor and nonmotor symptoms are not present in all patients, suggesting that blepharospasm is phenomenologically a heterogeneous condition. This emphasizes the need for tools for severity assessment that take into account both motor and nonmotor manifestations. The cause of blepharospasm remains elusive, but several lines of evidence indicate that blepharospasm is a multifactorial condition in which one, or several, as yet unknown genes together with epigenetic and environmental factors combine to reach the threshold of the disease. Although blepharospasm was originally believed to be solely a basal ganglia disorder, neurophysiological and neuroimaging evidence point to anatomical and functional involvement of several brain regions. The contribution of multiple areas has led to the hypothesis that blepharospasm should be considered as a network disorder, and this might reflect the varying occurrence of motor and nonmotor manifestations in blepharospasm patients. Despite advances in the aetiology and pathophysiology, treatment remains symptomatic. © 2017 International Parkinson and Movement Disorder Society     

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     

The splice variant D3nf reduces ligand binding to the D3 dopamine receptor: evidence for heterooligomerization

The D3 dopamine receptor belongs to the D2-like family of dopamine receptors. As with other members of this group, the D3 dopamine receptor gene contains introns which allow for alternative splicing of gene products. The best characterized of the human D3 dopamine receptor mRNA splice variants encodes a truncated protein called D3nf. The D3 dopamine receptor and D3nf were epitope-tagged and expressed in Sf9 insect cells by recombinant baculovirus infection. The D3 dopamine receptor showed saturable, high affinity binding of agonists and antagonists, consistent with reported D3 dopamine receptor pharmacology. When the D3 dopamine receptor and D3nf were co-expressed, the apparent density of D3 dopamine receptor expression, as determined by radioligand binding, was significantly lowered compared to D3 dopamine receptor expressed alone. This effect of D3nf was specific for the D3 dopamine receptor, since co-expression with the D2 dopamine receptor or beta2-adrenoceptor had no effect on binding. Confocal immunofluorescence studies were used to confirm that both D3 dopamine receptor and D3nf were well expressed on the cell surface and densitometric analysis of cell surface membrane protein confirmed that D3nf did not significantly alter the amount of D3 dopamine receptor expressed. Photoaffinity labelling with [125I]azidonemonapride showed that the amount of ligand bound by membranes co-expressing D3 dopamine receptor and D3nf was significantly less than that bound by membranes expressing D3 dopamine receptor alone. The greatest decrease in binding was observed in the D3 dopamine receptor oligomeric forms. Ligand binding to dimers and tetramers was reduced by 69 and 46%, respectively, indicating effects of a protein-protein interaction. Co-immunoprecipitation confirmed that the D3DR and D3nf interact with each other. These data indicate that D3nf heterodimerizes with the D3 dopamine receptor and decreases the capacity of D3 dopamine receptor to bind ligand.     

Risk factors for spread of primary adult onset blepharospasm: a multicentre investigation of the Italian movement disorders study group

OBJECTIVES: Little is known about factors influencing the spread of blepharospasm to other body parts. An investigation was carried out to deterrmine whether demographic features (sex, age at blepharospasm onset), putative risk, or protective factors for blepharospasm (family history of dystonia or tremor, previous head or face trauma with loss of consciousness, ocular diseases, and cigarette smoking), age related diseases (diabetes, hypertension), edentulousness, and neck or trunk trauma preceding the onset of blepharospasm could distinguish patients with blepharospasm who had spread of dystonia from those who did not. METHODS: 159 outpatients presenting initially with blepharospasm were selected in 16 Italian Institutions. There were 104 patients with focal blepharospasm (mean duration of disease 5.3 (SD 1.9) years) and 55 patients in whom segmental or multifocal dystonia developed (mainly in the cranial cervical area) 1.5 (1.2) years after the onset of blepharospasm. Information was obtained from a standardised questionnaire administered by medical interviewers. A Cox regression model was used to examine the relation between the investigated variables and spread. RESULTS: Previous head or face trauma with loss of consciousness, age at the onset of blepharospasm, and female sex were independently associated with an increased risk of spread. A significant association was not found between spread of dystonia and previous ocular diseases, hypertension, diabetes, neck or trunk trauma, edentulousness, cigarette smoking, and family history of dystonia or tremor. An unsatisfactory study power negatively influenced the validity and accuracy of the negative findings relative to diabetes, neck or trunk trauma, and cigarette smoking. CONCLUSIONS: The results of this exploratory study confirm that patients presenting initially with blepharospasm are most likely to experience some spread of dystonia within a few years of the onset of blepharospasm and suggest that head or face trauma with loss of consciousness preceding the onset, age at onset, and female sex may be relevant to spread. The suggested association between edentulousness and cranial cervical dystonia may be apparent because of the confounding effect of both age at onset and head or face trauma with loss of consciousness. The lack of influence of family history of dystonia on spread is consistent with previous findings indicating that the inheritance pattern is the same for focal and segmental blepharospasm.     

