Trigeminal neuralgia explained

Trigeminal neuralgia
Field:Neurology
Synonyms:Tic douloureux, prosopalgia,[1] Fothergill's disease,[2] suicide disease[3]
Symptoms:Typical: episodes of severe, sudden, shock-like pain in one side of the face that lasts for seconds to minutes
Atypical: constant burning pain
Complications:Depression
Onset:> 50 years old
Types:Typical and atypical trigeminal neuralgia
Causes:Believed to be due to problems with myelin of trigeminal nerve
Diagnosis:Based on symptoms
Differential:Postherpetic neuralgia
Treatment:Medication, surgery
Medication:Carbamazepine, oxcarbazepine
Prognosis:80% improve with initial treatment
Frequency:1 in 8,000 people per year

Trigeminal neuralgia (TN or TGN), also called Fothergill disease, tic douloureux, trifacial neuralgia, or suicide disease, is a long-term pain disorder that affects the trigeminal nerve,[4] [5] the nerve responsible for sensation in the face and motor functions such as biting and chewing. It is a form of neuropathic pain.[6] There are two main types: typical and atypical trigeminal neuralgia.[5]

The typical form results in episodes of severe, sudden, shock-like pain in one side of the face that lasts for seconds to a few minutes.[5] Groups of these episodes can occur over a few hours.[5] The atypical form results in a constant burning pain that is less severe.[5] Episodes may be triggered by any touch to the face.[5] Both forms may occur in the same person.[5] It is regarded as one of the most painful disorders known to medicine, and often results in depression and suicide.[7]

The exact cause is unknown, but believed to involve loss of the myelin of the trigeminal nerve. This might occur due to nerve compression from a blood vessel as the nerve exits the brain stem, multiple sclerosis, stroke, or trauma. Less common causes include a tumor or arteriovenous malformation. It is a type of nerve pain. Diagnosis is typically based on the symptoms, after ruling out other possible causes such as postherpetic neuralgia.

Treatment includes medication or surgery.[5] The anticonvulsant carbamazepine or oxcarbazepine is usually the initial treatment, and is effective in about 90% of people. Side effects are frequently experienced that necessitate drug withdrawal in as many as 23% of patients. Other options include lamotrigine, baclofen, gabapentin, amitriptyline and pimozide. Opioids are not usually effective in the typical form.[5] In those who do not improve or become resistant to other measures, a number of types of surgery may be tried.[8]

It is estimated that trigeminal neuralgia affects around 0.03% to 0.3% of people around the world with a female over-representation around a 3:1 ratio between women and men.[9] It usually begins in people over 50 years old, but can occur at any age.[5] The condition was first described in detail in 1773 by John Fothergill.[10]

Signs and symptoms

This disorder is characterized by episodes of severe facial pain along the trigeminal nerve divisions. The trigeminal nerve is a paired cranial nerve that has three major branches: the ophthalmic nerve (V1), the maxillary nerve (V2), and the mandibular nerve (V3). One, two, or all three branches of the nerve may be affected. Trigeminal neuralgia most commonly involves the middle branch (the maxillary nerve or V2) and lower branch (mandibular nerve or V3) of the trigeminal nerve.[11]

An individual attack usually lasts from a few seconds to several minutes or hours, but these can repeat for hours with very short intervals between attacks. In other instances, only 4–10 attacks are experienced daily. The episodes of intense pain may occur paroxysmally. To describe the pain sensation, people often describe a trigger area on the face so sensitive that touching or even air currents can trigger an episode; however, in many people, the pain is generated spontaneously without any apparent stimulation.

It affects lifestyle as it can be triggered by common activities such as eating, talking, shaving and brushing teeth. The wind, chewing, and talking can aggravate the condition in many patients. The attacks are said, by those affected, to feel like stabbing electric shocks, burning, sharp, pressing, crushing, exploding or shooting pain that becomes intractable.

