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Chronic (neuropathic) corneal pain and blepharospasm: Five case reports
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PAIN 152 (2011) 2427–2431
www.elsevier.com/locate/pain
Clinical note
Chronic (neuropathic) corneal pain and blepharospasm: Five case reports David Borsook a, Perry Rosenthal b,⇑ a b
Center for Pain and the Brain, McLean Hospital, Massachusetts General Hospital, and Children’s Hospital of Boston, Harvard Medical School, Boston, MA, USA Boston Foundation for Sight, Needham, MA, USA
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 7 March 2011 Received in revised form 1 June 2011 Accepted 7 June 2011
Keywords: Blepharospasm Cornea Neuropathic pain Confocal
a b s t r a c t Pain and focal dystonias have been associated with chronic pain conditions such as complex regional pain syndrome. Corneal pain, frequently known as ‘‘dry eye’’, may be a neuropathic pain condition with abnormalities of the nerve plexus. Here we present 5 case histories of patients with defined corneal pain (with associated neuropathic features) and objective measures of changes in the nerve plexus and associated blepharospasm. A putative relationship between pain and blepharospasm suggests potential involvement of the basal ganglia in both these conditions. Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
1. Introduction Corneal neuropathic pain and photosensitivity an under-recognized disorder [54], may be associated with focal facial dystonias, particularly blepharospasm [21], which is defined as the involuntary bilateral spasmodic closing of the eyelids [12]. Approximately 25% of blepharospasm patients report light sensitivity and symptoms and symptoms of corneal pain suggesting an association of these 2 conditions [36,50]. The notion that dystonias may be associated with pain is not new (see Section 3.3 below). Most patients with dry eye-like pain symptoms and blepharospasm experience photosensitivity which may be due to central visual neurons (ie, central visual neurons include those retinal neurons that send image information to brain regions, eg, lateral geniculate and visual cortex) and those that carry non-image-forming photic signals from the retina to other brain regions, including the thalamus [43] and trigeminal nucleus [47], exciting nociceptor centers in the interpolaris and to the caudalis regions of the spinal trigeminal nuclear complex. Specifically, projections from the cornea to the trigeminal nuclear complex have been documented in animals by a number of authors [34,35,48,63]. Thus, this type of photophobia likely represents a central process that evokes pain through activation of corneal trigeminal nociceptors [39]. The association of eye pain and focal dystonias raises the interesting question of whether ⇑ Corresponding author. Address: Boston Foundation for Sight, 464 Hillside Ave., Needham Heights, MA 02494, USA. Tel.: +1 781 726 7333. E-mail address: [email protected] (P. Rosenthal).
pain can induce brain changes responsible for dystonias. The literature is unclear on this issue except that (i) other pain conditions such as complex regional pain syndrome (CRPS) may present with dystonia, usually following the pain onset [58]; (ii) treatment of dystonias with Botox (Allergan Inc, Irvine, CA, USA) [22] and chronic bilateral pallidal stimulation is reported to help cervical dystonias and pain [29,30]. However, we are unaware of any reports that correlate blepharospasm and eye pain where the latter is evaluated on the basis of both subjective reports and objective evidence of corneal neuropathy diagnosed by in vivo confocal microscopy [49]. Furthermore, reports of evoked and spontaneous corneal pain, even in the absence of corresponding external signs of reduced tear metrics or corneal epitheliopathy, are suggestive of a neuropathic component (see Case Histories, Table 1, Fig. 1). Supportive external signs of neuropathic pain include corneal hypoesthesia as measured by the Cochet-Bonnet esthesiometer, and demonstrated by abnormal corneal nerve morphology imaged by in vivo laser scanning confocal microscopy. 2. Clinical case histories The 5 patients included in this article were selected from the patient database at the Boston Foundation for Sight as having corneal neuropathic pain (pain without corresponding signs) as the primary diagnosis and blepharospasm as the secondary diagnosis. All patients provided consent for anonymized data to be reported in a case report format. In addition, all patients underwent confocal microscopy of their corneas (Fig. 1) using methods described in the
0304-3959/$36.00 Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. doi:10.1016/j.pain.2011.06.006
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Table 1 Summary of patients with neuropathic corneal pain and blepharospasm.
a b
Patient number
Age (years)
Sex
Eye pain
Photophobia
Spontaneous pain
Corneal mechano sensitivitya
Corneal nerve abnormalitiesb
Blepharospasm
Pain/blepharospasm interactions
1
53
F
+
+
+
Decreased
+
+
2
70
M
+
+
+
Decreased
+
+
3
55
F
+
+
+
Decreased
+
+
4
57
F
+
+
+
Decreased
+
+
5
54
F
+
+
+
Decreased
+
+
Temporary resolution of pain and blepharospasm with corneal anesthesia Temporary resolution of pain and blepharospasm with corneal anesthesia Temporary resolution of pain and blepharospasm with corneal anesthesia Temporary resolution of pain and blepharospasm with corneal anesthesia; Worsening pain (scalp hyperalgesia) and dystonia None noted
Cochet Bonnet esthesiometer. Laser scanning confocal microscopy of corneal nerves.
