Neuropathic Pain: Why does my eye hurt? Why can the doctor not see anything wrong?

NEUROPATHIC EYE PAIN is a Chronic Pain condition which is often debilitating issue for patients. These patients often see multiple doctors from multiple specialties without pain relief.

How do I know if I have Neuropathic Eye Pain?
Here are some qualities of neuropathic eye pain: if you answer Yes to many of these items below, you may have a component of Neuropathic Eye Pain. The good news is that we have some treatment options that have helped many patients.

• Pain does not improve with artificial tears, Restasis, Xiidra
• Pain does not improve or minimally improves with anesthetics like topical lidocaine drops or even injections.
• Pain is usually constant with occasional relief from unclear reasons, and
moderate to severe in intensity
• Pain has specific qualities, including
burning (C fiber activation) and sharp,
shooting neuralgic pain sensation.
• Pain can have aching and throbbing qualities especially behind the eye
• Microscopic exam of the eye under the slit lamp microscope shows almost no signs of dryness or is completely normal.
• CT scan and/or MRI is all normal yet severe pain persists.

Other issues:
 • Precipitating factors may throw a patient into NEP Syndrome:
-Excessive Electronic Screen Use (for some this is as low as 2-3hrs per day).
-Accutane use
-Birth Control or certain IUDs or hormonal changes
-previous eye or eyelid or even sinus
surgery, maxillofacial trauma, dental
infection, viral infections, bacterial eye infection

 • Over-the-counter drugs such as NSAIDS, codeine, tramadol and even morphine do not reduce pain

 • Theory: This chronic neuropathic pain can involve the damage or neurons from the loss
of the cells ability to block magnesium from the
calcium channel, resulting in chronic nerve firing and pain.

• Pain can seem to be coming from behind the eye or around the eye and even sinus area.

• Persistent pain can cause frustration, depression,
anxiety, despair, suicidal thoughts.
• About 50-75% of
patients with neuropathic pain have a moderate to
severe psychiatric diagnosis, often
due to unremitting pain.

What is the Best Way to Treat Neuropathic Eye Pain?
First we start of trying to see if the usual treatments for dry eye help: ie, lid hygiene, warm compresses, non-preserved artificial tears, Xiidra, Restasis, Punctal Plugs, Steroid ointment/drops, Lipiflow, IPL, Autologous Serum, PRP, Prokera/Amniotic membrane. If these do not work often in this order, we try Meibomian Gland Probing with Expression (MGPE). If this does not help relieve the pain, we try MGPE with PRP insertion into the meibomian glands. If this does not work we try MGPE into the Lacrimal Gland. If all these do not help we try Autologous, Adipose Derived Stem Cells into the meibomian glands, lacrimal gland and IV (the theory is that stem cells may help through cell to cell contact, stimulate abnormal cells to work properly). If this does not help, we would try Stem Cell injection into the key nerve ganglion of the eye.

Stem cell therapy: This is investigational.
A friend from Harvard just inplanted the first human in-vitro-expanded- limbal stem cell implantation in which the patient’s limbal stem cells were expanded in vitro from the healthy eye to the unhealthy (chemical burn damaged) eye: it took her 10 YEARS to be able to do this.

Do our dry eye patients have 10 years to wait for proof? This is a problem.

Preliminary studies of autologous stem cell
therapy have shown it to be safe and effective
for treating neuropathic pain in animals and
humans.(Ref 1, 2) Results of the human study showed
a reduction in pain intensity (mean reduction
of 43%) in 78% of patients at six months from
a single administration of stem cells at the
trigeminal pain site.(Ref 2).
But all these stem cell treatments are investigational at this time for Neuropathic Eye Pain.


1. MedicineToday ❙ SEPTEMBER 2015, VOLUME 16, NUMBER 9

2. Vickers ER, Karsten E, Flood J, Lilischkis R. A preliminary report on stem
cell therapy for neuropathic pain in humans. J Pain Res 2014; 7: 255-263.