The pain also tends to occur in cycles with remissions lasting months or even years. Pain attacks are known to worsen in frequency or severity over time, in some people. Pain may migrate to other branches over time but in some people remains very stable.[12]

Bilateral (occurring on both sides) trigeminal neuralgia is very rare except for trigeminal neuralgia caused by multiple sclerosis (MS). This normally indicates problems with both trigeminal nerves, since one nerve serves the left side of the face and the other serves the right side. Occasional reports of bilateral trigeminal neuralgia reflect successive episodes of unilateral (only one side) pain switching the side of the face rather than pain occurring simultaneously on both sides.[13]

Rapid spreading of the pain, bilateral involvement or simultaneous participation with other major nerve trunks (such as Painful Tic Convulsif of nerves V & VII or occurrence of symptoms in the V and IX nerves) may suggest a systemic cause. Systemic causes could include multiple sclerosis or expanding cranial tumors.[14]

The severity of the pain makes it difficult to wash the face, shave, and perform good oral hygiene. The pain has a significant impact on activities of daily living especially as those affected live in fear of when they are going to get their next attack of pain and how severe it will be. It can lead to severe depression and anxiety.[15]

However, not all people will have the symptoms described above; there are variants of TN, one of which is atypical trigeminal neuralgia ("trigeminal neuralgia, type 2" or trigeminal neuralgia with concomitant pain),[16] based on a recent classification of facial pain.[17] In these instances there is also a more prolonged lower severity background pain that can be present for over 50% of the time and is described more as a burning or prickling, rather than a shock.

Trigeminal pain can also occur after an attack of herpes zoster. Post-herpetic neuralgia has the same manifestations as in other parts of the body. Herpes zoster oticus typically presents with inability to move many facial muscles, pain in the ear, taste loss on the front of the tongue, dry eyes and mouth, and a vesicular rash. Less than 1% of varicella zoster infections involve the facial nerve and result in this occurring.[18]

Trigeminal deafferentation pain (TDP), also termed anesthesia dolorosa, or colloquially as phantom face pain, is from unintentional damage to a trigeminal nerve following attempts to fix a nerve problem surgically. This pain is usually constant with a burning sensation and numbness. TDP is very difficult to treat as further surgeries are usually ineffective and possibly detrimental to the person.[19]

Causes

See also: Pathophysiology of nerve entrapment. The trigeminal nerve is a mixed cranial nerve responsible for sensory data such as tactition (pressure), thermoception (temperature), and nociception (pain) originating from the face above the jawline; it is also responsible for the motor function of the muscles of mastication, the muscles involved in chewing but not facial expression.[20]

Several theories exist to explain the possible causes of this pain syndrome. It was once believed that the nerve was compressed in the opening from the inside to the outside of the skull; but leading research indicates that it is an enlarged or lengthened blood vessel – most commonly the superior cerebellar artery – compressing or throbbing against the microvasculature of the trigeminal nerve near its connection with the pons.[21] Such a compression can injure the nerve's protective myelin sheath and cause erratic and hyperactive functioning of the nerve. This can lead to pain attacks at the slightest stimulation of any area served by the nerve as well as hinder the nerve's ability to shut off the pain signals after the stimulation ends. This type of injury may rarely be caused by an aneurysm (an outpouching of a blood vessel); by an AVM (arteriovenous malformation);[22] by a tumor; such as an arachnoid cyst or meningioma in the cerebellopontine angle;[23] or by a traumatic event, such as a car accident.[24]

Short-term peripheral compression is often painless.[7] Persistent compression results in local demyelination with no loss of axon potential continuity. Chronic nerve entrapment results in demyelination primarily, with progressive axonal degeneration subsequently.[7] It is, "therefore widely accepted that trigeminal neuralgia is associated with demyelination of axons in the Gasserian ganglion, the dorsal root, or both."[25] It has been suggested that this compression may be related to an aberrant branch of the superior cerebellar artery that lies on the trigeminal nerve.[25] Further causes, besides an aneurysm, multiple sclerosis or cerebellopontine angle tumor, include: a posterior fossa tumor, any other expanding lesion or even brainstem diseases from strokes.[25]

Trigeminal neuralgia is found in 3–4% of people with multiple sclerosis, according to data from seven studies.[26] [27] It has been theorized that this is due to damage to the spinal trigeminal complex.[28] Trigeminal pain has a similar presentation in patients with and without MS.[29]

Postherpetic neuralgia, which occurs after shingles, may cause similar symptoms if the trigeminal nerve is damaged, called Ramsay Hunt syndrome type 2.

