NEUROPATHIC CORNEAL PAIN: APPROACHES FOR MANAGEMENT 2017

pattismith

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very valuable article, with many interest for us and a great experience behind.

Neuropathic corneal pain is evoked from both peripheral and central perspective, and both from local and systemic origin.

NEUROPATHIC CORNEAL PAIN (NCP): APPROACHES FOR MANAGEMENT
Gabriela Dieckmann, MD,1,2 Sunali Goyal, MD,3 and Pedram Hamrah, MD, FACS1,2

Abstract

Neuropathic pain is caused by a primary lesion or dysfunction of the nervous system and can occur in the cornea.

However, neuropathic corneal pain (NCP) is currently an ill-defined disease.

Patients with NCP are extremely challenging to manage and evidence-based clinical recommendations for the management of patients with NCP are scarce.

The objectives of this review are to provide guidelines for diagnosis and treatment of patients with NCP and to summarize current evidence-based literature in this area.

We performed a systematic literature search of all relevant publications between 1966 and 2017.

Treatment recommendations are, in part, based on methodologically sound randomized controlled trials (RCTs), demonstrating superiority to placebo or relevant control treatments, and on the consistency of evidence, degree of efficacy, and safety.

In addition, the recommendations include our own extensive experience in the management of these patients over the past decade.

A comprehensive algorithm, based on clinical evaluation and complementary tests, is presented for diagnosis and subcategorization of patients with NCP.

Recommended first-line topical treatments include neuro-regenerative and anti-inflammatory agents, whilst first-line systemic pharmacotherapy includes tricyclic antidepressants and the anticonvulsant.

Second line oral treatments recommended include the opioid-antagonist and opiate analgesics.

Complementary and alternative treatments, such as cardio-exercise, acupuncture, omega-3 fatty acid, and gluten-free diet, may have additional benefits, as do potential non-invasive and invasive procedures in recalcitrant cases.

Medication selection should be tailored on an individual basis, considering side effects, comorbidities, and levels of peripheral and centralized pain.

Nevertheless, there is an urgent need for long-term studies and RCTs assessing the efficacy of treatments for NCP.
The Proparacaine Challenge Test
Establishing the origin of pain, whether central or peripheral is important for selecting appropriate treatment measures. Topical 0.5% proparacaine hydrochloride (Alcaine, Alcon, Fort Worth, TX) allows for differentiation of central from peripheral sources of pain.13 While proparacaine abolishes peripheral pain, it has no effect on pain from central sensitization. Patients experiencing complete or partial relief with proparacaine challenge, likely suffer from peripheral or mixed combined NCP. In contrast, patients not responding to proparacaine, suffer at least in part from central NCP (Fig. 2). It has been our clinical experience that many patients only achieve partial relief to topical proparacaine, suggesting that both peripheral and central sensitization are at play, albeit in different proportions depending on etiology and disease duration.

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In Vivo Confocal Microscopy to Confirm Corneal Nerve Damage
The cornea is innervated by branches of the nasociliary nerve, a branch of the ophthalmic division of the trigeminal nerve.43 Nerve bundles enter the peripheral cornea (limbus) in a radial fashion, migrate anteriorly, penetrate the Bowman’s layer, and form the subbasal plexus.

Neuro-Regenerative Therapy
Peripheral sensitization in NCP is initiated by corneal nerve injury and subsequent inflammation. Recently, therapeutic strategies targeting neuronal regeneration have been shown to alleviate patient symptoms with autologous serum tears (AST).6 The rationale for this approach was based on previous reports from preclinical non-ocular neuropathic pain models on the use of neurotrophic factors, in particular nerve growth factor (NGF).47,48 NGF reduced allodynia and hyperalgesia through reduction of reactive astrocytosis and glial modulation. Recovery of corneal nerve topography has been demonstrated with the use of AST in patients with NCP,49 photoallodynia,6 DED,50 as well as with autologous plasma in patients with neurotrophic keratopathy.51

Autologous Serum Tears (AST)
AST contain neurotrophic factors, including NGF and insulin-like growth factor ....

We recommend the use of 20% AST 8x/daily until significant relief/resolution of symptoms is achieved, followed by a very slow taper in order to prevent rebound. It has been our experience that initial symptom relief is observed within 3–4 months in NCP of peripheral origin and that taper can be successfully attempted within 9–12 months

Anti-Inflammatory Therapy

The pathophysiology of NCP includes injury to peripheral nerves (e.g. due to direct trauma, inflammation, toxicity) resulting in release of pro-inflammatory neuropeptides from both injured nerves and cytokines from surrounding healthy nerves,71,72 leading peripheral sensitization.73,74

Chronic inflammation can decrease neurite outgrowth and increased calcium influx across cell membranes, causing axonal degeneration.75,76 Thus, the critical role of inflammation in the pathophysiology of NCP provides the rationale for the use of anti-inflammatory therapy. Our clinical experience has corroborated this rationale in that concurrent use of low dose topical corticosteroids with AST resulted in significant increase in cornea nerve regeneration as compared to AST alone.

Topical corticosteroids have been used as a mainstay of anti-inflammatory therapy due to their inhibitory mechanism of action on cytokines, prostaglandins and leukotriene synthesis, as well as the inhibition of leukocyte migration.78

Among corticosteroids, loteprednol 0.5% suspension or gel have demonstrated lower rates of increased intraocular pressure and cataract formation due to decreased intraocular penetration.79, 80 Moreover loteprednol 0.5% gel has a much lower concentration of the neurotoxic8183 preservative benzalkonium chloride (BAK; 0.003%), as compared to other corticosteroids;

Thus, for NCP we recommend use of loteprednol 0.5% suspension or gel with a slow taper of four times daily for two weeks, followed by twice daily for two weeks and once daily over a 6- to 12-week period depending on individual patient response. Anti-inflammatory therapy is then attempted with steroid-sparing therapies, such as topical calcineurin inhibitors cyclosporine A 0.05% two to four times daily,86 and tacrolimus 0.03% three times daily,87 the interleukin-1 receptor antagonist Anakinra (Kineret) 2.5% three times daily,88 as well as topical testosterone 0.03% three times daily.



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743225/#R51
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743225/#R51
 

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pattismith

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Further, a new class of anti-inflammatory agents has become available with Lifitegrast 5%, which was recently approved by the FDA for the treatment of signs and symptoms of dry eye disease.90 Moreover, antibiotics such as topical and oral tetracycline and azithromycin have been used successfully for anti-inflammatory therapy.91,92 Nevertheless, topical loteprednol is the author’s first-line choice as an anti-inflammatory agent.

It is important to note that in patients with severe hyperalgesia, even low BAK concentrations are not tolerated, in which case preservative-free formulations are recommended, such as compounded methylprednisolone 1%. Depending on the level of inflammation, topical anti-inflammatory therapy may result in rapid decrease of pain. However, depending on the agent and preservatives used, they can result in significant discomfort.
 

pattismith

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in the systemic therapy part of the article:


Second Line Agents
Low-Dose Naltrexone (LDN)
LDN is an opioid antagonist for the μ-opioid and κ-opioid receptors.126,127 It has further been shown to be an antagonist to toll-like receptor 4 that has been linked to neuropathic pain,126,127 reducing the release of pro-inflammatory cytokines and modulating microglial activity.

LDN (3–5 mg) has recently been used effectively as an off-label treatment in patients with chronic neuropathic pain, including fibromyalgia, complex regional pain syndrome, low-back pain, and painful diabetic neuropathy. In a RCT of 31 patients with fibromyalgia, use of LDN 4.5mg resulted in significant decrease of pain and improved satisfaction with life as compared to placebo.127

Another recent paper reported a single case of successful treatment with LDN in a patient with refractory painful diabetic neuropathic pain.128

Common side effects include headache, tachycardia and vivid dreams.127

LDN is recommended by us in NCP patients at 1.5 mg at bedtime with gradual bi-weekly increase of 1.5 mg to a final maximum dose of 4.5 mg taken at bedtime.
Third line treatment
Sodium Channel Blocker (Mexiletine)

Mexiletine, a sodium channel blocker that is an orally active local anesthetic agent, is structurally related to lidocaine, and prescribed as a second- or third-line treatment for neuropathic pain.140

It is an orally active local anesthetic and anti-arryhythmic agent that can be used at doses of 225–675 mg/day. 140
The most common side effects are nausea, headache, sleep disturbances, and tiredness. Due to its poor side effect profile, we only recommend in NCP patients refractory to other treatments.
 
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SSRI's sure seem to be the cure for everything!

My worthless eye doctor wants me to come back for another worthless check up and never does nothing about my significant eye troubles.

Wonder what this is?

I wonder what ocular pain is?

I'm in eye misery every day.
 
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SSRI's sure seem to be the cure for everything!

My worthless eye doctor wants me to come back for another worthless check up and never does nothing about my significant eye troubles.

Wonder what this is?

I wonder what ocular pain is?

I'm in eye misery every day.
I completely agree and sympathise with you. I have been in constant pain since having a flare of acute uveitis over a year ago. I have had multiple hospital visits and the last rheumatologist I consulted suggested it could be fixed by swimming three times a week and over GET- this despite the fact I have severe M.E, was in a wheel chair and am 95% housebound!!!

I found this of some interest:

https://rarediseases.org/rare-diseases/neuropathic-ocular-pain/
 
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I completely agree and sympathise with you.
So that link describes a series of VERY REAL things that are VERY difficult to endure on a daily basis- in my case for probably ten years at least. Pretty much fully disabled me.

"A similar frequency was found in Salisbury, Maryland with 15% of the population reporting one or more symptoms (dryness, grittiness, burning, redness, crustiness, eyelids stuck shut) often or all the time."

Add to that list: eyes pouring liquid. Mine range from dried out to pouring, with pouring more common.

The visual acuity losses- a test I took online which said this is a common test- I have 60% loss described as: toxins.

Eyelashes are totally sick- its just another part of the body thats sick. Sick eye lashes. And then we are told You Look Fine. Oh?

Mostly they are thieves in the US, having gotten massive amounts of money from insurance that provides no treatments, and I don't exist as a person. I'm just a member of a herd. They got to bill my insurance, and I got nothing out of the deal. NEXT.
 

pattismith

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@Rufous McKinney

I get tearing on waking up, it is transient.

When does your tearing occurs? Is there a specific time in the day?

Tearing seems more frequent in central neuropathic pain than in peripheral NP in this survey

1621476924888.png


Table 3 summarizes the OPAS scores in the participants.

The ocular pain severity score was significantly higher in the central group (36.71 ± 11.48) than in the peripheral group (25.06 ± 11.21) (p < 0.01).

...
Non-ocular pains, such as headache, backache, and arthralgia, scored higher in the central group (6.12 ± 3.12) than in the peripheral group (3.81 ± 2.90, p = 0.04), and patients in the central group spent more time thinking about non-ocular pain than did those in the peripheral group (0.56 ± 0.35 vs. 0.27 ± 0.26) (p = 0.01).

The scores regarding QoL were highest for reading impairment in both groups, but no significant differences were observed between groups. Although the difference was not statistically significant, most of the QoL scores were higher in the central group (reading, driving, walking, mood, and social activity) than in the peripheral group.

The aggravating factors were scored by the percentage of worsening of ocular pain according to mechanical stimuli, such as wind, dry air, heat, and air conditioning, and chemical stimuli, such as volatile chemicals, fumes, and cosmetic fragrances.