produced by exposure to light as a result of inflammation of the anterior segment of the eye. 2.1. Patient 1 The patient is a 53-year-old woman who underwent bilateral photorefractive keratectomy (corneal surface laser ablation without flap) for high myopia from which she recovered uneventfully. Her eyes were asymptomatic for 2 years following laser surgery when she began to experience symptoms of dry eye-like pain on awakening that evolved to a burning sensation (like soap in the eyes) that, although intermittent, gradually increased in severity. She subsequently developed blepharospasm triggered by light exposure. On examination, she had decreased corneal sensitivity in the right eye (Cochet-Bonnet esthesiometry); reduced tears, but the corneal epithelium was normal (absent fluorescein staining). Corneal anesthesia suppressed symptoms of corneal pain and blepharospasm. Laser-scanning corneal confocal microscopy revealed the nerves in the subbasal plexus of both eyes to be unusually thin and sparse. Her past medical history was significant for episodic migraine (3–4 per month) and a lumpectomy (but no chemotherapy) for breast cancer. In this patient, neuropathic pain was considered because of prior trauma to the cornea, burning sensation, and decreased sensitivity, taken together with the abnormal nerve fiber morphology (Fig. 1, #1). 2.2. Patient 2
Fig. 1. Confocal microscopy of the right (OD) and left (OS) corneas of patients with neuropathic involvement of the cornea compared with a control. The fibers in the corneal basal plexus were imaged using a laser scanning confocal microscope (the HRT Rostock Cornea module confocal scanning microscope, Heidelberg Engineering). Abnormalities in corneal fiber morphology in the subbasal plexus include reduced density of axons associated with significantly increased numbers of dendritic cells, increased tortuosity, and branching.
literature [62]. Table 1 summarizes the patients’ demographics, eye pain (spontaneous or evoked with bright light, associated change in mechanical sensitivity, response to local anesthetic), and focal dystonias. In these patients we make a distinction between use the term photophobia and photoallodynia: photoallodynia refers to exacerbation of neuropathic pain triggered by sensitivity light such as occurs in migraine patients where light increases headache pain. Photophobia refers to pain or discomfort
The patient is a 70-year-old man whose eyes were asymptomatic until 2003 when, shortly after falling 12 ft. (no head injury), his eyes began to feel dry. Soon after the commencement of eye symptoms, he noted involuntary blinking and photophobia that gradually increased over the years. When first seen in 2008, he complained of severe dry eye-like pain, modest photophobia, and blepharospasm in both eyes. His eye examination was significant for scanty tear meniscus in both eyes but absent corneal fluorescein staining, marked decrease in corneal tactile sensitivity in both eyes (Cochet-Bonnet), and corneal nerves in both eyes appeared attenuated with signs of aberrant regeneration such as nerve sprouts and increased dendritic cells. Corneal anesthesia eliminated all eye symptoms temporarily, including blepharospasm. Although scleral lenses, which enclose a pool of oxygenated tears over the corneal surface, reduced dry eye-like symptoms significantly, blepharospasm progressively worsened and became associated with lid apraxia. Treatments with Botox injections became ineffective over time. Evidence for neuropathic pain included evoked pain (light) related to eye symptoms, diminished
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mechanosensitivity, and abnormal morphology of corneal nerves on confocal microscopy (Fig. 1, #2). 2.3. Patient 3 The patient is a 55-year-old woman whose eye symptoms began spontaneously 4 years previously with burning, photophobia, and blepharospasm in both eyes. Examination of her eyes was normal except for reduced tear meniscus and modest decrease in corneal tactile sensitivity. A scleral lens is a large rigid optical shell lens that rests on the sclera and vaults the cornea. The space created between the lens and cornea is filled with saline. Scleral lenses suppressed symptoms of corneal pain but did not mitigate photophobia or blepharospasm. The latter was also exacerbated by visual and auditory processing. Over time, her blepharospasm worsened and progressed to include spasms of neck/chin muscles (Meige’s syndrome), and it also occurred in total darkness. Her medical history was positive for 2 cervical diskectomies 10 years previously, radiation for carcinoma of the larynx 11 years previously, and radioactive isotope for thyroid carcinoma 6 years previously. Corneal anesthesia resolved pain symptoms and blepharospasm. Confocal microscopy of her corneas revealed increased nerve tortuosity and branching consistent with nerve regeneration (Fig. 1, #3). In addition to objective and subjective evidence of nerve damage, the lack of external signs commensurate with the photosensitivity and corneal symptoms is further support of the diagnosis of neuropathic pain. 2.4. Patient 4 The patient is a 57-year-old woman whose eye symptoms began 3 years previously with a transient episode of photosensitivity. Several months later she experienced the acute onset of ocular burning sensation, foreign body sensations and blepharospasm that were triggered by reading, computer use, light exposure, and walking. Her ocular symptoms which were mitigated by wearing scleral lenses, progressed to include hyperalgesia of her scalp and aching in her cheeks. Both eyes were normal to slit lamp examination. Tactile corneal sensitivity and nerve density were decreased, and excessive numbers of mature dendritic cells were present in both central corneas on confocal microscopy. These signs of aberrant nerve regeneration were greater in the right cornea than the left which correlated with the severity of her symptoms. Botoxrefractory blepharospasm exacerbated by light exposure and walking became virtually constant during her waking hours and her dystonia evolved to include lid apraxia. Corneal anesthesia temporarily relieved all symptoms, including blepharospasm/apraxia. Recent dental work requiring local anesthesia relieved her symptoms of eye pain and apraxia for about 24 h. Again, like the other patients, symptoms of eye burning, increased sensitivity hyperalgesia of the surrounding skin, and abnormal corneal nerve morphology (Fig. 1, #4) all support a possible neuropathic pain condition. 2.5. Patient 5 This 54-year-old woman noted blepharospasm involving her left lids while watching television 2 years previously that resolved spontaneously after several weeks. Shortly afterward she experienced the sudden onset of photosensitivity on awakening one morning, associated with severe headache in the posterior vertex skull area that radiated to the top of her head. Exposure to light triggered blepharospasm and aching of her eyes. Subsequently, she experienced a dry, burning sensation in her eyes that gradually intensified over time and was unresponsive to aggressive eye lubrication. She also reported episodes of paresthesia in her left leg, arm, and face. She carried a diagnosis of secondary Sjögren