When there is no apparent structural cause, the syndrome is called idiopathic.

Diagnosis

Trigeminal neuralgia is diagnosed via the result of neurological and physical tests, as well as the individual's medical history.[5] Magnetic resonance angiography can be used to detect vascular compression of the trigeminal nerve and refer patients to surgery.[30]

As with many conditions without clear physical or laboratory diagnosis, TN is often misdiagnosed, and other conditions are also frequently misdiagnosed as TN.[31] [32] A person with TN may see three or four clinicians before a firm diagnosis is made.

Temporomandibular disorder (TMD) can present similarly to TN, and differentiating between these conditions can be difficult.[33] Even suspected TN patients who experience brief attacks of sharp pain have had their symptoms resolve after being treated for TMD.[34] TMD pain can also be triggered by movements of the tongue or facial muscles, so TN must be differentiated from masticatory pain by differentiating between the clinical characteristics of deep somatic pain and neuropathic pain. Masticatory pain will not be arrested by a conventional mandibular local anesthetic block. One quick test a dentist might perform is a conventional inferior dental local anesthetic block. If the pain is in the treated branch, the block will not arrest masticatory pain but will alleviate TN pain.[35]

Management

There is evidence that points towards the need to quickly treat and diagnose TN. It is thought that the longer a patient has TN, the harder it may be to reverse the neural pathways associated with the pain.

Medical

Surgical

Microvascular decompression provides freedom from pain in about 75% of patients presenting with drug-resistant trigeminal neuralgia.[41] [42] [43] While there may be pain relief after surgery, there is also a risk of adverse effects, such as facial numbness. Percutaneous radiofrequency thermorhizotomy may also be effective[44] as may stereotactic radiosurgery; however the effectiveness decreases with time.[45]

Surgical procedures can be separated into non-destructive and destructive:

Non-destructive

Destructive

All destructive procedures will cause facial numbness, post relief, as well as pain relief.[42]

Support

Psychological and social support has found to play a key role in the management of chronic illnesses and chronic pain conditions, such as trigeminal neuralgia. Chronic pain can cause constant frustration to an individual as well as to those around them.[47]

History

Trigeminal neuralgia was first described by physician John Fothergill and treated surgically by John Murray Carnochan, both of whom were graduates of the University of Edinburgh Medical School. Historically TN has been called "suicide disease" due to studies by the pioneering forefather in neurosurgery Harvey Cushing involving 123 cases of TN during 1896 and 1912. In those studies it produced intense pain, higher rates of suicidal ideation in patients with severe migraines, and links to higher rates of depression, anxiety, and sleep disorders.[48] [49]

Society and culture

Some individuals of note with TN include:

