Debjani Roy Chowdhury1, Sarbani Sengupta2, Bhaskar Ghosh3
Address: B R Singh Hospital & Center for Medical Education & Research, Sealdah, Kolkata 700014, India
Blepharospasm (BSP) is a form of adult onset focal dystonia characterised by involuntary closure of eye lids. It may be primary (Benign Essential blepharospasm or part of other primary dystonia ) or secondary i.e. associated with neurodegenerative disorders, dystonic cerebral palsy, tardive phenomenon, structural brain lesion, secondary to anterior segment of eye disease. Most of the cases are benign but may progress to such an extent that patient may become functionally blind in spite of having two normal eyes.
Adequate treatment is required to avoid functional blindness and other complications like corneal abrasions, dermatochalasis.
Prevalence of BSP ranges from 16-133/ million1 where as Incidence is 1.7-4.6/100,000/yr2,3. It affects female more commonly than male and usually more prevalent in 5th to 6th decades of life.
One published data from Kolkata, Eastern India shows that crude prevalence rate of BSP is 5.72/100,000 with 95% CI, all affected are female.4
BSP is characterised by bilateral symmetric, stereotyped, synchronous spasm of orbicularis oculi. Though classical manifestation is bilateral, sometimes unilateral onset makes confusion between BSP and hemifacial spasm (HFS). Up to 20% of patients have unilateral onset.5
Usually excessive blinking heralds the disease in about a third of the patient5, gradually progressing to initially clonic, later sustained tonic spasm and eventually functional blindness in some cases. Up to two third of the patients are rendered functionally blind.5 Forceful sustained contraction not only involve orbicularis oculi but often associated with contraction of corrugators and procerus and compensatory contraction of frontalis muscle.5
It is non task specific dystonia but may have some task specific aggravating (bright light, reading, watching television) or alleviating (touching the eye, upper face, pinching neck, humming, speaking, singing, yawning, sleeping, relaxing, reading, concentrating, looking down) factors.
Normal person blinks more frequently during conversation than rest. In BSP patients this pattern is reversed5. Case control study of BSP shows that blink rate both at rest and conversation is higher in BSP patients. 76% patients blink more at rest than during conversation, where as 74% control blinks more during conversation than at rest6.
BSP may be an isolated phenomenon or associated with oromandibular dystonia (Meige’s syndrome) or dystonia involving other parts like limbs, trunk, and vocal cords. Unlike idiopathic BSP which is most prominent when active, secondary BSP may persists during rest, though the rule is not universal.
Progression of BSP occurs over few months to years, then stabilizes7. It may spread beyond the orbicularis oculi. The spread of BSP beyond head region is approximately 31% much higher than the other adult onset focal dystonias like upper limb (16%), larynx (12%), neck (12%) and usually in first 2 to 5 years.8,9 Chance of spread beyond orbicularis oculi occurs in following conditions : women, young age of onset, history of significant head and face trauma with loss of consciousness.5
Increased blinking that herald BSP may be associated with some subjective sensation like burning, grittiness of eyes, dry eyes, photophobia.
Psychiatric disorders10,11 may be a part of spectrum of BSP or secondary to it. Depressions, anxiety, psychosis-at onset, before or during the course of disease are identified in 18% of patients5. Obsessive compulsive disorder is significantly higher in BSP patients compared to HFS. Coexistence of psychogenic disorder may erroneously label BSP as psychogenic disorder, though psychogenic form of BSP is extremely rare.5 Impairment in working memory, information processing speed, set shifting12 is also found in detailed cognitive testing. Association with sleep disorder13 correlates not with severity of BSP but with depression.
Many neurological conditions may mimic BSP.
Common differentials include:
1. Eye lid tics: It is usually suppressible. Association with other motor, phonic tic is common. It may be clonic (70%) i.e. transient, ill sustained or tonic (15%) i.e. sustained.5
2. HFS: Common differential when onset of BSP is unilateral which is up to 20%.
3. Facial chorea: Oro-linguo-mandibular chorea is the common manifestation. History of drug intake or association with degenerative chorea should be looked into.
4. Eyelid apraxia: May be associated with BSP, Parkinson disease or Progressive supraneuclear palsy, even can be seen in isolation14. The mechanism is failure of Levator palpebrae contraction. It is demonstrated by the absence of EMG activity of Levator muscle despite an attempt of the patient to open the eye. Diagnosis of apraxia should be thought of when Botolinum toxin (BoNT) fails to improve BSP despite the production of eye lid weakness.
5. Ptosis due to myasthenia: History of fatigability, diurnal variation is the key differentiating features. Relevant investigations are Ice pack test, Repetitive nerve stimulation test, Single fibre EMG and antibody testing.
6. Aberrant regeneration of facial nerve: There is history of prior facial palsy, usually unilateral. May involve lower face.
7. Facial myokemia: There is flickering of muscles from frontalis to platysma. May be associated with intra – axial (multiple sclerosis, tumour), extra – axial (Guillain Barre Syndrome) lesions involving facial motor nucleus or facial nerve respectively.
8. Blepharo clonus: Resembles tremor, present during gentle closure of eye lid, associated with multiple sclerosis, obstructive hydrocephalous, Arnold-Chiari malformation.
9. Oculomasticatory myorrhythmia of Whipple disease: This is characterised by rhythmic contraction of eye lid, face, mouth with convergent eye oscillation associated with contraction of neck, pharyngeal, proximal distal musculature.
Etiology of BSP:
BSP may be primary or secondary5. The former may be seen in isolation or as a part of other primary dystonia.
A. Primary :
1. Benign essential BSP
2. Association with other primary dystonia
a. Classical Oppenheim dystonia (DYT1)
b. Childhood and adult onset cranial-cervical-limb dystonia (DYT6)
c. Adult onset cervical and other focal dystonia (DYT7)
d. Adult onset cranial- cervical dystonia (DYT13)
1. Associated with neurodegenerative disorder:
a. Sporadic :
i. Parkinson disease
ii. Progressive supraneuclear palsy
iii. Multisystem atrophy
b. Inherited :
i. Dystonia plus syndromes
ii. Tourette syndrome
iii. Wilson disease
iv. Huntington disease
v. Neuro degeneration with brain Iron accumulation
vi. Spinocerebellar ataxias (SCA) -SCA-3,SCA6,SCA16,SCA17
2. Associated with metabolic disease :
a. Gluteric academia
b. Metachromatic leukodystrophy
c. Lesch-Nyhan syndrome
d. Mitochondrial encephalopathy
e. Leigh disease
3. Specific causes :
a. Perinatal cerebral injury
i. Athetoid cerebral palsy
ii. Delayed onset dystonia
i. Dopa blocker
viii. Calcium channel blockers (flunarizine, cinarizine)
d. CNS infection
i. Viral encephalitis
ii. Reye syndrome
iii. Subacute sclerosing panencephalitis
iv. Creutzfeldt Jakob disease
e. CNS lesions involving rostral brain stem, thalamus, basal ganglia
iii. Arteriovenous malformation
iv. Multiple sclerosis
f. Ophthalmological causes
i. Sjogren syndrome
Tardive dystonia is probably the most common cause of secondary dystonia including BSP 5. BSP may be the initial presentation of Tardive dystonia.
Current BSP scales falls into three categories:
1. Clinical scales :
Jankovic rating scale15 is the most widely used current clinical scale. It has two subscales with 5 points (0-4) in each measuring frequency and severity. Simplicity and broad applicability are the major advantages. Disadvantages are lack of sensitivity to small changes in severity and frequency and omission of activity of daily living criteria.
2. Activity of daily living scale :
BSP Disability Scale (BDS) developed by Fahn emerged as useful functional disability rating scale in 1985. Lack of a “non applicable” option lead to the development of BSP disability index (BSDI)16 later on.
Considering recent emphasis on quality of life assessment, Craniocervical dystonia questionnaire (CDQ-24) is worth mentioning. It is made for evaluating the effect of BoNT on BSP and cervical dystonia.17
3. Global rating scale:
It is usually general rather than disease specific, designed to capture the overall subjective effects of treatment. This scales can be physician or patient rated. Mainly used in secondary outcome assessment.