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syndrome based on joint pains and magnetic resonance imaging of her hands that showed changes typical of rheumatoid arthritis (her sister suffers from rheumatoid arthritis). External examination of her eyes was within normal limits. Tactile corneal sensitivity was depressed in both eyes. Corneal laser scanning confocal microscopy revealed changes in the morphology of the nerves of the subbasal plexus of both corneas consistent with nerve regeneration (Fig. 1, #5). She reported hyperalgesia of the skin of her left forehead, neck, and ear. Total corneal anesthesia did not fully relieve her cornea-projected pain. No note was made of its effect on blepharospasm. Patient 5 had an onset of photophobia, burning, and alterations in corneal nerve integrity in addition to having a systemic disease associated with neuropathic pain. 3. Discussion Based on chronicity, absence of external findings (other than mild reduction in tear supply), decrease corneal sensitivity and morphometric changes in their corneal nerves, it is clear that these patients suffer from neuropathic corneal pain that is distinct from but temporally associated with blepharospasm. All patients in this cohort demonstrated objective and subjective evidence of corneal neuropathy (Table 1). Moreover, other than corneal anesthesia, treatments that mitigated symptoms of cornea-projected pain failed to improve blepharospasm. In CRPS patients, dystonia usually follows pain [64]. In this cohort, there was no clear pattern as to whether the onset of pain preceded or followed that of blepharospasm, and while associated, the relationship is not one of cause and effect. An association between dry eye-like pain and blepharospasm has been previously reported [36]. Some medical conditions such as Sjögren syndrome, a chronic inflammatory disorder of unknown origin [65], are frequently associated with symptoms of dry eye [42]. We believe that this is the first report of pathology in the corneal nerves similar to those observed in skin biopsies in patients with neuropathic pain that in some patients clearly preceded the onset of blepharospasm. 3.1. Corneal neuropathic pain and photoallodynia The evidence for nerve injury in the 5 patients was based on history, examination, and confocal microscopy. 3.1.1. Pain symptoms and signs All patients complained of dry eye-like symptoms, and spontaneous pain; the pain was exacerbated by bright light (photoallodynia). In addition, there was diminished corneal sensation, even in the context of ongoing discomfort. As such, these symptoms resemble those of neuropathic pain affecting the skin, where pain can be evoked by normally nonnoxious stimuli (eg, brush) even in the context of decreased sensation [2]. 3.1.2. Photoallodynia In contrast to photophobia which causes eye ache on exposure to non-noxious levels of light and is caused by inflammation of the anterior segment of the eye, photoallodynia refers to the phenomenon in which light exposure triggers or exacerbates symptoms of neuropathic eye pain similar to migraineurs in whom light exposure exacerbates the headache. Light has been shown to activate a trigeminal pathway in humans [37] and in rats [47]. In the latter study, the data suggest that non-imaging-forming light can activate the trigeminal system through a luminescent-sensitive pathway originating in the retina and passing along the optic nerve and through the trigeminal root ganglion. Unlike photophobia that is initiated and sustained by corneal and iris inflammation, photosensitivity associated with corneal neuropathic pain has its genesis
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in the central nervous system, similar to the photosensitivity associated with migrainous headaches [43], lesions of the chiasm [44], etc, in which externally visible triggers of photophobia are absent. The authors suggest the term ‘‘photoallodynia’’ for this neurological type of photosensitivity in which light exposure triggers/exacerbates the patient’s particular ocular neuropathic pain and is not relieved by cycloplegia. This is consistent with the findings of a non-image-transmitting, luminescent-sensitive circuit beginning in the retina and terminating in the trigeminal nucleus [44]. 3.1.3. Abnormal confocal microscopy In vivo corneal confocal microscopy can image corneal nerves [1,13]. Abnormalities of corneal fibers have been observed in specific corneal diseases and systemic diseases that effect corneal nerves (eg, diabetic neuropathy) [23]. Alterations in corneal nerves [13] are similar to those reported in skin biopsies of neuropathic pain conditions [32,60]. 3.1.4. Effects of local anesthetics on spontaneous and evoked pain While most patients had a temporary resolution of pain and blepharospasm with the application of a local corneal anesthetic, one did not. Local anesthetics do not always improve pain. For example, in a recent Cochrane report on the use of lidocaine patch, the applications in postherpetic neuralgia are unclear as to their efficacy [28]. The patch produces levels of analgesia similar to pregabalin [3], but only around 60% responded in each group. Such data are consistent with centralization of pain (ie, the process by which pain is exacerbated or occurs spontaneously as a result of changes in central nervous system pathways [66]) that is sustained independently of peripheral activity. Specifically, the effects of a topical local anesthetic (usually proparacaine) applied to the cornea in the form of drops last approximately 5–10 minutes. Blood levels are unmeasurable. The 5% lidocaine (700-mg) patch [11] produces measurable but low plasma levels [17]. Intravenous infusion of lidocaine has been reported to improve neuropathic pain [25] and attenuate eyelid dystonia in 21 patients for 5–7 days only [38]. In the patients described here, the local anesthetic was applied to the cornea topically. It should be noted that total corneal anesthesia is easily verified and the anesthetic drops are uniformly 100% effective. Photoallodynia may be associated with chronic corneal pain [18,61] that is not totally suppressed by total blockade of corneal afferents, suggesting that other inputs (eg, through nonimage-forming retinal cells) acting on sensitized central systems (see [44]) may be present. 3.2. Blepharospasm Clinical and biological aspects of blepharospasm have been summarized elsewhere [12,21]. Blepharospasm is believed to involve the basal ganglia based on the (i) morphometric changes in brain regions such as increased gray matter in the caudate head and cerebellum bilaterally, as well as a decrease in the putamen and thalamus bilaterally) [46], or increase in gray matter in the putamen and decrease in the left inferior parietal lobule [16]. In these patients, increased basal-ganglia activation could be demonstrated in tasks not primarily involving the musculature affected by blepharospasm [45]. Moreover, oscillatory local field potentials from deep brain stimulation electrodes implanted in the pallidum of dystonic patients correlate with the electromyogram recordings [6]. Blepharospasm can be associated with a constellation of symptoms such as involuntary movements of the platysma, lower face, and masticatory muscles – called Meige’s syndrome [33]. Many patients report a stressful event prior to developing blepharospasm [50], and anxiety may be a contributing factor to developing blepharospasm [20], in particular, obsessive compulsive disorder [14].