The associated factors were scored as a percentage of the frequency with which each symptom was accompanied by ocular pain. The percentage values were later divided by 100 for analysis. The values of aggravating and associated factors did not differ significantly between the two groups, except for burning sensation (0.43 ± 0.32 in the peripheral group and 0.73 ± 0.34 in the central group; p = 0.01).
doi: 10.1186/s12886-020-01733-1

HERE THE OPAS QUESTIONNAIRE

4-Figure2-1.png
 

ChookityPop

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I also have lots of issues with my eyes. Reading or focusing trigger my eye pain. Its terrible. But if I stop using screens etc and instead look around outside or inside it relieves the eye issues. Is it like this for you guys too?

So tetracyclines and azithromycine can help potentially.. interesting
 
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I get tearing on waking up, it is transient.

When does your tearing occurs? Is there a specific time in the day?

Tearing seems more frequent in central neuropathic pain than in peripheral NP in this survey
Oh gosh thank you so much for this info.

Conditions vary. a General common state is- a fewminutes after i wake up they start pouring. And they might pour most of the day.

However lately there is less all day and more the tears are goopy and not liquid enough.

I need to do more stay off the lap top and get much more serious about drops, which i don t use much- plus nobody ever gave me any, thank you eye doctors.
 

Pyrrhus

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I also have lots of issues with my eyes. Reading or focusing trigger my eye pain. Its terrible. But if I stop using screens etc and instead look around outside or inside it relieves the eye issues. Is it like this for you guys too?
Here are two discussions you may find interesting:
https://forums.phoenixrising.me/threads/are-you-ok-with-reading.78929/
https://forums.phoenixrising.me/thr...upils-constricting-dilating-back-forth.82520/

Note that not all eye issues are due to the eyes- some are due to the nerves that control the eyes.
(But that's a different discussion!)

Hope this helps.
 

ChookityPop

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Here are two discussions you may find interesting:
https://forums.phoenixrising.me/threads/are-you-ok-with-reading.78929/
https://forums.phoenixrising.me/thr...upils-constricting-dilating-back-forth.82520/


Note that not all eye issues are due to the eyes- some are due to the nerves that control the eyes.
(But that's a different discussion!)

Hope this helps.

I will look at them, thanks!

The pouring eyes symptom. What causes this? Can it be sfn or neuropathy related?
 
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The pouring eyes symptom.
Usually my eyes feel massively squeezed and full of pressure: during intense eye pourings.

I have lots of daily swellings- all cluster arounded- the geography of mouth, tongue, eyes, palette, pulp, lips, sinus,throat.

I suspect something exists to address this, and I just have not managed to figure it out. Take one quercetin- is about how far I've gotten.

but my chinese herbs I"m back on, are helping some.
 

ChookityPop

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Usually my eyes feel massively squeezed and full of pressure: during intense eye pourings.

I have lots of daily swellings- all cluster arounded- the geography of mouth, tongue, eyes, palette, pulp, lips, sinus,throat.

I suspect something exists to address this, and I just have not managed to figure it out. Take one quercetin- is about how far I've gotten.

but my chinese herbs I"m back on, are helping some.
Sorry to hear that. Im sure there are things that can address this. I just thought it was interesting to hear about the eye pouring.

A well known norwegian adventurer Lars Monsen got sick with basically ME CFS in 2012 or 2013. Lots of muscles twicthes, muscle weakness and lots of pain in his legs and in his organs etc if I remember correctly. They couldnt find anything wrong with him in Norway like they say with most of us. But he got diagnosed with lyme in a lyme clinic in Norway afterwards and then they took away that drs authorisation and shut down the clinic. He then went to germany to Dr Klemann. Long story short he got well again so he goes on month expeditions to canada etc. He didnt remember his last tick bite. He says it must be an old tick bite.

I know lyme can cause SFN and maybe he had that. With the pain and eye pouring etc. Im rambling Im sorry. Maybe I should try to contact him. What can cause eye pouring?
 

ChookityPop

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Have anyone tried steroid eye drops? I will Ask my doctor to try this. Im generally not into taking steroids but taking it in the form of eye drops it will only work locally.