Pathophysiology of BSP can be explained by general pathophysiology of dystonia. Possible hypothesis incudes
1. Loss of inhibition in brain
Recovery cycle of R2 of blink reflex is enhanced owing to lack of brainstem interneuronal inhibition.
Pairs of supraorbital stimulus are applied either 100ms or 200ms apart in normal and BSP patients. The conditioning stimulus (C) elicits the typical blink reflex composed of R1 and R2 response. Test stimulus (T) does not elicit any R2 response in healthy control in either 100ms as well as in 200ms reflecting lack of excitability at such short interval. The test stimulus elicits a R2 response in the patient, larger with the interval of 200ms reflecting enhanced blink reflex excitability characteristic of BSP.18 (Figure -1).
One Indian study showed the amplitude of R1, R2 and contra lateral R2 were higher in BSP patients. Following Botulinum toxin therapy there was a reduction in amplitude (p<0.001) and prolongation of R2 latency (p<0.5). The ratio of blink reflex amplitude/compound muscle action potential amplitude of orbicularis oculi showed a significant decline after BoNT therapy.19
2. Excessive neuronal plasticity.
3. Defect in sensory motor integration.
Association of numerous sensory tricks may be an explanation of this theory.
Genetic predisposition :
Frequent association of BSP with other dystonias, family history of dystonia and association with essential tremor lead to the hypothesis that BSP may have some genetic predisposition. In a study of 56 families with BSP, 27% of index cases had first degree relatives with BSP.
MRI brain in BSP patients is essentially normal unless secondary. Volumetric studies have shown some findings though contradicting, in patients with BSP. Few studies observed an increase in grey matter volume (GMV) of putamen and reduction of left inferior parietal lobe GMV compared to control21, 22 whereas another study found a reduction of GMV of putamen and thalamus bilaterally but symmetrical increase in GMV of caudate head and cerebellum.23
A functional study demonstrated increased glucose metabolism in striatum and thalamus.24
BoNT is the most commonly used effective therapy of BSP. Review in 2013 gave a level-A recommendation for BoNT-A (ona, inco), level-B recommendation for BoNT-A (abo) and level –U recommendation for BoNT-B (rima).25
BoNT can be given in pre tarsal, pre orbital and pre septal part of eye lids. Pre tarsal injection is painful but has fewer side effects. It is now considered to be the best method, in terms of higher response and long lasting maximum effect, for treatment of BSP and eye lid apraxia. Dose range of BoNT-A per session ranges from 25-50 U to as high as 100 U for Onabotulinum toxin A, 100-240 U for Incobotulinum toxin A. Treatment interval is approximately 3-4 months. Four sites are chosen around the eyes. Numbers of injections can be increased in lateral canthus depending on clinical situation. In severe BSP nearby facial muscles like corrugator, procerus and frontalis can also be injected.
Pharmacoherapy provides only partial, transient relief or not at all.
Commonly used drugs are:
1. GABA –A agonist : Benzodiazepine
2. GABA- B agonist : Baclofen
3. Anticholinergic : Trihexyphenidyl
4. Dopa depletory : Tetrabenazine
5. D4 receptor blocker : Clozapine
Tetrabenazine and Clozapine are more commonly used in drug induced BSP.
Numerous physical measures are also tried.
1. Tight band across lower forehead.
2. Tight glass with palpebral splint.
3. Dark glass during Sun exposure.
4. Avoidance of Dopamine blocking drugs.
Facial nerve lysis, orbicularis myotomies
BSP improves post operatively but recurs over years. Complications include scar, ectropion, exposure keratitis, facial asymmetry. Surgical treatment once used extensively have essentially abandoned because BoNT A is highly effective in most of the cases and does not have post operative complication.
Deep brain stimulation(DBS)
Use of DBS is very limited in BSP. Indications are following:
1. Refractory to other treatment
2. Severe tardive BSP
3. BSP as part of primary generalized dystonia.
Other treatment options under investigations:
1. Trans cranial Magnetic stimulation.
2. BoNT crème
3. Zinc supplement
5. Topical hexapeptide
Excluding the secondary causes, BSP is mostly a benign disorder though can lead to functional blindness. Till now no management is there either to cure or to halt the disease progression. BoNT, though expensive, is the most useful palliative therapy for BSP.
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