The blink reflex involves specific trigeminal circuits [51]. It is a protective mechanism that can be elicited by pain in trigeminal afferents and is altered in a number of diseases [15,26]. Of note is its relationship to the basal ganglia, since damage to these structures or changes in dopaminergic systems alters the blink reflex [59]. Ineffective blink reflex in blepharospasm may increase corneal exposure, resulting in corneal epithelial desiccation (see [7]). While functional magnetic resonance imaging studies report striatal activation in blepharospasm [52,57], other areas of activity including the cerebellum are also noted [24]. Positron emission tomography studies show altered glucose uptake in the cerebellar hemispheres and thalamus and caudate nucleus [27]. Taken together, it is likely that integrated circuits involving multiple regions of the brain (basal ganglia, thalamus, and cerebellum, among others) may be involved. A potential mechanism has been suggested where there is a loss of striatal dopamine that allows for increased excitability in blink circuits; an external ophthalmic insult may precipitate the process [56]. This is of note with respect to the cerebellum because of its specific connections with the basal ganglia [41], its role in the blink reflex [5], and its more general control of corticostriatal synaptic plasticity [55]. 3.3. Pain, blepharospasm, and dysregulation of basal ganglia functions Recent studies support dysfunction in the basal ganglia-thalamocortical circuits as the principal pathophysiology of pain with dystonia [10]. Chronic pain is common in diseases associated with abnormal basal ganglia function (eg, CRPS, Parkinson disease). Pain has direct and indirect inputs into the basal ganglia and affects cortical and thalamic circuits [4]. How does pain drive these circuits to produce dystonia or modify circuits that unmask dystonia in susceptible individuals? Basal ganglia respond directly to painful stimuli [8,9], and these brain regions are frequently activated in acute and chronic pain imaging studies [4]. Dystonia is also associated with a number of conditions and abnormalities of sensorimotor integration and cortical excitability [40], and is associated with a number of conditions and abnormalities of sensorimotor integration and cortical excitability [40]. Pain and blepharospasm have reportedly been suppressed by bilateral stimulation of the pallidum for dystonia associated with pain [30] and worsening of the dystonia and reemergence of pain when stimulation is stopped. In addition, supporting pain as a driver of basal ganglia dysfunction is the observation that ocular symptoms are commonly reported prior to the onset of blepharospasm [36]. 3.4. Conclusions From a biological point of view, blepharospasm is thought to involve alterations in the basal ganglia, particularly in the putamen [16]. Pain also affects basal ganglia function [4]. Peripheral trauma is an increasingly recognized trigger of dystonia [31]. Up to 12% of patients with blepharospasm report ocular trauma prior to the onset of their movement disorder [19]. The clinical evidence is supported by the theoretical construct of dopamine depletion causing disinhibition of the trigeminal blink circuit that may be triggered by afferent pain inputs onto this reflex, possibly at the level of the basal ganglia [53,56]. Conflict of interest statement Dr David Borsook and Dr Perry Rosenthal do not have any conflicts of interest to report.