See also

External links

Notes and References

  1. Book: Hackley CE . A text-book of practical medicine. 1869. D. Appleton & Co. 292. prosopalgia.. 2011-08-01.
  2. Bagheri SC, Farhidvash F, Perciaccante VJ . Diagnosis and treatment of patients with trigeminal neuralgia . Journal of the American Dental Association . 135 . 12 . 1713–1717 . December 2004 . 15646605 . 10.14219/jada.archive.2004.0124 . dead . 2011-08-01 . https://archive.today/20120711144557/http://jada.ada.org/cgi/content/full/135/12/1713 . July 11, 2012 .
  3. Adams H, Pendleton C, Latimer K, Cohen-Gadol AA, Carson BS, Quinones-Hinojosa A . Harvey Cushing's case series of trigeminal neuralgia at the Johns Hopkins Hospital: a surgeon's quest to advance the treatment of the 'suicide disease' . Acta Neurochirurgica . 153 . 5 . 1043–1050 . May 2011 . 21409517 . 10.1007/s00701-011-0975-8 . 28245294 .
  4. Web site: Trigeminal Neuralgia . National Organization for Rare Disorders, Inc. . 26 February 2014 .
  5. Web site: Trigeminal Neuralgia Fact Sheet. NINDS. National Institutes of Health. 5 April 2021. 17 March 2020.
  6. Cruccu G, Di Stefano G, Truini A . Trigeminal Neuralgia . The New England Journal of Medicine . 383 . 8 . 754–762 . August 2020 . 32813951 . 10.1056/NEJMra1914484 . Ropper AH . 221201036 .
  7. Book: Okeson JP . Bell's orofacial pains: the clinical management of orofacial pain. 2005. Quintessence Publishing Co, Inc. 0-86715-439-X. 114. http://www.quintpub.com/display_detail.php3?psku=B439X. Lindsay Harmon. 6. live. https://web.archive.org/web/20140112055333/http://www.quintpub.com/display_detail.php3?psku=B439X. 2014-01-12.
  8. Obermann M . Treatment options in trigeminal neuralgia . Therapeutic Advances in Neurological Disorders . 3 . 2 . 107–115 . March 2010 . 21179603 . 3002644 . 10.1177/1756285609359317 .
  9. Araya EI, Claudino RF, Piovesan EJ, Chichorro JG . Trigeminal Neuralgia: Basic and Clinical Aspects . Current Neuropharmacology . 18 . 2 . 109–119 . 2020-01-23 . 31608834 . 7324879 . 10.2174/1570159X17666191010094350 .
  10. Prasad S, Galetta S . Trigeminal neuralgia: historical notes and current concepts . The Neurologist . 15 . 2 . 87–94 . March 2009 . 19276786 . 10.1097/nrl.0b013e3181775ac3 . 23500191 .
  11. Web site: Trigeminal Neuralgia and Hemifacial Spasm . UF Health Shands Hospital. November 2012. 5 April 2021.
  12. Bayer DB, Stenger TG . Trigeminal neuralgia: an overview . Oral Surgery, Oral Medicine, and Oral Pathology . 48 . 5 . 393–399 . November 1979 . 226915 . 10.1016/0030-4220(79)90064-1 .
  13. Cruccu G, Finnerup NB, Jensen TS, Scholz J, Sindou M, Svensson P, Treede RD, Zakrzewska JM, Nurmikko T . Trigeminal neuralgia: New classification and diagnostic grading for practice and research . Neurology . 87 . 2 . 220–228 . July 2016 . 27306631 . 4940067 . 10.1212/WNL.0000000000002840 .
  14. Book: Okeson JP . Bell's orofacial pains: the clinical management of orofacial pain. 2005. Quintessence Publishing Co, Inc. 0-86715-439-X. 453. http://www.quintpub.com/display_detail.php3?psku=B439X. Lindsay Harmon. 17. live. https://web.archive.org/web/20140112055333/http://www.quintpub.com/display_detail.php3?psku=B439X. 2014-01-12.
  15. Smith JG, Elias LA, Yilmaz Z, Barker S, Shah K, Shah S, Renton T . The psychosocial and affective burden of posttraumatic neuropathy following injuries to the trigeminal nerve . Journal of Orofacial Pain . 27 . 4 . 293–303 . 2013 . 24171179 . 10.11607/jop.1056 . free .
  16. Web site: Neurological surgery: facial pain. https://web.archive.org/web/20040625061701/http://www.ohsu.edu/facialpain/facial_pain-dx.shtml. dead. June 25, 2004. Oregon Health & Science University. 2011-08-01.