Idiopathic blepharospasm does not lead to a parkinsonian syndrome: results of a questionnaire-based follow-up study

It has been suggested that a lesion in the dopaminergic neurons of the substantia nigra pars compacta combined with eye irritation is involved in the pathophysiology of idiopathic blepharospasm. If so, these patients might be prone to develop Parkinson’s disease or a parkinsonian syndrome. We therefore conducted a validated questionnaire-based follow-up study to estimate (a) the frequency of local eye disorders at onset and (b) frequency of development of parkinsonian symptoms in blepharospasm patients. Ninety-nine patients previously diagnosed with idiopathic blepharospasm were sent a two-part questionnaire to assess parkinsonian and other symptoms associated with their condition. The average period of follow-up was 12.7 years, ranging from 3 to 26 years, with an average age at onset of 53.5 years. Sixty-two patients reported other ocular symptoms prior to or at the onset of blepharospasm, and therefore ocular disease may act as a trigger to produce blepharospasm in those already predisposed. Only two patients had developed a score on the parkinsonism rating scale indicating possible Parkinson’s disease, but clinical examination confirmed this not to be the case. If a lesion in the dopaminergic neurons is involved in blepharospasm, it would appear to be relatively minor (and non-progressive), since patients with idiopathic blepharospasm do not seem prone to develop parkinsonian symptoms. Received: 14 April 1998 Received in revised form: 15 July 1998 Accepted: 4 August 1998     

Blepharospasm and obsessive-compulsive disorder.

Although essential blepharospasm is considered to be a form of focal dystonia, many patients with blepharospasm have been noted to have concomitant depression, anxiety, phobias, hypochondriasis, and other emotional and behavioral disorders, suggesting a psychiatric component to the disease that is phenomenologically similar to obsessive-compulsive disorder (OCD) in terms of the repetitive, perseverative, and persistent nature of the symptoms. The Maudsley OCD questionnaire was administered to 21 patients with blepharospasm and 19 normal controls. The blepharospasm patients scored significantly higher than the controls (p less than .01). Although preliminary, the current study does support at least a phenomenological link between OCD and blepharospasm.     

Bell's palsy-induced blepharospasm

We report two patients with blepharospasm that appeared during the recovery phase of Bell's palsy. It is well known that hemifacial spasm occasionally appears after Bell's palsy; however, blepharospasm associated with Bell's palsy has been rarely reported so far. Blepharospasm appeared within a month after the onset of Bell's palsy, suggesting that a certain causal relationship may be present between Bell's palsy and blepharospasm. We speculate that corneal irritation caused by lagophthalmos contributes to the induction of blepharospasm. Another speculation is that abnormal afferent input from the paralyzed side contributes to the abnormal sensitization of the blink reflex, thereby facilitating the induction of abnormal facial motor outputs such as blepharospasm. Received: 17 May 2001, Accepted: 27 August 2001     

Tardive blepharospasm associated with cinnarizine use

OBJECTIVE: To report a patient with chronic blepharospasm possibly induced by the calcium-channel blocker cinnarizine. CASE REPORT: A 53-year-old woman developed chronic blepharospasm during a prolonged therapy with calcium-channel blocker cinnarizine for the treatment of vertigo. CONCLUSIONS: "Tardive blepharospasm" should be considered as a possible adverse effect of cinnarizine.     

Exacerbation of blepharospasm associated with craniocervical dystonia after placement of bilateral globus pallidus internus deep brain stimulator

To report a case of exacerbation of blepharospasm after bilateral globus pallidus internus (GPi) deep brain stimulator (DBS) placement. A 69‐year‐old male presented after bilateral GPi DBS placement for blepharospasm and craniocervical dystonia with worsening eyelid spasms and associated apraxia of lid opening (ALO). Numerous attempts to adjust DBS parameters were ineffective. Consequently, bilateral upper eyelid myectomy was performed. Myectomy surgery was free of complications. The patient had significant improvement of blepharospasm and ALO. Although early success has been reported with DBS placement in a small number of patients with focal dystonias, further studies and longer follow‐up are needed to demonstrate whether this will prove to be a useful approach in the treatment of blepharospasm. Upper eyelid myectomy can provide an effective means for treating blepharospasm and associated ALO. © 2008 Movement Disorder Society