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[50] Peckham EL, Lopez G, Shamim EA, Richardson SP, Sanku S, Malkani R, Stacy M, Mahant P, Crawley A, Singleton A, Hallett M. Clinical features of patients with blepharospasm: a report of 240 patients. Eur J Neurol 2011;18:382–6. [51] Pellegrini JJ, Horn AK, Evinger C. The trigeminally evoked blink reflex. I. Neuronal circuits. Exp Brain Res 1995;107:166–80. [52] Peller M, Zeuner KE, Munchau A, Quartarone A, Weiss M, Knutzen A, Hallett M, Deuschl G, Siebner HR. The basal ganglia are hyperactive during the discrimination of tactile stimuli in writer’s cramp. Brain 2006;129:2697–708. [53] Powers AS, Schicatano EJ, Basso MA, Evinger C. To blink or not to blink: inhibition and facilitation of reflex blinks. Exp Brain Res 1997;113:283–90. [54] Rosenthal P, Baran I, Jacobs DS. Corneal pain without stain: is it real? Ocul Surf 2009;7:28–40. [55] Rossi S, Mataluni G, De Bartolo P, Prosperetti C, Foti F, De Chiara V, Musella A, Mandolesi L, Bernardi G, Centonze D, Petrosini L. Cerebellar control of corticostriatal LTD. Restor Neurol Neurosci 2008;26:475–80. [56] Schicatano EJ, Basso MA, Evinger C. Animal model explains the origins of the cranial dystonia benign essential blepharospasm. J Neurophysiol 1997;77:2842–6. [57] Schmidt KE, Linden DE, Goebel R, Zanella FE, Lanfermann H, Zubcov AA. Striatal activation during blepharospasm revealed by fMRI. Neurology 2003;60:1738–43. [58] Schwartzman RJ, Kerrigan J. The movement disorder of reflex sympathetic dystrophy. Neurology 1990;40:57–61. [59] Schwingenschuh P, Katschnig P, Edwards MJ, Teo JT, Korlipara LV, Rothwell JC, Bhatia KP. The blink reflex recovery cycle differs between essential and presumed psychogenic blepharospasm. Neurology 2011;76:610–4. [60] Sommer C. Skin biopsy as a diagnostic tool. Curr Opin Neurol 2008;21:563–8. [61] Tabbara KF, Sharara N. Dry eye syndrome. Drugs Today (Barc) 1998;34:447–53. [62] Tavakoli M, Malik RA. 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PAIN 152 (2011) 2427–2431
www.elsevier.com/locate/pain
Clinical note
Chronic (neuropathic) corneal pain and blepharospasm: Five case reports David Borsook a, Perry Rosenthal b,⇑ a b
Center for Pain and the Brain, McLean Hospital, Massachusetts General Hospital, and Children’s Hospital of Boston, Harvard Medical School, Boston, MA, USA Boston Foundation for Sight, Needham, MA, USA
Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.
a r t i c l e
i n f o
Article history: Received 7 March 2011 Received in revised form 1 June 2011 Accepted 7 June 2011
Keywords: Blepharospasm Cornea Neuropathic pain Confocal
a b s t r a c t Pain and focal dystonias have been associated with chronic pain conditions such as complex regional pain syndrome. Corneal pain, frequently known as ‘‘dry eye’’, may be a neuropathic pain condition with abnormalities of the nerve plexus. Here we present 5 case histories of patients with defined corneal pain (with associated neuropathic features) and objective measures of changes in the nerve plexus and associated blepharospasm. A putative relationship between pain and blepharospasm suggests potential involvement of the basal ganglia in both these conditions. Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain.
1. Introduction Corneal neuropathic pain and photosensitivity an under-recognized disorder [54], may be associated with focal facial dystonias, particularly blepharospasm [21], which is defined as the involuntary bilateral spasmodic closing of the eyelids [12]. Approximately 25% of blepharospasm patients report light sensitivity and symptoms and symptoms of corneal pain suggesting an association of these 2 conditions [36,50]. The notion that dystonias may be associated with pain is not new (see Section 3.3 below). Most patients with dry eye-like pain symptoms and blepharospasm experience photosensitivity which may be due to central visual neurons (ie, central visual neurons include those retinal neurons that send image information to brain regions, eg, lateral geniculate and visual cortex) and those that carry non-image-forming photic signals from the retina to other brain regions, including the thalamus [43] and trigeminal nucleus [47], exciting nociceptor centers in the interpolaris and to the caudalis regions of the spinal trigeminal nuclear complex. Specifically, projections from the cornea to the trigeminal nuclear complex have been documented in animals by a number of authors [34,35,48,63]. Thus, this type of photophobia likely represents a central process that evokes pain through activation of corneal trigeminal nociceptors [39]. The association of eye pain and focal dystonias raises the interesting question of whether ⇑ Corresponding author. Address: Boston Foundation for Sight, 464 Hillside Ave., Needham Heights, MA 02494, USA. Tel.: +1 781 726 7333. E-mail address: [email protected] (P. Rosenthal).
pain can induce brain changes responsible for dystonias. The literature is unclear on this issue except that (i) other pain conditions such as complex regional pain syndrome (CRPS) may present with dystonia, usually following the pain onset [58]; (ii) treatment of dystonias with Botox (Allergan Inc, Irvine, CA, USA) [22] and chronic bilateral pallidal stimulation is reported to help cervical dystonias and pain [29,30]. However, we are unaware of any reports that correlate blepharospasm and eye pain where the latter is evaluated on the basis of both subjective reports and objective evidence of corneal neuropathy diagnosed by in vivo confocal microscopy [49]. Furthermore, reports of evoked and spontaneous corneal pain, even in the absence of corresponding external signs of reduced tear metrics or corneal epitheliopathy, are suggestive of a neuropathic component (see Case Histories, Table 1, Fig. 1). Supportive external signs of neuropathic pain include corneal hypoesthesia as measured by the Cochet-Bonnet esthesiometer, and demonstrated by abnormal corneal nerve morphology imaged by in vivo laser scanning confocal microscopy. 2. Clinical case histories The 5 patients included in this article were selected from the patient database at the Boston Foundation for Sight as having corneal neuropathic pain (pain without corresponding signs) as the primary diagnosis and blepharospasm as the secondary diagnosis. All patients provided consent for anonymized data to be reported in a case report format. In addition, all patients underwent confocal microscopy of their corneas (Fig. 1) using methods described in the
0304-3959/$36.00 Ó 2011 Published by Elsevier B.V. on behalf of International Association for the Study of Pain. doi:10.1016/j.pain.2011.06.006
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Table 1 Summary of patients with neuropathic corneal pain and blepharospasm.