Journal of Pain Research Dovepress
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open access to scientific and medical research
Open Access Full Text Article
A preliminary report on stem cell therapy
for neuropathic pain in humans
E Russell Vickers1
Elisabeth Karsten2
John Flood3
Richard Lilischkis2
Sydney Oral and Maxillofacial
Surgery, NSW, Australia; 2
Ltd, Gordon, NSW, Australia; 3
St Vincents Hospital, Sydney, NSW,
Correspondence: E Russell Vickers
Sydney Oral and Maxillofacial
Surgery, Suite 1401, 520 Oxford
St, Bondi Junction, NSW, Australia
Tel 61 2 9369 2153
Fax 61 2 9369 2154
Objective: Mesenchymal stem cells (MSCs) have been shown in animal models to attenuate
chronic neuropathic pain. This preliminary study investigated if: i) injections of autologous
MSCs can reduce human neuropathic pain and ii) evaluate the safety of the procedure.
Methods: Ten subjects with symptoms of neuropathic trigeminal pain underwent liposuction.
The lipoaspirate was digested with collagenase and washed with saline three times. Following
centrifugation, the stromal vascular fraction was resuspended in saline, and then transferred to
syringes for local injections into the pain fields. Outcome measures at 6 months assessed reduction
in: i) pain intensity measured by standard numerical rating scale from 0–10 and ii) daily
dosage requirements of antineuropathic pain medication.
Results: Subjects were all female (mean age 55.3 years o standard deviation [SD] 14.67; range
27–80 years) with pain symptoms lasting from 4 months to 6 years and 5 months. Lipoaspirate
collection ranged from 102–214 g with total cell numbers injected from 33 million to 162 million
cells. Cell viability was 62%–91%. There were no systemic or local tissue side effects from the
stem cell therapy (n 41 oral and facial injection sites). Clinical pain outcomes showed that at 6
months, 5/9 subjects had reduced both pain intensity scores and use of antineuropathic medication.
The mean pain score pre-treatment was 7.5 (SD 1.58) and at 6 months had decreased to 4.3
(SD 3.28), P 0.018, Wilcoxon signed-rank test. Antineuropathic pain medication use showed
5/9 subjects reduced their need for medication (gabapentin, P 0.053, Student’s t-test).
Conclusion: This preliminary open-labeled study showed autologous administration of stem
cells for neuropathic trigeminal pain significantly reduced pain intensity at 6 months and is a
safe and well tolerated intervention.
Keywords: adipose, stem cells, neuropathic, orofacial, trigeminal

3.  2018 Feb;476(2):388-397. doi: 10.1007/s11999.0000000000000033.

Stem Cells Combined With Platelet-rich Plasma Effectively Treat Corticosteroid-induced Osteonecrosis of the Hip: A Prospective Study.



Randomized trials have shown the benefits of injecting bone marrow-derived mesenchymal stem cells (BmMSCs) after standard hip decompression in patients with osteonecrosis of the femoral head. However, the combination of BmMSCs and platelet-rich plasma (PRP) injected into the femoral head after decompression has not been reported previously. This study reports the results in a preliminary series of patients with osteonecrosis of the femoral head treated with BmMSCs plus PRP.


(1) What is the survivorship free from reoperation, hip arthroplasty, and femoral head collapse in a preliminary series of patients with osteonecrosis of the femoral head treated with BmMSCs plus PRP? (2) Is there a change in the degree of femoral head involvement based on modified Kerboul angle? (3) What were the scores observed for pain and function at last followup? (4) Was there a difference in survivorship free from reoperation as a function of in vitro MSC count and viability?


Twenty-two consecutive patients (35 hips; 11 men and 11 women) with corticosteroid-induced osteonecrosis who met study inclusion criteria were enrolled; none declined participation, and none was lost to followup, although one patient (two hips) died within a year of the procedure for reasons unrelated to it, and five patients (seven hips) did not undergo MRI at the 1-year followup. All patients had precollapse osteonecrosis, rated either University of Pennsylvania Stage 1 (n = 4) or Stage 2 (n = 31 hips). Mean age and body mass index were 43 years and 31 kg/m, respectively. Patients underwent pre- and postoperative radiographs and MRI to assess femoral head involvement using the modified Kerboul angle. Absolute cell count and colony-forming unit (CFU) assays were used to assess MSC abundance and viability of the bone marrow obtained at the time of surgery. Patients were followed at regular intervals to assess clinical response to treatment with a mean followup of 3 years (range, 2-4 years). The change in femoral head involvement was assessed with the modified Kerboul angle; the Harris hip score was used to assess clinical outcome; and conversion to THA, reoperation, and survivorship free from femoral head collapse were analyzed with the Kaplan-Meier method on a per-hip basis.