  17. Burchiel KJ . A new classification for facial pain . Neurosurgery . 53 . 5 . 1164–7 . November 2003 . 14580284 . 10.1227/01.NEU.0000088806.11659.D8 . 33538452 .
  18. Feller L, Khammissa RA, Fourie J, Bouckaert M, Lemmer J . Postherpetic Neuralgia and Trigeminal Neuralgia . Pain Research and Treatment . 2017 . 1681765 . 2017 . 29359044 . 5735631 . 10.1155/2017/1681765 . free .
  19. Web site: Anesthesia Dolorosa . 14 April 2021 . The Facial Pain Association .
  20. Web site: Pazhaniappan N . The Trigeminal Nerve (CN V) . TeachMeAnatomy . 5 April 2021 . 15 August 2020.
  21. Nurmikko TJ, Eldridge PR . Trigeminal neuralgia--pathophysiology, diagnosis and current treatment . British Journal of Anaesthesia . 87 . 1 . 117–132 . July 2001 . 11460800 . 10.1093/bja/87.1.117 . free .
  22. Singh N, Bharatha A, O'Kelly C, Wallace MC, Goldstein W, Willinsky RA, Aviv RI, Symons SP . Intrinsic arteriovenous malformation of the trigeminal nerve . The Canadian Journal of Neurological Sciences. Le Journal Canadien des Sciences Neurologiques . 37 . 5 . 681–683 . September 2010 . 21059518 . 10.1017/S0317167100010891 . free .
  23. Babu R, Murali R . Arachnoid cyst of the cerebellopontine angle manifesting as contralateral trigeminal neuralgia: case report . Neurosurgery . 28 . 6 . 886–887 . June 1991 . 2067614 . 10.1097/00006123-199106000-00018 .
  24. Book: Croft SM, Foreman AC . Whiplash injuries : the cervical acceleration/deceleration syndrome. 2002. Williams & Wilkins. Baltimore. 978-0-7817-2681-8. 481. 3rd. live. https://web.archive.org/web/20170314140758/https://books.google.com/books?id=De5LdqgeSf4C&pg=PA481&dq=trigeminal+neuralgia+injury&hl=en&sa=X&ei=O24nU5HoKIv8ywOIhYCoAw&redir_esc=y#v=onepage&q=trigeminal%20neuralgia%20injury&f=false. 2017-03-14.
  25. Book: Okeson JP . Bell's orofacial pains: the clinical management of orofacial pain. 2005. Quintessence Publishing Co, Inc. 0-86715-439-X. 115. http://www.quintpub.com/display_detail.php3?psku=B439X. Lindsay Harmon. 6. live. https://web.archive.org/web/20140112055333/http://www.quintpub.com/display_detail.php3?psku=B439X. 2014-01-12.
  26. Foley PL, Vesterinen HM, Laird BJ, Sena ES, Colvin LA, Chandran S, MacLeod MR, Fallon MT . Prevalence and natural history of pain in adults with multiple sclerosis: systematic review and meta-analysis . Pain . 154 . 5 . 632–642 . May 2013 . 23318126 . 10.1016/j.pain.2012.12.002 . 25807525 .
  27. De Santi L, Annunziata P . Symptomatic cranial neuralgias in multiple sclerosis: clinical features and treatment . Clinical Neurology and Neurosurgery . 114 . 2 . 101–107 . February 2012 . 22130044 . 10.1016/j.clineuro.2011.10.044 . 3402581 .
  28. Cruccu G, Biasiotta A, Di Rezze S, Fiorelli M, Galeotti F, Innocenti P, Mameli S, Millefiorini E, Truini A . Trigeminal neuralgia and pain related to multiple sclerosis . Pain . 143 . 3 . 186–191 . June 2009 . 19171430 . 10.1016/j.pain.2008.12.026 . 24353039 . 11573/361397 .
  29. De Simone R, Marano E, Brescia Morra V, Ranieri A, Ripa P, Esposito M, Vacca G, Bonavita V . A clinical comparison of trigeminal neuralgic pain in patients with and without underlying multiple sclerosis . Neurological Sciences . 26 . S2 . s150–s151 . May 2005 . 15926016 . 10.1007/s10072-005-0431-8 . 23024675 .
  30. Bora N, Parihar P, Raj N, Shetty N, Nunna B . A Systematic Review of the Role of Magnetic Resonance Imaging in the Diagnosis and Detection of Neurovascular Conflict in Patients With Trigeminal Neuralgia . Cureus . 15 . 9 . e44614 . September 2023 . 37799230 . 10547583 . 10.7759/cureus.44614 . free .