a b
Patient number
Age (years)
Sex
Eye pain
Photophobia
Spontaneous pain
Corneal mechano sensitivitya
Corneal nerve abnormalitiesb
Blepharospasm
Pain/blepharospasm interactions
1
53
F
+
+
+
Decreased
+
+
2
70
M
+
+
+
Decreased
+
+
3
55
F
+
+
+
Decreased
+
+
4
57
F
+
+
+
Decreased
+
+
5
54
F
+
+
+
Decreased
+
+
Temporary resolution of pain and blepharospasm with corneal anesthesia Temporary resolution of pain and blepharospasm with corneal anesthesia Temporary resolution of pain and blepharospasm with corneal anesthesia Temporary resolution of pain and blepharospasm with corneal anesthesia; Worsening pain (scalp hyperalgesia) and dystonia None noted
Cochet Bonnet esthesiometer. Laser scanning confocal microscopy of corneal nerves.
produced by exposure to light as a result of inflammation of the anterior segment of the eye. 2.1. Patient 1 The patient is a 53-year-old woman who underwent bilateral photorefractive keratectomy (corneal surface laser ablation without flap) for high myopia from which she recovered uneventfully. Her eyes were asymptomatic for 2 years following laser surgery when she began to experience symptoms of dry eye-like pain on awakening that evolved to a burning sensation (like soap in the eyes) that, although intermittent, gradually increased in severity. She subsequently developed blepharospasm triggered by light exposure. On examination, she had decreased corneal sensitivity in the right eye (Cochet-Bonnet esthesiometry); reduced tears, but the corneal epithelium was normal (absent fluorescein staining). Corneal anesthesia suppressed symptoms of corneal pain and blepharospasm. Laser-scanning corneal confocal microscopy revealed the nerves in the subbasal plexus of both eyes to be unusually thin and sparse. Her past medical history was significant for episodic migraine (3–4 per month) and a lumpectomy (but no chemotherapy) for breast cancer. In this patient, neuropathic pain was considered because of prior trauma to the cornea, burning sensation, and decreased sensitivity, taken together with the abnormal nerve fiber morphology (Fig. 1, #1). 2.2. Patient 2
Fig. 1. Confocal microscopy of the right (OD) and left (OS) corneas of patients with neuropathic involvement of the cornea compared with a control. The fibers in the corneal basal plexus were imaged using a laser scanning confocal microscope (the HRT Rostock Cornea module confocal scanning microscope, Heidelberg Engineering). Abnormalities in corneal fiber morphology in the subbasal plexus include reduced density of axons associated with significantly increased numbers of dendritic cells, increased tortuosity, and branching.
literature [62]. Table 1 summarizes the patients’ demographics, eye pain (spontaneous or evoked with bright light, associated change in mechanical sensitivity, response to local anesthetic), and focal dystonias. In these patients we make a distinction between use the term photophobia and photoallodynia: photoallodynia refers to exacerbation of neuropathic pain triggered by sensitivity light such as occurs in migraine patients where light increases headache pain. Photophobia refers to pain or discomfort
The patient is a 70-year-old man whose eyes were asymptomatic until 2003 when, shortly after falling 12 ft. (no head injury), his eyes began to feel dry. Soon after the commencement of eye symptoms, he noted involuntary blinking and photophobia that gradually increased over the years. When first seen in 2008, he complained of severe dry eye-like pain, modest photophobia, and blepharospasm in both eyes. His eye examination was significant for scanty tear meniscus in both eyes but absent corneal fluorescein staining, marked decrease in corneal tactile sensitivity in both eyes (Cochet-Bonnet), and corneal nerves in both eyes appeared attenuated with signs of aberrant regeneration such as nerve sprouts and increased dendritic cells. Corneal anesthesia eliminated all eye symptoms temporarily, including blepharospasm. Although scleral lenses, which enclose a pool of oxygenated tears over the corneal surface, reduced dry eye-like symptoms significantly, blepharospasm progressively worsened and became associated with lid apraxia. Treatments with Botox injections became ineffective over time. Evidence for neuropathic pain included evoked pain (light) related to eye symptoms, diminished
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mechanosensitivity, and abnormal morphology of corneal nerves on confocal microscopy (Fig. 1, #2). 2.3. Patient 3 The patient is a 55-year-old woman whose eye symptoms began spontaneously 4 years previously with burning, photophobia, and blepharospasm in both eyes. Examination of her eyes was normal except for reduced tear meniscus and modest decrease in corneal tactile sensitivity. A scleral lens is a large rigid optical shell lens that rests on the sclera and vaults the cornea. The space created between the lens and cornea is filled with saline. Scleral lenses suppressed symptoms of corneal pain but did not mitigate photophobia or blepharospasm. The latter was also exacerbated by visual and auditory processing. Over time, her blepharospasm worsened and progressed to include spasms of neck/chin muscles (Meige’s syndrome), and it also occurred in total darkness. Her medical history was positive for 2 cervical diskectomies 10 years previously, radiation for carcinoma of the larynx 11 years previously, and radioactive isotope for thyroid carcinoma 6 years previously. Corneal anesthesia resolved pain symptoms and blepharospasm. Confocal microscopy of her corneas revealed increased nerve tortuosity and branching consistent with nerve regeneration (Fig. 1, #3). In addition to objective and subjective evidence of nerve damage, the lack of external signs commensurate with the photosensitivity and corneal symptoms is further support of the diagnosis of neuropathic pain. 2.4. Patient 4 The patient is a 57-year-old woman whose eye symptoms began 3 years previously with a transient episode of photosensitivity. Several months later she experienced the acute onset of ocular burning sensation, foreign body sensations and blepharospasm that were triggered by reading, computer use, light exposure, and walking. Her ocular symptoms which were mitigated by wearing scleral lenses, progressed to include hyperalgesia of her scalp and aching in her cheeks. Both eyes were normal to slit lamp examination. Tactile corneal sensitivity and nerve density were decreased, and excessive numbers of mature dendritic cells were present in both central corneas on confocal microscopy. These signs of aberrant nerve regeneration were greater in the right cornea than the left which correlated with the severity of her symptoms. Botoxrefractory blepharospasm exacerbated by light exposure and walking became virtually constant during her waking hours and her dystonia evolved to include lid apraxia. Corneal anesthesia temporarily relieved all symptoms, including blepharospasm/apraxia. Recent dental work requiring local anesthesia relieved her symptoms of eye pain and apraxia for about 24 h. Again, like the other patients, symptoms of eye burning, increased sensitivity hyperalgesia of the surrounding skin, and abnormal corneal nerve morphology (Fig. 1, #4) all support a possible neuropathic pain condition. 