Survivorship free from THA, any procedure, and femoral head collapse was 84% (95% confidence interval [CI], 75%-93%), 67% (95% CI, 55%-79%), and 93% (95% CI, 76%-98%), respectively, at 3 years postoperatively; two patients (four hips) underwent a second decompression and MSC injection for persistent pain without signs of radiographic collapse. All patients with collapse underwent THA. The mean modified Kerboul angle improved from 205° ± 47° to 172° ± 48° postoperatively (mean change -30° ± 6°, p = 0.01). A greater proportion of patients who underwent an additional procedure had a modified Kerboul grade of 3 or 4 preoperatively (80% [four of five] versus 13% [four of 30 Grade 1 or 2; odds ratio, 26; 95% CI, 2-296; p = 0.005). Preoperatively the mean Harris hip score was 57 ± 12, which improved to 85 ± 15 (mean change 28 ± 3, p < 0.001) at most recent followup. Patients undergoing a reoperation or THA had a lower mean concentration of nucleated cells/mL (5.5 x 10 ± 2.8 x 10 cells/mL versus 2.3 x 10 ± 2.2 x 10 cells/mL, p = 0.02) and lower mean CFUs (13 ± 6 versus 19 ± 7, p = 0.04) compared with those who did not.


Core hip decompression with injection of concentrated bone marrow plus PRP improved pain and function; > 90% of hips in this series were without collapse at a minimum of 2 years. In this preliminary study, successful results were seen when nucleated cell count was high and modified Kerboul grade was low. Further randomized studies are needed to determine this procedure’s efficacy versus core decompression or nonoperative treatment alone.

4.  2018 May;7(5):415-427. doi: 10.1002/sctm.17-0257. Epub 2018 Mar 23.

Concise Review: Altered Versus Unaltered Amniotic Membrane as a Substrate for Limbal Epithelial Cells.


Limbal stem cell deficiency (LSCD) can result from a variety of corneal disorders, including chemical and thermal burns, infections, and autoimmune diseases. The symptoms of LSCD may include irritation, epiphora, blepharospasms, photophobia, pain, and decreased vision. There are a number of treatment options, ranging from nonsurgical treatments for mild LSCD to various forms of surgery that involve different cell types cultured on various substrates. Ex vivo expansion of limbal epithelial cells (LEC) involves the culture of LEC harvested either from the patient, a living relative, or a cadaver on a substrate in the laboratory. Following the transfer of the cultured cell sheet onto the cornea of patients suffering from LSCD, a successful outcome can be expected in approximately three out of four patients. The phenotype of the cultured cells has proven to be a key predictor of success. The choice of culture substrate is known to affect the phenotype. Several studies have shown that amniotic membrane (AM) can be used as a substrate for expansion of LEC for subsequent transplantation in the treatment of LSCD. There is currently a debate over whether AM should be denuded (i.e., de-epithelialized) prior to LEC culture, or whether this substrate should remain intact. In addition, crosslinking of the AM has been used to increase the thermal and mechanical stability, optical transparency, and resistance to collagenase digestion of AM. In the present review, we discuss the rationale for using altered versus unaltered AM as a culture substrate for LEC. Stem Cells Translational Medicine 2018;7:415-427.

4.  2018 Mar 12. doi: 10.1111/cns.12843. [Epub ahead of print]

Low-dose curcumin stimulates proliferation of rat embryonic neural stem cells through glucocorticoid receptor and STAT3.

Ma XX1,2,3Liu J1,2Wang CM1,2Zhou JP1,2He ZZ3Lin H1,2.



This study was to determine whether curcumin had any effect on the proliferation of neural stem cell (NSC), analyze the expression of glucocorticoid receptor (GR), signal transducer and activator of transcription 3 (STAT3), and Notch1 at transcription and protein level, and discuss the related mechanisms.


NSCs were harvested from E15 SD rat brain and cultured. All experiments were performed at the second passage. Cell cytotoxicity, cell viability, and proliferation assays were used to figure out the optimal concentration of curcumin, which can be used for the protein and mRNA studies. The results showed that by downregulation of GR and STAT3 expression, 0.5 μmol L-1 curcumin exhibited the most pronounced effect in promoting the proliferation of NSCs, which were also induced by antagonists of GR and STAT3, but was inhibited by GR agonist.


This study shows that low-dose curcumin stimulates the proliferation of NSCs, which is probably by inhibiting the mRNA and protein expressions of GR and directly or indirectly regulating the STAT3 via the synergistic effect of GR and STAT3 pathways and its related signal pathways.

5.  2018 Mar 1:2472555218764678. doi: 10.1177/2472555218764678. [Epub ahead of print]

Plate-Based Phenotypic Screening for Pain Using Human iPSC-Derived Sensory Neurons.