  31. Antonaci F, Arceri S, Rakusa M, Mitsikostas DD, Milanov I, Todorov V, Ramusino MC, Costa A . Pitfals in recognition and management of trigeminal neuralgia . The Journal of Headache and Pain . 21 . 1 . 82 . June 2020 . 32605593 . 7325374 . 10.1186/s10194-020-01149-8 . free .
  32. Slettebø H . Is this really trigeminal neuralgia? Diagnostic re-evaluation of patients referred for neurosurgery . Scandinavian Journal of Pain . 21 . 4 . 788–793 . October 2021 . 34333890 . 10.1515/sjpain-2021-0045 . free .
  33. Drangsholt M, Truelove EL . 2001 . Trigeminal neuralgia mistaken as temporomandibular disorder . Journal of Evidence Based Dental Practice . 1 . 1 . 41–50 . 10.1067/med.2001.116846.
  34. Ceneviz C, Maloney G, Mehta N . Myofascial pain may mimic trigeminal neuralgia . Cephalalgia . 26 . 7 . 899–901 . July 2006 . 16776712 . 10.1111/j.1468-2982.2006.01123.x .
  35. Web site: 9 December 2020 . Trigeminal Nerve Block . live . https://web.archive.org/web/20151026075104/http://emedicine.medscape.com/article/2040595-overview . 26 October 2015 . 20 November 2015 . MedScape . Cherian A, Maroju NK . Raghavendra M.
  36. Sindrup SH, Jensen TS . Pharmacotherapy of trigeminal neuralgia . The Clinical Journal of Pain . 18 . 1 . 22–27 . 2002 . 11803299 . 10.1097/00002508-200201000-00004 . 24407923 .
  37. Ahmed OL, Akinyele OA, Akindayo OA, Bamidele K . Management of Trigeminal Neuralgia using Amitriptyline and Pregablin combination Therapy. African Journal of Biomedical Research. September 2012. 15. 1. 201–203. etal. live. https://web.archive.org/web/20160822053222/http://www.bioline.org.br/pdf?md12033. 2016-08-22.
  38. Hsu CC, Chang CW, Peng CH, Liang CS . Rapid Management of Trigeminal Neuralgia and Comorbid Major Depressive Disorder With Duloxetine . The Annals of Pharmacotherapy . 48 . 8 . 1090–1092 . August 2014 . 24788987 . 10.1177/1060028014532789 . 38592913 .
  39. Lunn MP, Hughes RA, Wiffen PJ . Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia . The Cochrane Database of Systematic Reviews . 2014 . 1 . CD007115 . January 2014 . 24385423 . 10711341 . 10.1002/14651858.CD007115.pub3 .
  40. Zakrzewska JM, Linskey ME . Trigeminal neuralgia . BMJ . 348 . feb17 9 . g474 . February 2014 . 24534115 . 10.1136/bmj.g474 . live . 45305211 . https://web.archive.org/web/20161220132327/http://www.bmj.com/bmj/section-pdf/752707?path=%2Fbmj%2F348%2F7946%2FClinical_Review.full.pdf . 20 December 2016 .
  41. Holste K, Chan AY, Rolston JD, Englot DJ . Pain Outcomes Following Microvascular Decompression for Drug-Resistant Trigeminal Neuralgia: A Systematic Review and Meta-Analysis . Neurosurgery . 86 . 2 . 182–190 . February 2020 . 30892607 . 8253302 . 10.1093/neuros/nyz075 .
  42. Zakrzewska JM, Akram H . Neurosurgical interventions for the treatment of classical trigeminal neuralgia . The Cochrane Database of Systematic Reviews . 2011 . 9 . CD007312 . September 2011 . 21901707 . 8981212 . 10.1002/14651858.CD007312.pub2 .
  43. Web site: Barbor M . 5 October 2015 . MVD Bests Gamma Knife for Pain in Trigeminal Neuralgia . https://web.archive.org/web/20151110112736/http://www.medscape.com/viewarticle/852161 . 2015-11-10 .
  44. Sindou M, Tatli M . [Treatment of trigeminal neuralgia with thermorhizotomy] . Neuro-Chirurgie . 55 . 2 . 203–210 . April 2009 . 19303114 . 10.1016/j.neuchi.2009.01.015 .
  45. Dhople AA, Adams JR, Maggio WW, Naqvi SA, Regine WF, Kwok Y . Long-term outcomes of Gamma Knife radiosurgery for classic trigeminal neuralgia: implications of treatment and critical review of the literature. Clinical article . Journal of Neurosurgery . 111 . 2 . 351–358 . August 2009 . 19326987 . 10.3171/2009.2.JNS08977 .
