Trigger point injections and Greater Occipital Nerve block treating transofrmed migraine. The Role of Neuromuscular Dentistry in Long Term Relief

Transformed Migraine (common Migraine) usually has a history of beginning as episodic migraine attacks which increse in frequency. This occurs over aperiod of months to years and the Transformed Migraine (TM) occur frequently, often daily and are a combination of vascular and Tension-type Headaches. The TM can very from mild to moderate severity with epsodes of increased severity. These headaches usually begin in teen years or early 20's. Transformed Migraine attacks are frequently accompanied by nauseau, phonophobia (sensitivity to noise), photophobia (sensitivity to light) which lessen over time. A large porportion of patients are women with 90% of whom have a history of migraine without aura.

Patients with Transformed Migraines frequently report a vascular quality, that exhibits a throbbing nature. In some cases, it can be difficult to distinguish between tension-type headaches and TM. These headaches are also identical to headaches frequently seen in patients with TMD or temporomandibular dysfunction. The history of headaches beginning in teen years and usually women fit the profile of TMD sufferers. There is a theory that all headaches are a combination of neurovascular and muscular headache pain. In this view of headaches the muscular or tension-type headache can trigger the vascular (or neurogenic) headache and the Vascular (or neurogenic ) headache can serve trigger the muscular headache. This theory always fits headaches arising from the trigeminal nervous system because it controls meningeal blood flow and masticatory muscles.

These headaches usually respon beautifully to treatment with a neuromuscular orthotic which can frequently eliminate the majority of pain. Some patients, especially those with long standing pain have developed myofascial trigger points that are not completely relieved by TENS and an orthotic. Those patients frequently can be helped by manual trigger point therapy, trigger point injections and/or nerve blocks to break up myofascial trigger points.

Unfortunately clinical studies have shown that almost 80% of these patients overuse symptomatic medications. This medication over-use can frequently increase migraine occurrence. The development of Medication Overuse Headache (MOH), also known as Rebound Headache is often seen with daily use of analgesics, either prescription or over-the-counter. Other risk factors for TM or CM include high life stress (as seen in TMJ or TMD patients), snoring and /or sleep apnea a TMJ disorder according to the NHLBI (http://www.nhlbi.nih.gov/meetings/workshops/tmj_wksp.pdf), head injury and history of orofacial trauma including wisdom teeth extraction and/or orthodontics (especially involving 4 bicuspid extraction).

Depression and anxiety are features shared by patients with Migraine, TMJ disorders, Tension-type headaches and Chronic Daily Headaches. Healthy lifestyle habits including sleeping, eating and exercising are important for all of these disorders. The typical neurologist will prescribe a variety of preventive therapies including Antidepressant and Anticonvulsant medications for transformed Migraine with a goal of reverting the headaches back from daily to episodic attacks. The Neuromuscular Dentist approach is to eliminate the myofascial pain by use of TENS and a neuromuscular orthotic and eventually eliminate the nociceptive input to the brain to eliminate the original migraineor vascular headache. The original migraine is usually a result of unhealthy neuromuscular input from the trigeminal nerve or airway collapse at night due to uderlying jaw pathology that leads to snoring, sleep apnea and upper airway resistance syndrome (sleep distrubance known to cause/promote fibromyalgia)

The use of triggr point infections is a way to hasten recovery when utilizing neuromuscular dentistry. An article in The Journal of Neurology, Neurosurgery and Psychiatry examined the effect of greater occipital nerve blocks and trigger point injections on Transformed Migraine (pubmed abstract below). The article compared these proceedures with and without use of triamcinolone which the authors concluded was unnecessary for the therapeutic effect. The therapeutic effect was impressive, there was immediate reduction in pain (3.2 points) and neck pain was reduced(1.5 points) and resulted in 2.7/3.8 headache free days. Th results were equal with or without the steroid. The use of anaesthetic injections to turn off migraine pain is effective for a short period of time but when combined with neuromuscular dentistry and the use of TENS and an orthotic to prevent recurrence of the problem can be part of a long term correction of this difficult problem.

Another article in Cranio (pubmed abstract below) "Botulinum toxin, lidocaine, and dry-needling injections in patients with myofascial pain and headaches." compared treatment of myofascial trigger points with three different methods.They found that " Statistically, all the groups showed favorable results for the evaluated requisites" "Considering its reduced cost, lidocaine could be adopted as a substance of choice, and botulinum toxin should be reserved for refractory cases, in which the expected effects could not be achieved, and the use of a more expensive therapy would be mandatory." The treatment of myofascial trigger points successly treated the headaches. Breaking up the trigger points with the injection or the needle is effecteive without botulinum toxin or steroid use. Use of manual medicine, myotherapy and /or massage will also brek-up trigger points. Regardless of the method of eliminating the trigger points long term relief will depend on eliminating the noxious input to the trigeminal nervous system for long term relief. The use of the diagnostic neuromuscular dentistry orthotic is essential for most patients wanting to avoid a lifetime of drug use to treat the condition.

Yet another study in Headache (pubmed abstract below) "Botulinum toxin a in the treatment of chronic tension-type headache with cervical myofascial trigger points: a randomized, double-blind, placebo-controlled pilot study." found very significant relief of headache pain of ETTH, Episodic Tension-Type Headaches by treatment of Cervical Myofacial Trigger Points. The study showed that trigger point injection with saline gave good results for up to 12 weeks where the Botox results did last for longer periods. Again this is a case calling for combination therapy of a Neuromuscular dentistry diagnostic orthotic and trigger point injections. Utilizing the combination should cause long term elimination of myofascial trigger points. Many patients will nor require the trigger point injections but they are helpful for difficult cases and to decrease treatment time with the diagnostic orthotic.

A diagnostic orthotic is used in Neuromuscular Dentistry (http://www.sleepandhealth.com/neuromuscular-dentistry) to eliminate pain and symptoms prior tolong term correction. This 2 phase treatment protocol allows patient neuromuscular stabilization and pain relief before making any irreverible occlusal changes.

One additional PubMed article is included below "The effects of greater occipital nerve block and trigger point injection on brush allodynia and pain in migraine." which evaluated the effect of Greater Occipital Nerve Block on Migraine and
allodynia. Allodynia is when a stimulus that is not normally perceived as painful causes pain. The study had 19 patients and 17 or almost 90% had headache relief. All 19 patients had relief of allodynia. Neuromuscular Dentists should learn to use trigger point injections and Greater Occipital Nerve Blocks as part of comprehensive phase 1 treatment with neuromuscular orthotics to increase pain relief. Long term relief without the chronic use of drugs is ideally and frequently attainable with Neuromuscular Dentistry.

The Las Vegas Institute now teaches stimulation of the Accesory Nerve (cranial nerve XI) along with the Trigeminal Nerve (cranial nerve V) when utilizing TENS to relax muscles i


J Neurol Neurosurg Psychiatry. 2008 Apr;79(4):415-7. Epub 2007 Aug 6.
Greater occipital nerve block using local anaesthetics alone or with triamcinolone for transformed migraine: a randomised comparative study.
Ashkenazi A, Matro R, Shaw JW, Abbas MA, Silberstein SD.

Department of Neurology, Thomas Jefferson University, 111 South 11th Street, Suite 8130, Philadelphia, PA 19107, USA. avi.ashkenazi@jefferson.edu
OBJECTIVE: To determine whether adding triamcinolone to local anaesthetics increased the efficacy of greater occipital nerve block (GONB) and trigger-point injections (TPIs) for transformed migraine (TM). METHODS: Patients with TM were randomised to receive GONB and TPIs using lidocaine 2% and bupivacaine 0.5% + either saline or triamcinolone 40 mg. We assessed the severity of headache and associated symptoms before and 20 minutes after injection. Patients documented headache and severity of associated symptoms for 4 weeks after injections. Changes in symptom severity were compared between the two groups. RESULTS: Thirty-seven patients were included. Twenty minutes after injection, mean headache severity decreased by 3.2 points in group A (p<0.01) and by 3.1 points in group B (p<0.01). Mean neck pain severity decreased by 1.5 points in group A (p<0.01) and by 1.7 points in group B (p<0.01). Mean duration of being headache-free was 2.7+/-3.8 days in group A and 1.0+/-1.1 days in group B (p = 0.67). None of the outcome measures differed significantly between the two groups. Both treatments were well tolerated. CONCLUSIONS: Adding triamcinolone to local anaesthetics when performing GONB and TPIs was not associated with improved outcome in this sample of patients with TM.

PMID: 17682008 [PubMed - indexed for MEDLINE]

Cranio. 2009 Jan;27(1):46-53.
Botulinum toxin, lidocaine, and dry-needling injections in patients with myofascial pain and headaches.
Venancio Rde A, Alencar FG Jr, Zamperini C.

Marquette University School of Dentistry TMD and Orofacial Pain, P.O. Box 1881 Milwaukee, WI 53201-1881, USA.
Trigger point injections with different solutions have been studied mainly with regard to the management of myofascial pain (MFP) patient management. However, few studies have analyzed their effect in a chronic headache population with associated MFP. The purpose of this study was to assess if trigger point injections using botulinum toxin, lidocaine, and dry-needling injections for the management of local pain and associated headache management. Forty-five (45) myofascial pain patients with headaches that could be reproduced by activating at least one trigger point, were randomly assigned into one of the three groups: G1, dry-needling, G2, 0.25% lidocaine, at 0.25% and G3 botulinum toxin and were assessed during a 12 week period. Levels of pain intensity, frequency and duration, local postinjection sensitivity, obtainment time and duration of relief, and the use of rescue medication were evaluated. Statistically, all the groups showed favorable results for the evaluated requisites (p < or = 0.05), except for the use of rescue medication and local post injection sensitivity (G3 showed better results). Considering its reduced cost, lidocaine could be adopted as a substance of choice, and botulinum toxin should be reserved for refractory cases, in which the expected effects could not be achieved, and the use of a more expensive therapy would be mandatory.

PMID: 19241799 [PubMed - indexed for MEDLINE]

Headache. 2009 May;49(5):732-43. Epub 2008 Oct 24.
Botulinum toxin a in the treatment of chronic tension-type headache with cervical myofascial trigger points: a randomized, double-blind, placebo-controlled pilot study.
Harden RN, Cottrill J, Gagnon CM, Smitherman TA, Weinland SR, Tann B, Joseph P, Lee TS, Houle TT.

Center for Pain Studies, Rehabilitation Institute of Chicago, 446 E. Ontario, Chicago, IL 60611, USA.
OBJECTIVE: To evaluate the efficacy of botulinum toxin A (BT-A) as a prophylactic treatment for chronic tension-type headache (CTTH) with myofascial trigger points (MTPs) producing referred head pain. BACKGROUND: Although BT-A has received mixed support for the treatment of TTH, deliberate injection directly into the cervical MTPs very often found in this population has not been formally evaluated. METHODS: Patients with CTTH and specific MTPs producing referred head pain were assigned randomly to receive intramuscular injections of BT-A or isotonic saline (placebo) in a double-blind design. Daily headache diaries, pill counts, trigger point pressure algometry, range of motion assessment, and responses to standardized pain and psychological questionnaires were used as outcome measures; patients returned for follow-up assessment at 2 weeks, 1 month, 2 months, and 3 months post injection. After 3 months, all patients were offered participation in an open-label extension of the study. Effect sizes were calculated to index treatment effects among the intent-to-treat population; individual time series models were computed for average pain intensity. RESULTS: The 23 participants reported experiencing headache on a near-daily basis (average of 27 days/month). Compared with placebo, patients in the BT-A group reported greater reductions in headache frequency during the first part of the study (P = .013), but these effects dissipated by week 12. Reductions in headache intensity over time did not differ significantly between groups (P = .80; maximum d = 0.13), although a larger proportion of BT-A patients showed evidence of statistically significant improvements in headache intensity in the time series analyses (62.5% for BT-A vs 30% for placebo). There were no differences between the groups on any of the secondary outcome measures. CONCLUSIONS: The evidence for BT-A in headache is mixed, and even more so in CTTH. However, the putative technique of injecting BT-A directly into the ubiquitous MTPs in CTTH is partially supported in this pilot study. Definitive trials with larger samples are needed to test this hypothesis further.

PMID: 19178577 [PubMed - indexed for MEDLINE]

Headache. 2005 Apr;45(4):350-4.
The effects of greater occipital nerve block and trigger point injection on brush allodynia and pain in migraine.
Ashkenazi A, Young WB.

Department of Neurology, Jefferson Headache Center, Thomas Jefferson University Hospital, Philadelphia, PA 19107, USA.
OBJECTIVE: To evaluate the effect of GONB, with or without trigger point injection (TPI), on dynamic mechanical (brush) allodynia (BA) and on head pain in migraine. Background.-Patients with migraine often have cutaneous allodynia that is related to sensitization of central pain neurons. Greater occipital nerve block (GONB) is an effective treatment for migraine headache; however, its effect on cutaneous allodynia in migraine is unknown. METHODS: We studied patients with migraine and BA who were treated with GONB with or without TPI. Demographic data, migraine history, and headache features were documented. Allodynia was evaluated using a structured questionnaire and by applying a 4 x 4-inch gauze pad to skin areas in the trigeminal and cervical dermatomes. Degree of allodynia (the allodynia score) was measured on a 100-mm visual analog scale (VAS) before treatment and 10 and 20 minutes thereafter. Headache levels were assessed using an 11-point verbal scale. Allodynia scores, as well as headache levels, before and after treatment were compared. RESULTS: Nineteen patients were studied. Mean age was 43.6+/-11.8 years. Twenty minutes after treatment, headache was reduced in 17 patients (89.5%) and did not change in 2 (10.5%). The average headache level was 6.53 before treatment and 3.47, 20 minutes after it. The average allodynia score decreased after 20 minutes in all patients. Average allodynia score per site was reduced by 18.69 mm and 13.74 mm in the trigeminal and cervical areas, respectively. There was a positive correlation between allodynia index, obtained through the questionnaire, and allodynia score, obtained by examination. CONCLUSION: GONB, with or without TPI, reduced both head pain and brush allodynia in this migraine patient group.

PMID: 15836572 [PubMed - indexed for MEDLINE]

Chronic Daily Headache in Children and Adolescents

Chronic Daily Headache which affects 2-4% of female adolescents and as high as 2% of males can have a devastating effect on children. They usually occur with a chronic baseline headache with episodes of severe migraine-like are severe in intensity. This condition can last for months and there is no known underlying pathology. A neuromuscular dentist (NEUROMUSCULAR DENTISTRY http://www.sleepandhealth.com/neuromuscular-dentistry) should evaluate these patients early in treatment after organic disease is ruled out. Children are experiencing numerous changes at this period of their life including changes in hormonal status, increase peer pressures in school as well as increasing demands from school. They are also frequently going thru transitional dentition.

The advantage to orthotic treatment is there is at least a 50-80% improvement in the majority of patients treated with an orthotic. Even this partial relief could be life changing. If there is a primary problem related to jaw function and/or trigeminal nerve function Neuromuscular Dentistry allows early correction and orthodontics for case completion. It must be recognized that this condition frequently begins during orthodontic treatment.

Children with Chronic Daily Headache (CDH) problems have associated symptoms including sleep disturbances, other pain problems, dizziness that frequently results in school absence. Temporomandibular disorders are also known to cause severe Tension-Type headaches as well as other symptoms including facial pain, neck pain dizziness, ear pain, stuffy ears , sinus pain and sleep disorders. The National Heart Lung and Blood Institute considers Sleep Apnea to be a TMJ disorder in their report "CARDIOVASCULAR AND SLEEP-RELATED CONSEQUENCES OF TEMPOROMANDIBULAR DISORDERS" The report defines The term TMD as "a collection of MEDICAL and dental conditions affecting the temporomandibular joint (TMJ) and/or muscles of mastication, as well as contiguous tissue components. Symptoms range from occasional discomfort to debilitating pain and severely compromised jaw function. The masticatory apparatus is not only involved in chewing and swallowing but also in other critical tasks, including breathing and talking. This is not a dental problem but a medical problem that can cause wide spread problems including Migraines, Chronic Daily Headaches, Episodic Tension Type Headaches and Morning Headaches.

CDH is frequently associated with medication-overuse headache which is a bigger problem in children than adults as it can lead to a lifetime pattern of overuse. CDH is known to have "psychiatric comorbidity (anxiety and mood disorders) these may be a direct result of living with severe pain but may also be do to sleep apnea or other sleep disorders such as primary insomnia that is suspected as an etiology for central sensitization. The NHLBI report states " Pain linked to the TMJ and/or muscles of mastication constitutes the essential criterion for case assignment. It often qualifies as “aching”, “throbbing”, “tiring” and exhausting. About 60-90% of cases appear to experience satisfactory resolution of symptoms with a range of interventions. In contrast, the remaining group of patients does not respond well to these treatments and continues to exhibit persistent pain. Comorbid complaints, such as problems with sleep, blood pressure and breathing are not uncommon for this group of TMD patients but have not been well characterized. " The report of 60-90% relief is astounding compared to reports from neurological journals. Cases should be evaluated for TMD by a neuromuscular dentist for early treatment to lower the risk of developing central sensitization and a lifetime of chronic headaches and/or migraines. While there is a group reported to not respond to treatment it is a minority of patient.

This view is supported by Dr Barry Cooper in his paper " Relationship of temporomandibular disorders to muscle tension-type headaches and a neuromuscular orthosis approach to treatment." published in Cranio in April 2009. He reported "there was a substantial amount of evidence for a positive relationship between TMD and the prevalence of headaches, and most importantly, that these were the muscle tension-type". Dr Cooper reported " Evidence for a cause and effect relationship was strong." The paper concluded that "TMD should be considered and explored as a possible causative factor when attempts are made to determine and resolve the cause of headaches in patients with this affliction. A benefit of resolving headaches at an early stage in their development is that it might result in the reduction of its potential for progression to a chronic and possibly migraine headache condition." Early treatment to prevent progression is the ideal but relief of symptoms for 60-90 % of children as reported by the NHLBI would be sufficient to warrant evaluation of all pediaric and adolescent headaches.

Another paper in Cranio by Cooper BC, Kleinberg I. "Establishment of a temporomandibular physiological state with neuromuscular orthosis treatment affects reduction of TMD symptoms in 313 patients." reported Patients reported "overwhelming symptom relief" This study was based specifically on neuromuscular dental treatment and the results were overwhelming including "reduction of headaches and other pain symptoms." Experts consider relief of symptoms as the gold standard for assessment of effectiveness of TMD treatment. It is evident that this outcome has been achieved in this study and that taking patients from a less to a more physiological state is an effective means for reducing or eliminating TMD symptoms, especially those related to pain, most notably, headaches.

Unfortunately both adult and pre-adult patients are often not referred for neuromuscular dental evaluation for numerous reasons. A surprising reason is that physicians are not comfortable referring to dentists. This is beginning to change as physicians see excellent results of treatment of sleep apnea with oral appliances (http://www.ihatecpap.com/oral_appliance.html) and the medical community recognizes the effects of periodontal disease on chronic inflamation, cytokines and the cardiovascular effects of these changes.






PubMed abstract below:
Rev Neurol (Paris). 2009 Jun-Jul;165(6-7):521-31. Epub 2008 Nov 28.
[Management of chronic daily headache in children and adolescents]
[Article in French]

Cuvellier JC.

Service de neuropédiatrie, clinique de pédiatrie, hôpital Roger-Salengro, centre hospitalier régional et universitaire de Lille, rue du Professeur-Laine, 59037 Lille cedex, France. jc-cuvellier@chru-lille.fr
Chronic daily headache (CDH) affects 2 to 4% of adolescent females and 0,8 to 2% of adolescent males. CDH is diagnosed when headaches occur more than 4 hours a day, for greater than or equal to 15 headache days per month, over a period of 3 consecutive months, without an underlying pathology. It is manifested by severe intermittent headaches, that are migraine-like, as well as a chronic baseline headache. Silberstein and Lipton divided patients into four diagnostic categories: transformed migraine, chronic tension-type headache, new daily-persistent headache, and hemicrania continua. The second edition of the International Classification of Headache Disorders did not comprise any CDH category as such, but provided criteria for all four types of CDH: chronic migraine, chronic tension-type headache, new daily-persistent headache, and hemicrania continua. Evaluation of CDH needs to include a complete history and physical examination to identify any possibility of the headache representing secondary headaches. Children and adolescents with CDH frequently have sleep disturbance, pain at other sites, dizziness, medication-overuse headache and a psychiatric comorbidity (anxiety and mood disorders). CDH frequently results in school absence. CDH management plan is dictated by CDH subtype, the presence or absence of medication overuse, functional disability and presence of attacks of full-migraine superimposed. Reassuring, explaining, and educating the patient and family, starting prophylactic therapy and limiting aborting medications are the mainstay of treatment. It includes pharmacologic (acute and prophylactic therapy) and nonpharmacologic measures (biobehavioral management, biofeedback-assisted relaxation therapy, and psychologic or psychiatric intervention). Part of the teaching process must incorporate life-style changes, such as regulation of sleep and eating habits, regular exercise, avoidance of identified triggering factors and stress management. Emphasis must be placed on preventive measures rather than on analgesic or abortive strategies. Stressing the reintegration of the patient into school and family activities and assessing prognosis are other issues to address during the first visit. There are limited data evaluating the outcome of CDH in children and adolescents.

Cranio. 2009 Apr;27(2):101-8.
Relationship of temporomandibular disorders to muscle tension-type headaches and a neuromuscular orthosis approach to treatment.
Cooper BC, Kleinberg I.

Department of Oral Biology and Pathology of the State University of New York (SUNY) Stony Brook School of Dental Medicine, NY, USA. tmjbcooper@aol.com
A prominent etiological theory proposed for TMD related headache is that it results from a dysfunctional masticatory muscle system, wherein muscle hyperactivity is frequently caused by dental temporomandibular disharmony. The central goal of this article was to determine from a literature review of the subject whether there is significant evidence to support a relationship between headaches and TMD prevalence. A second purpose was to determine from such a review whether any relationship was one of cause and effect and whether treatment of the TMD condition can result in meaningful reduction or resolution of headaches. In the literature, there was a substantial amount of evidence for a positive relationship between TMD and the prevalence of headaches, and most importantly, that these were the muscle tension-type. Evidence for a cause and effect relationship was strong. It generally showed in numerous patients that TMD treatment of a large number of patients resulted in significant improvement in the physiological state of the masticatory system (muscles, joints and dental occlusion). Reduction or resolution of muscle tension-type headaches that were present was clinically significant. The authors concluded that TMD should be considered and explored as a possible causative factor when attempts are made to determine and resolve the cause of headaches in patients with this affliction. A benefit of resolving headaches at an early stage in their development is that it might result in the reduction of its potential for progression to a chronic and possibly migraine headache condition.

PMID: 19455921 [PubMed - indexed for MEDLINE]

Cranio. 2008 Apr;26(2):104-17.
Establishment of a temporomandibular physiological state with neuromuscular orthosis treatment affects reduction of TMD symptoms in 313 patients.
Cooper BC, Kleinberg I.

Department of Oral Biology and Pathology, State University of New York (SUNY) Stony Brook School of Dental Medicine, USA. tmjbcooper@aol.com
Comment in:

Cranio. 2008 Jul;26(3):166; author reply 167.
The objective of this investigation was to test the hypothesis that alteration of the occlusions of patients suffering from temporomandibular disorders (TMD) to one that is neuromuscularly, rather than anatomically based, would result in reduction or resolution of symptoms that characterize the TMD condition. This hypothesis was proven correct in the present study, where 313 patients with TMD symptoms were examined for neuromuscular dysfunction, using several electronic instruments before and after treatment intervention. Such instrumentation enabled electromyographic (EMG) measurement of the activities of the masticatory muscles during rest and in function, tracking and assessment of various movements of the mandible, and listening for noises made by the TMJ during movement of the mandible. Ultra low frequency and low amplitude, transcutaneous electrical neural stimulation (TENS) of the mandibular division of the trigeminal nerve (V) was used to relax the masticatory muscles and to facilitate location of a physiological rest position for the mandible. TENS also made it possible to select positions of the mandible that were most relaxed above and anterior to the rest position when the mandible was moved in an arc that began at rest position. Once identified, the neuromuscular occlusal position was recorded in the form of a bite registration, which was subsequently used to fabricate a removable mandibular orthotic appliance that could be worn continuously by the patient. Such a device facilitated retention and stabilization of the mandible in its new-found physiological position, which was confirmed by follow up testing. Three months of full-time appliance usage showed that the new therapeutic positions achieved remained intact and were associated with improved resting and functioning activities of the masticatory muscles. Patients reported overwhelming symptom relief, including reduction of headaches and other pain symptoms. Experts consider relief of symptoms as the gold standard for assessment of effectiveness of TMD treatment. It is evident that this outcome has been achieved in this study and that taking patients from a less to a more physiological state is an effective means for reducing or eliminating TMD symptoms, especially those related to pain, most notably, headaches.

PMID: 18468270 [PubMed - indexed for MEDLINE]