2.5. Patient 5 This 54-year-old woman noted blepharospasm involving her left lids while watching television 2 years previously that resolved spontaneously after several weeks. Shortly afterward she experienced the sudden onset of photosensitivity on awakening one morning, associated with severe headache in the posterior vertex skull area that radiated to the top of her head. Exposure to light triggered blepharospasm and aching of her eyes. Subsequently, she experienced a dry, burning sensation in her eyes that gradually intensified over time and was unresponsive to aggressive eye lubrication. She also reported episodes of paresthesia in her left leg, arm, and face. She carried a diagnosis of secondary Sjögren
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syndrome based on joint pains and magnetic resonance imaging of her hands that showed changes typical of rheumatoid arthritis (her sister suffers from rheumatoid arthritis). External examination of her eyes was within normal limits. Tactile corneal sensitivity was depressed in both eyes. Corneal laser scanning confocal microscopy revealed changes in the morphology of the nerves of the subbasal plexus of both corneas consistent with nerve regeneration (Fig. 1, #5). She reported hyperalgesia of the skin of her left forehead, neck, and ear. Total corneal anesthesia did not fully relieve her cornea-projected pain. No note was made of its effect on blepharospasm. Patient 5 had an onset of photophobia, burning, and alterations in corneal nerve integrity in addition to having a systemic disease associated with neuropathic pain. 3. Discussion Based on chronicity, absence of external findings (other than mild reduction in tear supply), decrease corneal sensitivity and morphometric changes in their corneal nerves, it is clear that these patients suffer from neuropathic corneal pain that is distinct from but temporally associated with blepharospasm. All patients in this cohort demonstrated objective and subjective evidence of corneal neuropathy (Table 1). Moreover, other than corneal anesthesia, treatments that mitigated symptoms of cornea-projected pain failed to improve blepharospasm. In CRPS patients, dystonia usually follows pain [64]. In this cohort, there was no clear pattern as to whether the onset of pain preceded or followed that of blepharospasm, and while associated, the relationship is not one of cause and effect. An association between dry eye-like pain and blepharospasm has been previously reported [36]. Some medical conditions such as Sjögren syndrome, a chronic inflammatory disorder of unknown origin [65], are frequently associated with symptoms of dry eye [42]. We believe that this is the first report of pathology in the corneal nerves similar to those observed in skin biopsies in patients with neuropathic pain that in some patients clearly preceded the onset of blepharospasm. 3.1. Corneal neuropathic pain and photoallodynia The evidence for nerve injury in the 5 patients was based on history, examination, and confocal microscopy. 3.1.1. Pain symptoms and signs All patients complained of dry eye-like symptoms, and spontaneous pain; the pain was exacerbated by bright light (photoallodynia). In addition, there was diminished corneal sensation, even in the context of ongoing discomfort. As such, these symptoms resemble those of neuropathic pain affecting the skin, where pain can be evoked by normally nonnoxious stimuli (eg, brush) even in the context of decreased sensation [2]. 3.1.2. Photoallodynia In contrast to photophobia which causes eye ache on exposure to non-noxious levels of light and is caused by inflammation of the anterior segment of the eye, photoallodynia refers to the phenomenon in which light exposure triggers or exacerbates symptoms of neuropathic eye pain similar to migraineurs in whom light exposure exacerbates the headache. Light has been shown to activate a trigeminal pathway in humans [37] and in rats [47]. In the latter study, the data suggest that non-imaging-forming light can activate the trigeminal system through a luminescent-sensitive pathway originating in the retina and passing along the optic nerve and through the trigeminal root ganglion. Unlike photophobia that is initiated and sustained by corneal and iris inflammation, photosensitivity associated with corneal neuropathic pain has its genesis
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in the central nervous system, similar to the photosensitivity associated with migrainous headaches [43], lesions of the chiasm [44], etc, in which externally visible triggers of photophobia are absent. The authors suggest the term ‘‘photoallodynia’’ for this neurological type of photosensitivity in which light exposure triggers/exacerbates the patient’s particular ocular neuropathic pain and is not relieved by cycloplegia. This is consistent with the findings of a non-image-transmitting, luminescent-sensitive circuit beginning in the retina and terminating in the trigeminal nucleus [44]. 3.1.3. Abnormal confocal microscopy In vivo corneal confocal microscopy can image corneal nerves [1,13]. Abnormalities of corneal fibers have been observed in specific corneal diseases and systemic diseases that effect corneal nerves (eg, diabetic neuropathy) [23]. Alterations in corneal nerves [13] are similar to those reported in skin biopsies of neuropathic pain conditions [32,60]. 3.1.4. Effects of local anesthetics on spontaneous and evoked pain While most patients had a temporary resolution of pain and blepharospasm with the application of a local corneal anesthetic, one did not. Local anesthetics do not always improve pain. For example, in a recent Cochrane report on the use of lidocaine patch, the applications in postherpetic neuralgia are unclear as to their efficacy [28]. The patch produces levels of analgesia similar to pregabalin [3], but only around 60% responded in each group. Such data are consistent with centralization of pain (ie, the process by which pain is exacerbated or occurs spontaneously as a result of changes in central nervous system pathways [66]) that is sustained independently of peripheral activity. Specifically, the effects of a topical local anesthetic (usually proparacaine) applied to the cornea in the form of drops last approximately 5–10 minutes. Blood levels are unmeasurable. The 5% lidocaine (700-mg) patch [11] produces measurable but low plasma levels [17]. Intravenous infusion of lidocaine has been reported to improve neuropathic pain [25] and attenuate eyelid dystonia in 21 patients for 5–7 days only [38]. In the patients described here, the local anesthetic was applied to the cornea topically. It should be noted that total corneal anesthesia is easily verified and the anesthetic drops are uniformly 100% effective. Photoallodynia may be associated with chronic corneal pain [18,61] that is not totally suppressed by total blockade of corneal afferents, suggesting that other inputs (eg, through nonimage-forming retinal cells) acting on sensitized central systems (see [44]) may be present. 3.2. Blepharospasm Clinical and biological aspects of blepharospasm have been summarized elsewhere [12,21]. Blepharospasm is believed to involve the basal ganglia based on the (i) morphometric changes in brain regions such as increased gray matter in the caudate head and cerebellum bilaterally, as well as a decrease in the putamen and thalamus bilaterally) [46], or increase in gray matter in the putamen and decrease in the left inferior parietal lobule [16]. In these patients, increased basal-ganglia activation could be demonstrated in tasks not primarily involving the musculature affected by blepharospasm [45]. Moreover, oscillatory local field potentials from deep brain stimulation electrodes implanted in the pallidum of dystonic patients correlate with the electromyogram recordings [6]. Blepharospasm can be associated with a constellation of symptoms such as involuntary movements of the platysma, lower face, and masticatory muscles – called Meige’s syndrome [33]. Many patients report a stressful event prior to developing blepharospasm [50], and anxiety may be a contributing factor to developing blepharospasm [20], in particular, obsessive compulsive disorder [14].
The blink reflex involves specific trigeminal circuits [51]. It is a protective mechanism that can be elicited by pain in trigeminal afferents and is altered in a number of diseases [15,26]. Of note is its relationship to the basal ganglia, since damage to these structures or changes in dopaminergic systems alters the blink reflex [59]. Ineffective blink reflex in blepharospasm may increase corneal exposure, resulting in corneal epithelial desiccation (see [7]). While functional magnetic resonance imaging studies report striatal activation in blepharospasm [52,57], other areas of activity including the cerebellum are also noted [24]. Positron emission tomography studies show altered glucose uptake in the cerebellar hemispheres and thalamus and caudate nucleus [27]. Taken together, it is likely that integrated circuits involving multiple regions of the brain (basal ganglia, thalamus, and cerebellum, among others) may be involved. A potential mechanism has been suggested where there is a loss of striatal dopamine that allows for increased excitability in blink circuits; an external ophthalmic insult may precipitate the process [56]. This is of note with respect to the cerebellum because of its specific connections with the basal ganglia [41], its role in the blink reflex [5], and its more general control of corticostriatal synaptic plasticity [55]. 3.3. Pain, blepharospasm, and dysregulation of basal ganglia functions Recent studies support dysfunction in the basal ganglia-thalamocortical circuits as the principal pathophysiology of pain with dystonia [10]. Chronic pain is common in diseases associated with abnormal basal ganglia function (eg, CRPS, Parkinson disease). Pain has direct and indirect inputs into the basal ganglia and affects cortical and thalamic circuits [4]. How does pain drive these circuits to produce dystonia or modify circuits that unmask dystonia in susceptible individuals? Basal ganglia respond directly to painful stimuli [8,9], and these brain regions are frequently activated in acute and chronic pain imaging studies [4]. Dystonia is also associated with a number of conditions and abnormalities of sensorimotor integration and cortical excitability [40], and is associated with a number of conditions and abnormalities of sensorimotor integration and cortical excitability [40]. Pain and blepharospasm have reportedly been suppressed by bilateral stimulation of the pallidum for dystonia associated with pain [30] and worsening of the dystonia and reemergence of pain when stimulation is stopped. In addition, supporting pain as a driver of basal ganglia dysfunction is the observation that ocular symptoms are commonly reported prior to the onset of blepharospasm [36]. 3.4. Conclusions From a biological point of view, blepharospasm is thought to involve alterations in the basal ganglia, particularly in the putamen [16]. Pain also affects basal ganglia function [4]. Peripheral trauma is an increasingly recognized trigger of dystonia [31]. Up to 12% of patients with blepharospasm report ocular trauma prior to the onset of their movement disorder [19]. The clinical evidence is supported by the theoretical construct of dopamine depletion causing disinhibition of the trigeminal blink circuit that may be triggered by afferent pain inputs onto this reflex, possibly at the level of the basal ganglia [53,56]. Conflict of interest statement Dr David Borsook and Dr Perry Rosenthal do not have any conflicts of interest to report.
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