Screening against a disease-relevant phenotype to identify compounds that change the outcome of biological pathways, rather than just the activity of specific targets, offers an alternative approach to find modulators of disease characteristics. However, in pain research, use of in vitro phenotypic screens has been impeded by the challenge of sourcing relevant neuronal cell types in sufficient quantity and developing functional end-point measurements with a direct disease link. To overcome these hurdles, we have generated human induced pluripotent stem cell (hiPSC)-derived sensory neurons at a robust production scale using the concept of cryopreserved “near-assay-ready” cells to decouple complex cell production from assay development and screening. hiPSC sensory neurons have then been used for development of a 384-well veratridine-evoked calcium flux assay. This functional assay of neuronal excitability was validated for phenotypic relevance to painand other hyperexcitability disorders through screening a small targeted validation compound subset. A 2700-compound chemogenomics screen was then conducted to profile the range of target-based mechanisms able to inhibit veratridine-evoked excitability. This report presents the assay development, validation, and screening data. We conclude that high-throughput-compatible pain-relevant phenotypic screening with hiPSC sensory neurons is feasible and ready for application for the identification of new targets, pathways, mechanisms of action, and compounds for modulating neuronal excitability.

6.  2017 Apr 9;9:76-88. doi: 10.1016/ eCollection 2017 Apr.

Cartilage repair by mesenchymal stem cells: Clinical trial update and perspectives.

Lee WY1,2,3Wang B1,2,3.


Osteoarthritis is a degenerative disease of joints with destruction of articular cartilage associated with subchondral bone hypertrophy and inflammation. OA is the leading cause of joint pain resulting in significant worsening of the quality-of-life in the elderly. Numerous efforts have been spent to overcome the inherently poor healing ability of articular cartilage. Mesenchymal stem cells (MSCs) have been in the limelight of cell-based therapies to promote cartilage repair. Despite progressive advancements in MSC manipulation and the introduction of various bioactive scaffolds and growth factors in preclinical studies, current clinical trials are still at early stages with preliminary aims to evaluate safety, feasibility and efficacy. This review summarises recently reported MSC-based clinical trials and discusses new research directions with particular focus on the potential application of MSC-derived extracellular vehicles, miRNAs and advanced gene editing techniques which may shed light on the development of novel treatment strategies. The translational potential of this article: This review summarises recent MSC-related clinical research that focuses on cartilage repair. We also propose a novel possible translational direction for hyaline cartilage formation and a new paradigm making use of extra-cellular signalling and epigenetic regulation in the application of MSCs for cartilage repair.
7.  2018 Mar 6. doi: 10.1007/s00167-018-4883-9. [Epub ahead of print]

Intra-articular injections of expanded mesenchymal stem cells with and without addition of platelet-rich plasma are safe and effective for knee osteoarthritis.



To compare the effectiveness and safety of intra-articular injections of autologous expanded mesenchymal stromal stem cellsalone (MSCs), or in combination with platelet-rich plasma (MSCs + PRP), in patients with knee osteoarthritis.


Eighteen patients (57.6 ± 9.6 years) with radiographic symptomatic knee osteoarthritis (Dejour grades II-IV) were randomized to receive intra-articular injections of MSCs (n = 9) or MSCs + PRP (n = 9). Injections were performed 2-3 weeks after bone marrow aspiration (± 80-100 ml) which was obtained from both posterior iliac crests.


The Knee Injury and Osteoarthritis Outcome Score (KOOS) improved significantly throughout the 12 months for both groups (p < 0.05). No statistically significant differences between groups were found in KOOS subscales and global score improvements at 12-month end-point (n.s.). The MSCs group showed significant improvements in the pain, function and daily living activities, and sports and recreational activities subscales (p < 0.05). Similarly, the MSCs + PRP group showed significant improvements in the pain, function and daily living activities and quality of life subscales (p < 0.05). The average number of fibroblast colony forming units (CFU-F) was 56.8 + 21.9 for MSCs group and 50.7 ± 21.7 for MSCs + PRP group. Minimal adverse effects were seen in both groups (10 adverse events, in 5 patients).


Intra-articular injections of expanded MSCs alone or in combination with PRP are safe and have a beneficial effect on symptoms in patients with symptomatic knee osteoarthritis. Adding PRP to the MSCs injections did not provide additional benefit. These results are encouraging and support the recommendation of this minimally invasive procedure in patients with knee osteoarthritis, without requiring hospitalization. The CFU-F results may be used as reference for future research.
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