  46. Web site: Yi-Bin C . Stereotactic radiosurgery – Cyber Knife. MedLine Plus. 20 November 2015. live. https://web.archive.org/web/20151121045317/https://www.nlm.nih.gov/medlineplus/ency/article/007274.htm. 21 November 2015.
  47. Web site: Molitor N . Dr. American Psychological Association. 27 June 2015. live. https://web.archive.org/web/20150626215241/http://www.apa.org/helpcenter/chronic-pain.aspx. 26 June 2015.
  48. Web site: Why Trigeminal Neuralgia is Considered the "Suicide Disease" . Arizona Pain Specialists LLC . 26 September 2021 .
  49. Prasad S, Galetta S . Trigeminal neuralgia: historical notes and current concepts . The Neurologist . 15 . 2 . 87–94 . March 2009 . 19276786 . 10.1097/NRL.0b013e3181775ac3 . 23500191 .
  50. Sack JJ . William Gladstone: New Studies and Perspectives. Edited by Roland Quinault, Roger Swift, and Ruth Clayton Windscheffel.Farnham: Ashgate, 2012. Pp. xviii+350. $134.95. . The Journal of Modern History . 86 . 4 . 904–905 . en . 10.1086/678722 . December 2014.
  51. Web site: Melissa Seymour: My perfect life is over . Womansday.ninemsn.com.au . 2009-06-18 . 2013-10-09 . dead . https://web.archive.org/web/20091214172147/http://womansday.ninemsn.com.au/trueconfessions/truelifestories/827292/melissa-seymour-my-perfect-life-is-over . 2009-12-14 .
  52. Web site: Salman suffering from the suicide disease . Hindustan Times . www.hindustantimes.com . 2011-08-24 . 2014-06-18 . dead . https://web.archive.org/web/20140715123125/http://www.hindustantimes.com/news-feed/archives/salman-suffering-from-the-suicide-disease/article1-737044.aspx . 2014-07-15 .
  53. News: Foley A . Serious illness meant Christy Toye didn't play in 2013 but now he's set for All-Ireland final: The Donegal player has experienced a remarkable revival . The Score . 16 September 2014 . 16 September 2014 . dead . https://web.archive.org/web/20141004120740/http://www.thescore.ie/christy-toye-donegal-1674498-Sep2014/ . 4 October 2014 .
  54. News: MP urges greater awareness of trigeminal neuralgia. BBC – Democracy Live. BBC. 20 November 2015. live. https://web.archive.org/web/20151121052602/http://news.bbc.co.uk/democracylive/hi/house_of_commons/newsid_8856000/8856344.stm. 21 November 2015. 2010-07-27.
  55. Web site: U.S. Senate: Jefferson Davis' Farewell . 2011-06-09 . live . https://web.archive.org/web/20110301111146/https://www.senate.gov/artandhistory/history/minute/Jefferson_Davis_Farewell.htm . 2011-03-01 .
  56. Book: Brent J . Charles Sanders Peirce: A Life . Bloomington . Indiana University Press . 1993 . 39–40 .
  57. News: Gorney C . Gloria. Mother Jones. November–December 1995. July 1, 2016. live. https://web.archive.org/web/20160729073134/https://www.motherjones.com/politics/1995/11/gloria. July 29, 2016.
  58. Web site: Anneli van Rooyen's road to recovery. 2016-09-12. live. https://web.archive.org/web/20170305172100/http://www.channel24.co.za/News/Local/Anneli-van-Rooyens-road-to-recovery-20110826. 2017-03-05. 2011-08-26 . News24 .
  59. News: Hardcore legend HR of Bad Brains to undergo brain surgery. The Guardian. 2017-03-02. live. https://web.archive.org/web/20170302001331/https://www.theguardian.com/music/2017/feb/03/hr-bad-brains-surgery. 2017-03-02. 2017-02-03. Guardian Music .
  60. Web site: The latest news from TNA UK. 2020-09-23. 2020-06-01.
  61. Web site: February 5, 2019. Blink 182 Drummer Travis Barker Uses CBD to Treat Rare Condition: "I Love CBD". 2021-02-11 . vaporvanity.