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Dry Eye And The Brain

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Dry Eye And The Brain

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Perry Rosenthal, M.D. October 2015


Eyes that feel dry are dry. This has been the mantra of studies focused on dry eye disease (DED). Even its name leaves no room for debate. Presented as dogma, it explains the enigmatic disparities between tear metrics and symptoms in this patient population as caused by abnormal tears to the exclusion of all other possibilities. Nevertheless, despite the impressive underlying science, anecdotal observations clearly challenge the premise that adding variable evaporative rates to that of tear volumes can explain the striking disparity between tear metrics and symptoms in many cases. On the other hand, challenging this dogma has been stymied by the lack of a better explanation (and other factors). To fill this void I have suggested that malfunctions in the dry eye alarm system itself may be a plausible alternative theory [1].


The neuropathic theory of non-desiccating DED

Proinflammatory cytokines products of inflammation increase the sensitivity of the sensors of noxious stimuli including those of the cornea [2, 3]. Moreover, it seems reasonable to expect that sensitized corneas require thicker tear films than non-sensitized corneas in order to avoid triggering the dry eye alarm. Can increased corneal sensitivity to tear evaporation (corneal evaporative hyperalgesia) explain the disparities between signs and symptoms among patients with non-desiccating dry eye disease?


Dry eye-like symptoms are a unique type of pain and like all physiological (normal) pain its role is to warn us of impending or actual tissue damage. In this regard, the dry eye alarm has been critical for preserving a mirror-smooth precorneal tear layer that has been critical to our survival. On the other hand, symptoms caused by dysfunctional pain systems are consequences of the disease known as neuropathic pain. Its components include hyperalgesia (increased sensitivity and responsiveness to noxious stimuli) and more specifically, allodynia (non-noxious stimuli perceived as painful). Whereas hyperalgesia can originate in the peripheral and/or central pain system and can also be a physiological response, allodynia as a clinical correlate of central sensitization originates exclusively in the central nervous system and is neuropathic. The purpose of this blog is to remind us of the important studies that brought to light the important role of the dysfunctional trigeminal brainstem in so-called DED.


One of the perplexing symptoms of this syndrome often includes disabling photophobia that, in the absence of an observable cause, has been typically attributed to dry eye disease for want of an explanation or (more often) patient fabrication. Whereas unexplained photophobia (which I describe as neuropathic) can be associated with this trigeminal pain syndrome, its pathogenetic mechanisms have not been addressed despite the availability of relevant studies. Those by the Bereiter group are especially notable. Consider the paper reported by Hirata et al in 2004 [4] that highlights the critical role played by the trigeminal subnucleus Interpolaris/caudalis transition region in the brainstem for monitoring ocular surface fluid status and modulating tear production in order to maintain the homeostasis of the pre-corneal tear film thickness. This poses a question: What is its role in the reduced tear secretion associated with trigeminal pain disorders?


Equally important is the paper by Okamoto et al [5] (validated in a human by Moulton [6]) that pointed to the key role played by the trigeminal subnucleus interpolaris/caudalis (Vi/Vc) transition and subnucleus caudalis/upper cervical cord (Vc/C1) junction regions in the brainstem for triggering and generating the blinking response of rats to hypertonic saline and exposure to bright light. The results led them to conclude that these regions represent the primary interface for the trigeminal nerve system that supplies the ocular surface. Isn’t it important to know if bright light and hypertonic saline selectively activate the ocular surface via intraocular trigeminal nerves and excite second-order neurons at the Vi/Vc and Vc/C1 regions? No less interesting, the authors reported that while the application of lidocaine to the ocular surface inhibited the responses to hypertonic saline, it did not alter the noxious response to intense light. This supports the suggestion that the trigeminal brainstem region is an important link in the genesis of non-desiccating DED. Moreover, that the injection of lidocaine in the trigeminal ganglion blocked the responses to hypertonic saline and noxious light suggests that it serves as the trigeminal connection for intraocular light. The absence of a response to hypertonic saline and bright light following synaptic blockade of the Vi/Vc or Vc/C1 region indicates that the activity triggered by stimuli known to cause eye discomfort in humans depends on an intact relay in this region of the brain. This raises the question of whether disorders involving that part of the CNS might also cause hyperalgesia in its receptive fields such as that triggered by corneal surface evaporation (evaporative hyperalgesia). Since this could explain the absence of observable signs of the cause of symptoms in patients with corneal hyperalgesia/allodynia, it will hopefully end the shameful history of doctors accusing these victims of exaggerating and even fabricating their agonizing symptoms, thereby serving to promote suicidal thoughts.



  1. Rosenthal P, Borsook D: Ocular neuropathic pain. The British journal of ophthalmology 2015.
  2. Sommer C, Kress M: Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neuroscience letters 2004, 361(1-3):184-187.
  3. Watkins LR, Wiertelak EP, Goehler LE, Smith KP, Martin D, Maier SF: Characterization of cytokine-induced hyperalgesia. Brain Res 1994, 654(1):15-26.
  4. Hirata H, Okamoto K, Tashiro A, Bereiter DA: A novel class of neurons at the trigeminal subnucleus interpolaris/caudalis transition region monitors ocular surface fluid status and modulates tear production. The Journal of neuroscience : the official journal of the Society for Neuroscience 2004, 24(17):4224-4232.
  5. Okamoto K, Tashiro A, Chang Z, Bereiter DA: Bright light activates a trigeminal nociceptive pathway. Pain 2010, 149(2):235-242.
  6. Moulton EA, Becerra L, Borsook D: An fMRI case report of photophobia: activation of the trigeminal nociceptive pathway. Pain 2009, 145(3):358-363.



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