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Neurology, Yale University School of Medicine, New Haven, CT, USA (Dr. Tepper); Cleveland Clinic Foundation—Neurology, Cleveland, OH, USA (Dr. Stillman); Park Nicollet Headache Clinic and Research Center, Minneapolis, MN, USA (Dr. Taylor)

Note: This month's abstract review section represents my turn in the rotation as the lead editor who chooses the articles to review; in other words, “the decider.” Apparently, I was asked to join my colleagues, Dr. Fred Taylor and Dr. Stew Tepper, when Dr. Bigal decided to step down to spend more time with his family. But Stewart made it sound like he needed my input in the areas of general pain medicine, bioethics, and education.

Concerning the latter, on these pages, from time to time, I may ask my fellows to comment as an exercise in their monthly journal club. For their sake and for those interested, I will on occasion choose an article to emphasize certain points in study design and execution.

I sincerely hope the readers find this always interesting, occasionally entertaining, rarely dull, and never offensive.

—Mark J. Stillman, MD

CLASSIFICATION/CLINICAL SYNDROMES/SEMIOLOGY

  1. Top of page
  2. CLASSIFICATION/CLINICAL SYNDROMES/SEMIOLOGY
  3. CLINICAL TRIALS AND DESIGN
  4. QUALITY OF LIFE AND ITS MEASUREMENT
  5. PATHOPHYSIOLOGY AND BIOLOGY
  6. NEUROGENETICS AND CHANNELOPATHIES
  7. CLUSTER

Savioardo M, Minati L, Farina L, De Simone T, Aquino D, Mea E, Filippini G, Bussone G, Chiapparini L. Spontaneous intracranial hypotension with deep brain swelling. Brain. 2007;130:1884-1893.

Spontaneous intracranial hypotension (SIH) is caused by leakage of CSF, and characterized on magnetic resonance imaging (MRI) by brain sagging, dilatation of veins and dural sinuses, subdural fluid collections and post-contrast enhancement of the thickened dura. A few cases may present a very severe brain sagging through the tentorial notch and swelling of the diencephalic–mesencephalic structures, with absent or scarce subdural collections and post-contrast enhancement. These patients may have surprisingly few neurological signs or may become drowsy and even lapse into coma due to central herniation. We retrospectively examined the diffusion studies obtained in five patients with these MRI findings, in seven patients with SIH without brain swellings and in 10 controls. Mean diffusivity was increased in SIH patients with brain swelling in areas draining into the deep venous system, collected by the vein of Galen (vG) and straight sinus (SS). In the hypothesis that central herniation might be responsible for venous stagnation because of impaired flow of the vG into the SS, the vG/SS angle was measured. The angle formed by the vG entering the SS was not altered in patients without brain swelling (group E, 67.8 ± 10.3°, mean ± SD, range 49-80°) when compared with controls (group C, 73.3 ± 12.3°, mean ± SD, range 56-95°). It was, however, grossly decreased in patients with brain swelling (group D, 40.7 ± 12.8°, mean ± SD, range 22-61°), P < 0.001 for comparison with groups E and C. As suggested by previous studies, downward stretching of the vG and narrowing of the vG/SS angle may cause a functional stenosis at the vG–SS junction. We suggest that in the application of the Monro–Kellie doctrine to SIH, the brain volume should not be considered as always invariable.

Schievink WI, Louy C. Precipitating factors of spontaneous spinal CSF leaks and intracranial hypotension. Neurology. 2007;69:700-702.

Spontaneous intracranial hypotension is caused by a spontaneous spinal CSF leak and is an important cause of new headaches in young and middle-aged adults. Typically, the headaches are orthostatic in character, but various other headache patterns and numerous associated symptoms have been reported as well. Most patients are able to recall the exact day, if not the exact time, of the onset of symptoms. The precise cause of spontaneous spinal CSF leaks remains largely unknown, but, along with an underlying connective tissue disorder, a contribution of mechanical factors has been recognized for decades. We examined the circumstances preceding the onset of symptoms in of recurrent symptoms.

Comments: These two descriptive studies, one by an Italian group and the other from the US, elucidate the varied clinical features of a secondary headache being recognized more often in the last 15 years. The headache associated with spontaneous intracranial hypotension (SIH), as with the post-dural puncture headache, is usually a postural headache. With the availability of MRI and contrast injection, it can be diagnosed by thickening of the dura, diffuse dural enhancement, and sagging of the hindbrain in the posterior fossa. Venous engorgement and subdural collections of blood or fluid are attributed to the Monro-Kellie Doctrine*; in a closed compartment such as the skull or the spine, the loss of volume (eg, CSF) must be compensated by a corresponding increase in volume of another component (blood, plasma, or tissue).

The American study itemizes the causes of spontaneous intracranial hypotension in 80 consecutive cases, but only 1/3 could recall the precipitating event. One half of these cases noted the immediate onset of headache, and the remainder developed a headache within 24 hours. Most commonly the event recalled was a trivial nonpenetrating spine injury, but Valsalva and rapid change in position could also be associated.

Unlike post-dural puncture headache, SIH can be difficult to diagnose, especially when chronic. Savoiardo et al describe a particularly malignant presentation in which little, if any, dural enhancement is seen, and there are no subdural collections of fluid. Instead, the patient may present with coma, confusion, or a rapidly developing subcortical dementia. In their series, 11/86 (13%) patients presented with upper brainstem edema (diencephalic and mesencephalic enlargement, obliteration of the cisterns, flattening of the pons against the clivus and descent of the upper brainstem through the tentorial incisura). Almost no enhancement was seen in the dura, and there were no subdural effusions. Diffusion weighted imaging (DWI) was able to visualize the edematous process, presumably due to vasogenic edema from venous obstruction. An alternative measurement to DWI was the direct measurement of the angle between the vein of Galen and the straight sinus. In such cases, the angle was consistently decreased, compared with normals.

Failure to recognize and correct the cause of this form of SIH might result in devastating consequences.

*Has nothing to do with the Monroe Doctrine which tried to prevent foreign powers from infiltrating American spheres of influence in the Western Hemisphere during the 19th and 20th centuries.

—Mark J. Stillman, MD

One variant presentation important to remember is the “time of day” onset of headache for some SIH patients. For normal sleep pattern individuals SIH may manifest as a consistent “end of day” headache due likely to the persistence of an upright posture. The “end of day headache” may also be due to end of the day stress, or letdown from stress.

—Frederick R. Taylor, MD

The authors of the abstracted study comment on an already previously noted risk of coma with SIH, described by Dr. Randy Evans and Dr. Bahram Mokri.1 Dr. Taylor and I recommend the work of Dr. Mokri on the topic of SIH. Dr. Mokri further outlines the three major clinical presentations of SIH:

“Several modes of presentation are recognized, including:

  • 1. 
    the typical clinical-imaging syndrome with CSF pressures consistently within normal limits;
  • 2. 
    absence of diffuse pachymeningeal gadolinium enhancement with presence of low CSF pressures and typical clinical manifestations; and
  • 3. 
    absence of headaches despite low CSF pressures and presence of diffuse pachymeningeal gadolinium enhancement.

Furthermore, in some patients with headaches, the orthostatic headaches may evolve into lingering chronic daily headaches, although they may be more prominent in upright positions.”2

Evans RW, Mokri B. Spontaneous intracranial hypotension resulting in coma. Headache. 2002;42:159-160.

Mokri B. Spontaneous cerebrospinal fluid leaks: From intracranial hypotension to cerebrospinal fluid hypovolemia—evolution of a concept. Mayo Clin Proc. 1999;74:1113-1123.

—Stewart J. Tepper, MD

Young WB, Gangal KS, Aponte RJ, Kaiser RS. Migraine with unilateral motor symptoms: A case–control study. J Neurol Neurosurg Psychiatry. 2007;78:600-604.

Objective: To characterize the clinical features of nonfamilial migraine with unilateral motor symptoms (MUMS) and compare these features with those of migraine without weakness.

Methods: In total, 24 patients with MUMS and 48 matched controls were identified from a tertiary care headache centre. Using a structured interview, the migraine symptoms of both groups were characterized. Results of previously administered Beck Depression Inventories (BDI), Minnesota Multiphasic Personality Inventories and psychiatric diagnoses were collected, when available, and compared between groups.

Results: Nine patients had episodic migraine and 15 had chronic migraine. Patients with MUMS always had weakness involving the arm subjectively, and both arm and leg objectively. A give-way character was always present. Only 17% of patients with MUMS reported facial weakness; 58% reported persistent interictal weakness; 92% reported sensory symptoms. A rostrocaudal march of sensory and motor symptoms was frequently reported. Weakness was ipsilateral to unilateral headache in two-thirds of the patients. Compared with controls, patients with MUMS had had similar pain intensities, but were more likely to report other migrainous symptoms, including allodynia. In total, 38% of patients with MUMS were told they had had a stroke, and 17% believed they had had a stroke despite normal brain imaging. Patients with MUMS reported fewer affective disorders and more adjustment disorders than controls, and had similar BDI scores.

Conclusions: A syndrome of severe migraine with accompanying give-way weakness is common in tertiary care headache centres. It is accompanied by other neurological symptoms.

Dr. Peter Goadsby wrote an accompanying commentary, which we include, in part:

Goadsby PJ. MUMS the word. Migraine with unilateral motor symptoms: What can you say? J Neurol Neurosurg Psychiatry. 2007;78:553.

. . . Migraine has many secrets to uncover, and in the article by Young et al. . . . unilateral motor symptoms that do not easily fit classical descriptions for hemiparetic weakness are described. Are the patients just crazy, perhaps even malingering, or are there features clinical neurology has yet to understand about migraine?

Young et al identified 24 subjects from their tertiary referral service and compared them with 48 controls. Nine subjects had episodic migraine and 15 had chronic migraine. Each index case had a complaint of weakness in the limbs, two-thirds of which were homolateral to unilateral headache, and in each there was the phenomenon of give-away weakness. . . . More than half had weakness between attacks, and nearly all had concomitant sensory symptoms. There was frequently a rostro-caudal march of symptoms. Depression, as measured by the Beck inventory, was no more common in the affected patients.

. . . It is easy to dismiss these patients as being either benignly or malignantly crazy, elaborating symptoms for the purpose of attention to a problem that is not medically serious. However, they seem to have no excess of psychopathology, and frankly their problem (migraine) is serious and it is high time it is considered as such. Young et al offer several possibilities, including that this weakness is a form of delayed or prolonged aura, although these symptoms are unlike classical sporadic hemiplegic migraine. They suggest it is like “clasp-knife” weakness, as in classical spasticity, but my experience is that it is not velocity-dependent but rather almost attention-dependent. These patients very often perform normal tasks, such as walking, better than one might predict, unless one predicted that the more they are asked to attend the worse the weakness gets, which is what happens. If this correlation is accepted, is the problem a motor complication of disordered sensory attentional mechanisms that seem a fundamental feature of migraine? It is my clinical experience that these symptoms dissipate with good control of migraine with appropriate preventives.

I have had the privilege of working with some of the greatest clinical neuroscientists of the 20th century; neurologists bridging the bench-to-bedside valley that separates our clinical observations from scientific explanation. The enduring lesson of that studentship is that sometimes it is better to err on the generous side when judging the worthiness of symptoms, so-to-speak, rather than to jump to the judgment that symptoms not easily explained are just modified madness . . . 

Comments: The authors relate their observations of a group of migraine patients seen in a tertiary care headache center who exhibit an atypical form of unilateral weakness, and they compare this syndrome to familial and sporadic hemiplegic migraine. The 24 patients described were studied clinically and given psychometric tests and structured psychological interviews. Forty-eight controls were studied similarly and chosen from age-matched migraine patients without weakness.

What might interest the reader is the nature of the weakness in the 24 patients afflicted with MUMS (Migraine with Unilateral Motor Symptoms); all exhibit a give-way character to the weakness which raises the question of its authenticity. As noted, the motor weakness is usually ipsilateral to the headache. And, to repeat, nearly all the patients have sensory complaints which, as with the motor symptoms, progress in a rostral-caudal direction, and speech disorders, dizziness and visual symptoms are commonly seen.

If the weakness is “real”—and of course there is no way for the reader to tell without direct examination—then the patients can be considered to have a variant of sporadic hemiplegic migraine. If the appropriate family history is discovered to exist, the familial hemiplegic migraine classification can be applied. But as the authors point out, MUMS differs phenotypically from hemiplegic migraine in that the onset is later in life, it does not have occipital to frontal spreading aura, and it has a greater association with allodynia. No genetic data are presented in the study.

The authors weigh in on possible mechanisms and conjecture that the give-way weakness is related to a disordered protective reflex associated with allodynia. Allodynia, in this hypothesis, somehow is able to induce inhibition of motor activity.

If MUMS really exists, have we been missing it or misdiagnosing it all this time? Is the weakness real or just a conversion reaction? I cannot say, but we should not forget that it was not too long ago that dystonia and weakness were first described in patients with RSD (complex regional pain disorder [CRPS] type 1) [please see the next abstract by van Rijn et al]. The theories pertaining to dystonia in CRPS invoke similar mechanisms as the ones mentioned above. One wonders whether they could be part of the same disease spectrum.

—Mark J. Stillman, MD

It would seem that a phenotypic MUMS patient exists given that the Co-Editors have all seen this patient type and that my experience echoes that of Dr. Goadsby. I have even seen one patient previously diagnosed twice with stroke with normal MRI and two Stroke Rehab stays, one of up to 6 weeks. I have now followed her for 4 years and as she has improved control she no longer displays this clinical picture. Would this MUMS experience indicate that Dr. Young's work is seminal, with discovery forthcoming of the exact underlying mechanisms?

—Frederick R. Taylor, MD

van Rijn MA, Marinus J, Putter H, van Hilten JJ. Onset and progression of dystonia in Complex Regional Pain Syndrome. Pain. 2007;130:287-293.

Complex regional pain syndrome (CRPS) may lead to movement disorders (MDs) in some patients. Reliable information on the nature, chronology, and clinical determinants of MDs in CRPS patients is lacking but could provide better insight into the underlying pathophysiological mechanism. We retrospectively evaluated the clinical and temporal characteristics of MDs in patients with CRPS. Cox's proportional hazards model was used to evaluate factors influencing the onset of MDs. One hundred and eighty-five patients suffered CRPS in one or more extremities. MDs occurred in 121 patients, with dystonia (91%) being the most prevalent. Sixty-two percent of these patients displayed dystonia in multiple extremities. Patients with dystonia were on average 11 years younger and more often had CRPS in multiple extremities. The interval between the onset of CRPS and dystonia in the first affected extremity varied from less than 1 week in 26% of the patients to more than 1 year in 27%. The hazard of developing dystonia in subsequent extremities increased with the number of extremities affected by dystonia. We conclude that dystonia in CRPS shows highly variable onset latency and is associated with younger age at onset and increased risk of developing dystonia in other extremities. The delayed onset and progression of dystonia in CRPS may indicate the involvement of a different underlying mechanism, possibly associated with maladaptive neuroplasticity.

Comment: This article by Dutch researchers describes the temporal characteristics of dystonia in RSD (CRPS type 1). As mentioned above, this movement disorder has only recently been described in detail after over 150 years of recognition of causalgia and RSD.1,2CRPS and chronic daily headache share many characteristics. The nonmotor (sensory and autonomic) signs and symptoms of CRPS share the same inciting event, neurogenic inflammation. Over time, with persistent primary sensitization and neurogenic inflammation, the stage is set for the development of central sensitization, with chronic causalgic pain, spontaneous jabs of pain, allodynia, and hyperpathia. How weakness or dystonia evolves from this has something to do with alterations in the modulation of the circuitry involving the segmental communication between dorsal horn afferents and anterior horn efferent fibers, and this also includes the monosynaptic noxious withdrawal reflex. Application of the gaba-ergic agent baclofen intrathecally has led to remarkable improvement of the motor disorder in many patients with RSD-associated dystonia.3

This brings me to the topic of the head-neck connection in relation to chronic migraines and chronic post-traumatic headaches. In our clinic, my colleagues and I frequently see chronic cervical spine postural disorders and pain without any apparent structural causes. We are familiar with the literature on the frequent association of cervical pain and migraines,4likely based on the proximity of the spinal nucleus of V and the dorsal horn of the upper cervical spinal cord, but these wry necks in chronic headache sufferers look very much like dystonias. Considering the underlying mechanisms of CRPS I and migraine headaches, could we, in fact, be seeing a variant of CRPS manifesting as headache and associated C1-C2 malrotation? I feel that trigger point therapy with local anesthetic, to which I frequently add botulinum neurotoxin type A (when insurance allows it), followed by PT, is an effective treatment for this.

Mitchell SW. Injuries of Nerves and Their Consequences. London: Smith Elder; 1872.

Schwartzman RJ, Kerrigan J. The movement disorder of reflex sympathetic dystrophy. Neurology. 1990;40: 57-61.

van Hilten BJ, van de Beek WJT, Hoff JI, Voormolen JH, Delhaas EM. Intrathecal Baclofen for the treatment of dystonia in patients with reflex sympathetic dystrophy. N Engl J Med. 2000;343:625-630.

Kaniecki RB, Totten J. Cervicalgia in migraine: Prevalence, clinical characteristics, and response to treatment [Abstract]. Cephalalgia. 2001;21:296.

—Mark J. Stillman, MD

CLINICAL TRIALS AND DESIGN

  1. Top of page
  2. CLASSIFICATION/CLINICAL SYNDROMES/SEMIOLOGY
  3. CLINICAL TRIALS AND DESIGN
  4. QUALITY OF LIFE AND ITS MEASUREMENT
  5. PATHOPHYSIOLOGY AND BIOLOGY
  6. NEUROGENETICS AND CHANNELOPATHIES
  7. CLUSTER

Winner P, Cady RK, Ruoff GE, Frishberg BM, Alexander WJ, Zhang Y, Kori SH, Lener SH. Twelve-month tolerability and safety of sumatriptan–naproxen sodium for the treatment of acute migraine. Mayo Clin Proc. 2007;82:61-68.

Objectives: To evaluate the long-term safety and tolerability of sumatriptan–naproxen sodium for the treatment of moderate to severe acute migraines and to assess the safety of administration of an optional second dose.

Patients and Methods: A 12-month, multicenter, open-label safety study was conducted in adults treated for migraine attacks of moderate to severe intensity from April 14, 2004 to August 18, 2005. Safety evaluations included adverse events and laboratory tests.

Results: Of 600 patients enrolled, 565 (94%) were treated for at least one migraine. Of treated patients, 414 (73%) and 362 (64%) completed six and 12 months of treatment, respectively. Of the 24,485 attacks treated, 17,144 (70%) were treated with only one dose. On average, patients treated five migraine attacks per month, with a median of 6 days between attacks. The most common treatment-related adverse events were nausea, muscle tightness, and dizziness. Fourteen patients reported one or more serious adverse event with only one judged probably related to treatment. No deaths occurred. Eight percent of patients discontinued participation in the study because of adverse events or pregnancy. The rates of adverse events reported were no higher after treatment with two tablets (at least 2 hours apart) compared with one tablet.

Conclusions: In this 12-month data set of more than 24,000 migraine attacks in 565 patients, sumatriptan–naproxen sodium formulated in a single tablet was well tolerated when used episodically for the treatment of acute migraine. The adverse events did not differ from those expected for the individual components alone, and no new or unexpected findings occurred.

Comments: We include this article in the review this month for several reasons. This is a Phase III safety extension trial of a combination tablet which takes advantage of the possible synergy of two distinct agents – a triptan and a nonsteroidal anti-inflammatory agent. It is possible that this combination drug, the combined parts of which have been used by clinicians almost since the dawn of the triptans, may never see the light of day. This may be due to the FDA's concern about potential side effects, and in particular cardiovascular side effects; since the Vioxx debacle this issue has been a pebble in the FDA's shoe, forever irritating but hard to detect. Triptans, which are incredibly safe from the cardiovascular standpoint, are vasoconstrictors and the package insert has to be heeded if we, the presribers, are to avoid legal ramifications. Then there is the problem of the NSAIDs, which may be pro-thrombotic and have cardiovascular risks of their own.

This study follows over 24,000 treatments with the tablet, and only one cardiac event is attributed to the drug. By the study's very nature as an open label study, it cannot compare real-time cardiovascular morbidity with the morbidity of its individual components. The authors revert to comparing the tablet to the historical record of adverse side effects for its respective components.

Nowhere in the tablet's short but illustrious life has it been compared with a study arm that utilizes the individual components given simultaneously. So there is no comparison of the combination tablet with naproxen sodium tablet PLUS sumatriptan tablet in terms of efficacy and adverse events. Might the addition of sumatriptan with naproxen sodium lead not only to improved efficacy but also to increased cardiovascular adverse events?

There's the rub!

—Mark J. Stillman, MD

After the case described above of the woman who had an acute coronary syndrome temporally related to taking the combination medication, the FDA requested additional safety data on the combination tablet from multiple Phase IIIB trials, and also requested the sumatriptan naratriptan data base (SNAP data base) on adverse events. My understanding of the final stumbling block on the approval of the combination was that it was held up due to one chromosomal study on the combination vs the individual components in laboratory animals.

In the meantime, the FDA remains divided on the issue of cardiovascular risk for naproxen. At the Arcoxia panel convened by the FDA in 2007, two members of the FDA differed in their assessment of this risk:

Dr. David Graham Office of Surveillance and Epidemiology, CDER, FDA: “In 2005, the evidence . . . for naproxen was based on a study that I was a senior author on. In that study, we found an increased risk with naproxen. It was an observational study carried out at Kaiser Permanente; it wasn't a meta-analysis. [Both] the world's literature on both randomized clinical trials and published observational studies . . . agree that there is no increased risk of cardiovascular outcomes with naproxen. . . . Abstracts from 2005 [with] the data that was available [then] . . . did not say that naproxen has an increased risk. [However], it may not have reached the level of certitude that people in the reviewing divisions like to insist upon, P < .05, before they will believe that there isn't a problem. But, if you go back and you look at . . . the data, [they] suggest that naproxen does not increase the risk. It just didn't. reach the level of certitude that [the FDA] would like to see . . . If we look back at the rofecoxib program, there were signals left and right of increased cardiovascular risk at lower doses and higher doses. It's there in the medical officers review. Anybody in the world who wants it can go to the FDA website and see it . . . But if you look at the label when rofecoxib first came on the market, there is no mention of cardiovascular disease there. That's because FDA uses a “P” value.

When a drug comes for approval, it says, “The drug doesn't work, and you've got to show me that it does”. The “P” has to be <0.05 for the FDA to say, “Okay, we believe that the drug works”. For safety, it is just reversed.

We assume that the drug is safe, and unless you can show me P < .05 that it is not safe, we go ahead and assume it is safe. That's what I am saying is a misuse of “P” values and statistics to the way FDA approaches safety. What I would recommend for safety is establishing a predefined threshold that you have to have the risk be below . . .”

Dr. Meyer of FDA: “Given what Dr. Graham has just said, I would think we would want definitive data to inform a conclusion that naproxen is safe. Absent that, our decision in 2005 . . . [was] the safest thing . . . to conclude, that Naprosyn probably did have a cardiovascular risk.”1

—Stewart J. Tepper, MD

QUALITY OF LIFE AND ITS MEASUREMENT

  1. Top of page
  2. CLASSIFICATION/CLINICAL SYNDROMES/SEMIOLOGY
  3. CLINICAL TRIALS AND DESIGN
  4. QUALITY OF LIFE AND ITS MEASUREMENT
  5. PATHOPHYSIOLOGY AND BIOLOGY
  6. NEUROGENETICS AND CHANNELOPATHIES
  7. CLUSTER

Cole JC, Lin P, Rupnow MF. Validation of the Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v. 2.1) for patients undergoing prophylactic migraine treatment. Qual Life Res. 2007;16:1231-1237.

Objective: Health-related quality of life (HRQoL) is an important outcome measure of migraine treatments. Although a number of migraine-specific HRQoL questionnaires exist, their measurement characteristics have only been examined for patients undergoing acute treatment of migraine. The goal of the current study was to evaluate measurement properties of the widely used Migraine-Specific Quality of Life Questionnaire version 2.1 (MSQ v. 2.1) within a group of patients undergoing prophylactic migraine treatment.

Methods: Various measurement properties of the MSQ were examined in a sample of 916 migraineurs undergoing prophylactic treatment who had scores at baseline and follow-up, as well as baseline SF-36. First, we used confirmatory factor analysis and differential item functioning to assure the accuracy and stability across groups of the MSQ scoring for all three subscales (Role Restrictive, Role Preventive, and Emotional Functioning). Next, item- and scale-level properties were examined, such as item-total correlations, internal consistency, and convergent and discriminant validity.

Results: Initial findings revealed that item 12 (measuring frustration on the Emotional Functioning subscale) performed poorly. Subsequent to its removal, the 13-item MSQ displayed excellent measurement properties, including stable latent structure at baseline and endpoint, no gender or age biases on items, appropriate item-level and scale-level reliabilities, and markedly higher convergent validity compared with discriminant validity.

Conclusion: The 13-item MSQ appears to be an appropriate measure of migraine-specific HRQoL for patients undergoing migraine prophylaxis. Moreover, given the stability of the latent structure over time, the interpretation of scores is likely to remain quite consistent throughout a clinical trial.

Comments: The development of any screening test or scale, such as a scale of quality of life, entails much more work than meets the eye, and successfully bringing it to common usage, a major challenge. A researcher soon discovers the difficulties when he is trying to mount a multinational study, as the study must show internal consistency, validity, sensitivity, and specificity not only in the native language but also in the other languages used by patients in the study. The Migraine-Specific Quality of Life (MSQ) is one such questionnaire, but it was designed and validated to study migraine patients given abortive therapy.

The above study validates an altered version of the MSQ for patients undergoing prophylactic therapy and uses the HIT-6 and HDI as comparison. As with the original MSQ, the MSQ version 2.1 delves into the three domains of function: role restrictive, role preventive, and emotional function. The authors felt that one of the 14 questions, question 12, which dealt with the frustration of patients with migraines that prevent function was not integral to the sensitivity of the test. They therefore eliminated it, leaving a 13-item scale that demonstrated good internal consistency, convergent validity and discriminant validity.

This questionnaire should get lots of use in the near future as there is greater emphasis on preventive migraine therapy and resultant quality of life.

—Mark J. Stillman, MD

I concur that a migraine preventive QOL tool is needed. Currently I screen disability at consult with HDI, MIDAS, and HIT-6, with Migraine-ACT for the success of acute therapy. I have considered MIDAS as a preventive QOL measure albeit the tool was designed for acute therapy assessment. But I know I will have to consider dropping one of these tools as patients already complain about the measurement burden. I do have the patients do these tests at home at their leisure as they determine when they wish to send them. As for their use in a busy primary care practice, generally “forget about it”!

—Frederick R. Taylor, MD

I participated in the international study group that created Migraine-ACT, a validated instrument for evaluation of acute migraine treatment, which allows a decision as to whether acute treatment is working or requires a switch. As Dr. Stillman suggests, we had to deal with English, Spanish, Italian, and German in our international team and results. We, too, evaluated different domains before coming up with following test for acute treatment:

  • • 
    “Consistency of response: Does your migraine medication work consistently, in the majority of your attacks?
  • • 
    Global assessment of relief: Does the headache pain disappear within 2 hours?
  • • 
    Impact: Are you able to function normally within 2 hours?
  • • 
    Emotional response: Are you comfortable enough with your medication to be able to plan your daily activities?”1

“Scoring the questionnaire is by simple summing of the ‘yes’ scores (range: 0 to 4) . . . A Migraine-ACT score of ≤2 corresponded with a need to consider changing the patient's acute medication.”2

The importance of the Cole et al study is the potential for a similar test in migraine preventive treatment.

Dowson AJ, Tepper SJ, Baos V, Baudet F, D’Amico D, Kilminster S. Identifying patients who require a change in their current acute migraine treatment: The Migraine Assessment of Current Therapy (Migraine-ACT) questionnaire. Curr Med Res Opin. 2004; 20:1125-1135.

Kilminster SG, Dowson AJ, Tepper SJ, Baos V, Baudet F, D’Amico D. Reliability, validity, and clinical utility of the Migraine-ACT questionnaire. Headache. 2006; 46:553-562.

—Stewart J. Tepper, MD

PATHOPHYSIOLOGY AND BIOLOGY

  1. Top of page
  2. CLASSIFICATION/CLINICAL SYNDROMES/SEMIOLOGY
  3. CLINICAL TRIALS AND DESIGN
  4. QUALITY OF LIFE AND ITS MEASUREMENT
  5. PATHOPHYSIOLOGY AND BIOLOGY
  6. NEUROGENETICS AND CHANNELOPATHIES
  7. CLUSTER

Levy D, Burstein R, Kainz V, Jakubowski M, Strassman AM. Mast cell degranulation activates a pain pathway underlying migraine headache. Pain. 2007;130:166-176.

Intracranial headaches such as that of migraine are generally accepted to be mediated by prolonged activation of meningeal nociceptors but the mechanisms responsible for such nociceptor activation are poorly understood. In this study, we examined the hypothesis that meningeal nociceptors can be activated locally through a neuroimmune interaction with resident mast cells, granulated immune cells that densely populate the dura mater. Using in vivo electrophysiological single unit recording of meningeal nociceptors in the rat we observed that degranulation of dural mast cells using intraperitoneal administration of the basic secretagogue agent compound 48/80 (2 mg/kg) induced a prolonged state of excitation in meningeal nociceptors. Such activation was accompanied by increased expression of the phosphorylated form of the extracellular signal-regulated kinase (pERK), an anatomical marker for nociceptor activation. Mast cell-induced nociceptor interaction was also associated with downstream activation of the spinal trigeminal nucleus as indicated by an increase in c-fos expression. Our findings provide evidence linking dural mast cell degranulation to prolonged activation of the trigeminal pain pathway believed to underlie intracranial headaches such as that of migraine.

Comment: Yet another study from this productive laboratory in Boston and one that adds another piece to the jigsaw puzzle depicting the genesis of a migraine. The authors have created a laboratory model showing that mast cells, those peculiar purple corpuscles on H & E, are major players in neurogenic inflammation and trigeminovascular reflex.

When the trigeminal ganglion is electrically stimulated, mast cells, which populate the dura, degranulate. At the same time, electrically activated nociceptors release the cytokines CGRP and substance P, in turn leading to further dural mast cell degranulation. Mast cell degranulation releases not only histamine but other mediators, such as prostaglandins, leukotrienes, cytokines and chemokines, renin, TNF alpha, and IL-6. One or any of these may be responsible for further stimulation of the meningeal nociceptors involved in the trigeminovascular reflex. The result of this cascade is auto-stimulation and amplification of the migraine pain (primary sensitization). Some believe that the experimental construct of electrical stimulation of the trigeminal ganglion may best simulate a migraine with aura, where H+, K+, and glutamate are expressed during cortical spreading depression.

In another experiment, when chemically stimulated, mast cells also degranulate and this results in prolongation of excitation in the trigeminal nucleus caudalis (TNC) nociceptive neurons, as measured by c-fos expression. Sumatriptan, as a serotonin agonist, prevents c-fos expression in the face of experimental mast cell degranulation. This was felt to be through sumatriptan's ability to prevent the release of inflammatory neuropeptide mediators.

Combining the above, dural mast cells exhibit the potential ability to auto-amplify pain once a cortical spreading depression activates a meningeal nociceptor during migraine with aura. This opens new avenues for the abortive treatment of migraines, and even prevention of migraine.

Besides the brain, the other organ where mast cells may play an important pathological role is the heart. They are a previously unknown source of renin, which acts on constitutive angiotensinogen to make angiotensin I. Angiotensin converting enzyme converts this to angiotensin II, the potent vasospastic agent. In the heart. Neuropeptide Y is released with norepinephrine by sympathetic nerves, allowing the degranulation of mast cells, which may start the cascade of vasospasm and ischemia associated with such phenomena as myofibrillary necrosis.1,2In the brain, this cascade may be another set of mechanisms for mast cell activation, along with cortical spreading depression associated with migraines with aura. The role played by the renin-angiotensin system in migraine may explain the unexplained white matter lesions seen in chronic migraine patients as well as the efficacy of ACE inhibitors and ARBs in the prophylaxis of migraines. (See the article by Fusayasu abstracted here.)

Silver RB, Reid AC, et al. Mast cells: A unique source of renin. Proc Natl Acad Sci USA. 2004;101:13607-13612. (published on line September 1, 2004, 10.1073/pnas.0403208101).

Davisson RL, Oliverio MI, et al. Divergent functions of angiotensin II receptor isoforms in the brain. J Clin Invest. 2000;106:103-106.

—Bushra Malik, MD (Headache Fellow); Mark J. Stillman, MD

Fusayasu E, Kowa H, Takeshima T, Nakaso K, Nakashima K. Increased plasma substance P and CGRP levels, and high ACE activity in migraineurs during headache-free periods. Pain. 2007;128:209-214.

Substance P (SP), calcitonin gene-related peptide (CGRP), and angiotensin converting enzyme (ACE) may have roles in trigeminovascular nociceptive mechanisms. We investigated interictal levels of SP, CGRP, ACE activity, and their correlation, in a sample of migraineurs. Forty-one patients suffering from migraine with aura (MA), 54 without aura (MO), and 52 nonheadache subjects (controls) participated in this study. Blood samples were collected from cubital veins. Plasma levels of SP and CGRP were measured by enzyme immunoassay. Plasma ACE activities were measured spectrophotometrically. SP levels in MA (6.6 ± 3.7 pg/mL; mean ± SD) and MO (6.6 ± 3.2 pg/mL) were significantly higher than in controls (4.8 ± 2.4 pg/mL) (P < .01). CGRP levels in MA (18.8 ± 8.8 pg/mL) and MO (19.1 ± 9.4 pg/mL) were also significantly higher than in controls (13.4 ± 4.4 pg/mL) (P < .01). ACE activities in MA (34.6 ± 19.0 U/L) were significantly higher than in MO (25.3 ± 13.2 U/L) and controls (27.0 ± 20.4 U/L) (P < .05). There was a significant correlation between SP and CGRP levels (P < .05). In MA, SP and CGRP showed a tendency toward positive correlation, which was not significant. There was a weak, but significant positive correlation between SP levels and ACE activities (P < .01). However, a relationship between ACE activities and CGRP levels was not observed. The data suggest that SP, CGRP, and ACE are relevant to migraine pathophysiology, and that they may interact.

Comments: Dr. Taylor listed this reference in the October 2007 Abstracts, but we ran out of room to abstract it fully, and it never received a formal comment. I have therefore revived it because it pertains to the Levy et al article in Pain on mast cell degranulation.

Substance P (SP) and CGRP are neuropeptides released from activated nociceptors during migraine initiation. In the currently held construct of migraine, CGRP is felt to be the most important effector of migraine trigeminovascular nociceptive mechanisms and among the most potent vasodilators in the human body. Angiotensin converting enzyme is the enzyme involved in the degradation of SP, but its role, along with the role of angiotensin receptors is not entirely known. These researchers found interictal plasma levels of SP and CGRP to be significantly higher in patients with migraines with and without aura compared with age-matched nonheadache controls. And interictal ACE levels were significantly higher in a population of migraineurs with aura than in the group of migraineurs without aura or nonheadache controls. This suggested that the two neuropeptides might be associated with vascular dysregulation interictally and that the ACE activity seen in the migraineurs with aura might predispose these migraineurs to cranial vascular reactivity (leading to cortical spreading depression).

This article should be read in context with the article about mast cell degranulation and activation of migraine pain pathways by Levy et al, discussed above. In contrast to another recently published article on a potential inflammatory mediator of migraine pain,1this study by Fusayasu et al commends itself in that it:

  • 1.
    Makes appropriate use of age-matched nonheadache controls, instead of relying on historical controls; and
  • 2.
    Adequately documents the necessary oversight of patient confidentiality, human rights protections, and informed consent.

Rozen T, Swidan SZ. Elevation of CSF tumor necrosis factor alpha levels in new daily persistent headache and treatment refractory chronic migraine. Headache. 2007;47:1050-1057.

—Mark J. Stillman, MD

Several additional points. The SP antagonists have proven ineffective in the treatment of migraine, while the CGRP antagonists show great clinical promise.1,2

Despite initial enthusiasm for leukotriene antagonists working on the mast cell model described by Dr. Stillman, the one randomized clinical trial of montelukast in migraine prevention failed the primary endpoint.3,4As noted by Dr. Stillman, there is evidence for effectiveness for lisinopril, and ACE inhibitor, and candesartan, an ARB, in migraine prevention, in the form of one small randomized controlled study for each.5,6And I would like to recommend two excellent reviews on the issue of CGRP and migraine by Dr. Paul Durham.7,8

Olesen J, Diener HC, Husstedt IW, Goadsby PJ, Hall D, Meier U, Pollentier S, Lesko LM; BIBN 4096 BS Clinical Proof of Concept Study Group. Calcitonin gene-related peptide receptor antagonist BIBN 4096 BS for the acute treatment of migraine. N Engl J Med. 2004;350:1104-1110.

Ho T, Mannix L, Fan X, Assaid C, Furtek C, Jones C, Rapoport A. Efficacy and tolerability of a novel, oral CGRP antagonist, MK-0974, in the acute treatment of migraine: Results from a phase 2 randomized, controlled, clinical trial. Headache. 2007;47:748-749 (abstract).

Sheftell F, Rapoport A, Weeks R, Walker B, Gammerman I, Baskin S. Montelukast in the prophylaxis of migraine: A potential role for leukotriene modifiers. Headache. 2000;40:158-163.

Brandes JL, Visser WH, Farmer MV, Schuhl AL, Malbecq W, Vrijens F, Lines CR, Reines SA; Protocol 125 Study Group. Montelukast for migraine prophylaxis: A randomized, double-blind, placebo-controlled study. Headache. 2004;44:581-586.

Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): Randomised, placebo controlled, crossover study. BMJ. 2001;322:19-22.

Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker: A randomized controlled trial. JAMA. 2003;289:65-69.

Durham PL. CGRP-receptor antagonists – a fresh approach to migraine therapy? N Engl J Med. 2004;350:1073-1075.

Durham PL. Calcitonin gene-related peptide (CGRP) and migraine. Headache. 2006;46(Suppl. 1): S3-S8.

—Stewart J. Tepper, MD

As in life and scientific endeavors, the greater the complexity, the more questions there are to be answered. This is good for migraine patients and their practitioners, as one day this may all lead to improved therapies. So let's commend good science and add as much complexity as we can handle!

—Frederick R. Taylor, MD

Obermann M, Yoon M-S, Ese D, Maschke M, Kaube H, Diener H-C, Katsarava Z. Impaired trigemninal nociceptive processing in patients with trigeminal neuralgia. Neurology. 2007;69:835-841.

Background: Trigeminal neuralgia (TN) usually leads to paroxysms of short lasting but very severe pain. Between the attacks the patient is usually asymptomatic, but a constant dull background pain may persist in some cases. The mechanisms associated with the development of this chronic pain are not well understood.

Objective: To determine trigeminal nociceptive fiber impairment in patients with TN comparing symptomatic and nonsymptomatic sides using the nociceptive blink reflex (nBR) and pain-related evoked potentials (PREP) and to identify possible central mechanisms of pain chronicity.

Methods: We investigated 24 patients with TN without and 18 patients with TN with concomitant chronic facial pain. PREP and nBR were investigated following nociception specific electrical stimulation on both sides of the face and in each division of the trigeminal nerve (V1, V2, and V3).

Results: We found prolonged PREP and nBR latencies and reduced amplitudes comparing symptomatic and nonsymptomatic sides in all patients with TN. In patients with chronic facial pain, however, PREP amplitudes were larger and latencies shorter compared with patients with TN without facial pain, while nBR results were similar across groups.

Conclusion: The data suggest an impairment of the trigeminal nociceptive system due to demyelination and/or axonal dysfunction on the symptomatic side and locate this defect close to the root entry zone in the brainstem. Moreover, central facilitation of trigeminal nociceptive processing was observed in patients with trigeminal neuralgia with concomitant chronic facial pain indicating overactivation of central sensory transmission. This may represent a possible adaptive mechanism for the development of chronic pain.

Comment: Using a custom-built planar concentric electrode that effectively limits depolarization to the superficial dermis containing nociceptive A-delta fibers (and spares the deeper A-beta fibers), these researchers studied patients with typical trigeminal neuralgia (TN) and compared them to patients with trigeminal neuralgia with concomitant chronic facial pain (TNcp). The parameters they measured were the nociceptive blink reflex (nBR) and the pain-related evoked potential (PREP) in an attempt to explain the neurophysiology of the chronic pain seen in TNcp. In each patient, they studied all three divisions of the trigeminal nerve on the symptomatic and asymptomatic sides. The nBR was used as a gauge of peripheral damage as it is a monosynaptic reflex arc, while the PREP reflects the functioning of the supraspinal pathways.

Their findings have important implications in the understanding of chronic facial pain disorders and actually pose more questions for the future. The latter point relates to the fact that the chronification of trigeminal neuralgia, manifested by the lingering pain that remains after the tic-like pain episodes, is NOT related to duration of the disease according to this study, but to the development of some supraspinal mechanism of dysmodulation.

The researchers, who have been studying patients with this novel electrode method for the better part of a decade, found pronounced decreases in PREP and nBR amplitudes, associated with delayed latencies on the symptomatic side independent of the presence of chronic pain. As these abnormalities in both the PREP and nBR were found in all divisions of the trigeminal nerve on the symptomatic side, they reasoned the lesion to be proximal to the trigeminal ganglion, in the region of root entry zone. When results of the nBR and PREP were compared between TN and TNcp patients, there was no statistical difference in the nBR, but the PREPs exhibited increased amplitudes and shortened latencies on both symptomatic and nonaffected sides of the TNcp patients only. This important finding suggests central facilitation of sensory transmission in patients with trigeminal neuralgia and chronic lingering pain (ie, TNcp patients).

Readers familiar with the cascade of sensitization of headaches will recognize the parallels with Dr. Rami Burstein's arguments on sensitization of secondary and tertiary (thalamic) nociceptive neurons.1The fact that the painful and nonpainful side of the face in TNcp patients all show this speaks for a site of sensitization higher up than the trigeminal nucleus caudalis.

Burstein R, et al. An association between migraine and cutaneous allodynia. Ann Neurol. 2000;47:614-624.

Dr. James Watson wrote an accompanying editorial to this article from which we quote in part:

Watson PC. From paroxysmal to chronic pain in trigeminal neuralgia: Implication of central sensitization. Neurology. 2007;69:817-818.

What is most novel in the Obermann et al study is the comparison between typical and atypical TN. While patient numbers were small, there was no difference in duration of disease between those who had lingering pain (atypical TN) and those with classic TN, challenging the theory that atypical TN is a function of TN disease duration. Second, they were able to electrophysiologically demonstrate central sensitization in the atypical TN group, suggesting a possible explanation for the development of atypical TN. More interestingly, localization of where this central sensitization occurs is possible from their data. Contrary to prior theories of TN central sensitization, since there was no difference between the nBRs in those with and without chronic pain, it does not appear to represent wind-up of wide-dynamic neurons within the brainstem spinal trigeminal nucleus . . . caudalis. Localization would suggest higher supraspinal pathways are implicated.

—Mark J. Stillman, MD

Maarrawi J, