I have got to say, I love her blunt style!
"My lab developed a model of complex regional pain syndrome type I (CRPS-I), formerly known as reflex sympathetic dystrophy, after discovering that patients with CRPS-I have evidence of peripheral nerve injury. It’s a myth that patients with CRPS-I don’t have nerve injury—most of them have undiagnosed nerve injury. Hardly any among the clinicians who treat CRPS-I patients are nerve experts...
"Another reason why the nerve injuries in CRPS-I remain unrecognized is that patients often have injuries to small sensory nerve branches that are not routinely tested by nerve conduction study, or partial injuries that involve only a few of the axons. So the injured limb may still work reasonably well, and there will still be sensation in the affected area, giving a misleading impression of no nerve injury. Furthermore, EMG [electromyography] and nerve conduction study, the usual tests for diagnosing nerve injury, are completely insensitive to small-fiber function. Many CRPS-I patients have normal EMG and nerve conduction studies, even in the face of injury and dysfunction of their nociceptive fibers."
See RSD/CRPS: The end of the beginning, open access.
".. distal axons are exquisitely vulnerable to energy deprivation, so vasodysregulation or inflammation can trigger axonopathy. My working hypothesis is that although specific patients may enter the CRPS rotary from different points, malfunctioning small-fiber axons are central. Somatic and autonomic small-fibers densely innervate and regulate tissues to maintain homeostasis. In CPRS, even subtle axonal injuries appear sufficient to trigger remaining fibers into inappropriate firing and neuropeptide release. This combination suffices to cause chronic pain, vasodysregulation, neurogenic inflammation as well as changes in non-neural innervated tissues. Then, too much or too little small-fiber afferent input can wreak additional havoc among central neurons and glia."
She has been especially interested in post-herpetic neuropathic itch. See Common Neuropathic Itch Syndromes, open access.
"The sensation of itch – pruritus in medical terminology – can only be perceived by a few tissues, specifically the skin and superficial mucous membranes such as the conjunctiva. So chronic itch complaints are the province of dermatologists, and indeed they most often signal cutaneous injury or inflammation. However, substantial numbers of patients who complain of disabling chronic itch have no apparent cause in the skin. Many of these patients have systemic or medical causes of itch such as drug reactions, allergic or hypersensitivity syndromes, metabolic or endocrine disorders, or toxins associated with kidney or liver dysfunction. Itch is most likely a small-fiber-mediated protective (nocifensive) sensation like pain." (sic: should be nociception. Also, I think there would be some quibble coming her way about whether "perception" is anything "skin" would be capable of doing.. but still, I think she's brilliant.)
She is investigating noninvasive brain stimulation for neuropathic pain.
"The technology that is furthest advanced is called transcranial magnetic stimulation, or TMS, which involves using high-strength electromagnets to generate electrical pulses that travel through the skull, dura, and cerebrospinal fluid to trigger action potentials in the cortex. The technique is being used to investigate and treat several neurologic dysfunctions including stroke, movement disorders, and visual problems. TMS has been approved by the FDA [US Food and Drug Administration] for treating major depression. For treating neuropathic pain, it is the motor cortex that is often targeted. It’s not clear if it’s the firing of the motor axons themselves that produce the pain relief or whether it is the second-order synapses affecting the thalamus, for instance. But several clinical trials find TMS is effective for a number of neuropathic pain syndromes and other syndromes that may or may not be neuropathic, including fibromyalgia."
About animal models
"We also work on animal models, but we tend to do the animal models after we have characterized the human condition. The greatest need is not for more animal models; it’s for better characterization of the actual human diseases. One of the problems of animal models is that, because the phenotyping is so rudimentary for many neuropathic pain conditions, it’s not clear how relevant the animal models are. For instance, the chronic constriction injury (CCI) model, the most widely used neuropathic pain model, is a wonderful model, but it doesn’t correspond to any particular human disease. It has both nerve injury and inflammatory components, and it changes over time as the sutures that are used are absorbed. So all of the wonderful studies that are done in CCI… Not to dismiss them, because we have learned a tremendous amount about how the nervous system works from them, but the model corresponds loosely at best to an actual human disease or illness."
The topic that kept me awake and fascinated late into the night is her insight into Tarlov cysts, which I had never heard of before.
What they are:
"Tarlov cysts... are small cysts that form only on the sensory nerve roots. They form in the arachnoid space that is pulled distally when the cell bodies of primary afferent neurons migrate out of the spinal cord to form the dorsal root ganglia during embryogenesis.So, in a sense, they are like a minor birth defect. Until they start making trouble. Then they are more like a major birth defect.
"This space allows cerebrospinal fluid to track along the sensory nerve roots through tenuous connections. In some cases, fluid is forced into the neural tissues when intracranial pressure increases (during a cough or bowel movement, for instance), and this gradually causes cysts to form. These cysts in some cases damage the sensory axons and cell bodies in the dorsal root ganglia, and the most common symptom they produce is neuropathic pain."Wow. It's like the "bulging disc" model, only small, and overlooked by everyone, until she put it together.
"These perineurial cysts were first described in 1937 by neurosurgeon Isadore Tarlov, who discovered them at autopsy. He had no information about the patients’ symptoms, so he opined in his first paper that they did not cause clinical symptoms. He later treated patients who had these cysts during life and recognized that they are a cause of radiculopathy, much like a herniated disk. But his later papers did not receive adequate attention, because everyone is taught to cite the first paper. So a medical myth was born that Tarlov cysts are irrelevant lesions, and it remains widespread today. In fact, radiologists often see Tarlov cysts on MRIs but don’t report them, because they have been taught these cysts are an incidental finding of no medical significance—just as a dermatologist might not report freckles.Oh. My. Good. Grief.
The link to vulvodynia:
"I learned about Tarlov cysts from patients. My first patient with Tarlov cysts had vulvodynia—pain in the vulva present for decades and often attributed to psychiatric causes. Many treatments had been tried, including vulvar vestibulectomy, or amputation of the outer parts of her vulva, a standard treatment; however, she had never seen a neurologist before me. When I ordered spinal cord imaging, it revealed large Tarlov cysts. At first I had no idea if these were related. Since there was no mention of Tarlov cysts in the textbooks or recent literature, I had to obtain and read the historical papers, which opened my eyes and enabled me to reformulate her illness as neurologic rather than psychiatric.She made the crucial link. In her head. She recognized that the woman wasn't necessarily crazy or making up a wild story about pain in her pelvic floor.
"This is important because Tarlov cysts can be treated and in some cases cured completely using surgical or percutaneous procedures that definitively collapse or remove the cysts, but only if the correct diagnosis is recognized and the clinician knows the treatment options. So Tarlov cysts are a curable cause of painful radiculopathy—and they are not rare, it turns out. But because so few physicians know about them, most patients never get adequate diagnosis and never get treated.Well, this kinda plops the old "bio" right back into "biopsychosocial" doesn't it?
"I proposed symposia on Tarlov cysts to be presented at the American Pain Society meeting, and for two years in a row the scientific program committee turned down my request because, they said, no one had ever heard of this, so how important could it be?Face-palm.
"In fact, pain practitioners should welcome this information as they could learn to do the percutaneous CT-guided cyst aspiration, which has been published as an effective and definitive treatment.They could practice a nice effective operator model, cure patients, and everyone could be more happy, especially patients.
"Because I am a woman who specializes in neuropathic pain, I was sought out by so many Tarlov cyst patients that it became inescapable for me to make the correct diagnosis and begin to investigate the pathophysiology. In 2010, several colleagues and I published the first paper on Tarlov cysts in the pain literature [Hiers et al, 2010]. A subsequent paper in press in the New England Journal of Medicine describes a detailed study of a nurse who had 21 Tarlov cysts, and despite many medical visits for her chronic neuropathic pain, the cause remained undiagnosed for most of her adult life. When she died unexpectedly of leukemia, I arranged for a very detailed autopsy and neuropathologic study. I hope that once the NEJM paper appears, the pain community will take another look. And I hope that the neurology, neurosurgery, radiology, and gynecology communities will become aware of this disease entity as well so that more patients can get correct diagnosis and treatment.
"I obtained the world’s first-ever research grant on Tarlov cysts, and we conducted the largest study of radiologically identified cysts, and the first report of cyst symptoms, from a cohort of 500 symptomatic patients. A big part of the problem is that the average Tarlov-cyst patient is a woman with chronic pelvic pain, but the average spine clinician is a man, which has impeded forthright communication needed to establish the link between symptoms and cause.Face-palm II.
"Some of the patients don’t even mention their pelvic pain and dysfunction, and it’s not a topic that many male physicians feel comfortable asking their female patients about. This has created a “don’t ask, don’t tell” situation that neither side—the clinicians nor the patients—has been able to bridge, to bring this condition to medical and public awareness."Face-palm III.
OK, I'm sold. I am going to follow this woman closely, because her insight, into everything persistently painful, everything persistently tormenting in human existence, could be the best thing that has happened to humans, especially female humans, in a very long time.
There are 95 papers so far, on pubmed, about Tarlov cysts.
Here are some with open access.
1. Jung KT, Lee HY, Lim KJ. Clinical Experience of Symptomatic Sacral Perineural Cyst. Korean J Pain. 2012 Jul;25(3):191-4. Epub 2012 Jun 28.
2. Hur W, Choi SS, Lee JJ. Caudal epidural injections for the treatment of tarlov cysts: suggestions for the better results. Pain Physician. 2012 May-Jun;15(3):E351-353; author reply E353.
3. Sen RK, Goyal T, Tripathy SK, Chakraborty S. Tarlov cysts: a report of two cases. J Orthop Surg (Hong Kong). 2012 Apr;20(1):87-9.
4. Freidenstein J, Aldrete JA, Ness T. Minimally invasive interventional therapy for Tarlov cysts causing symptoms of interstitial cystitis. Pain Physician. 2012 Mar-Apr;15(2):141-6.
5. Smith ZA, Li Z, Raphael D, Khoo LT. Sacral laminoplasty and cystic fenestration in the treatment of symptomatic sacral perineural (Tarlov) cysts: Technical case report. Surg Neurol Int. 2011;2:129. Epub 2011 Sep 27.
6. Kong WK, Cho KT, Hong SK. Symptomatic Tarlov Cyst Following Spontaneous Subarachnoid Hemorrhage. J Korean Neurosurg Soc. 2011 Aug;50(2):123-5. Epub 2011 Aug 31.
7. Neulen A, Kantelhardt SR, Pilgram-Pastor SM, Metz I, Rohde V, Giese A. Microsurgical fenestration of perineural cysts to the thecal sac at the level of the distal dural sleeve. Acta Neurochir (Wien). 2011 Jul;153(7):1427-34; discussion 1434. Epub 2011 May 12.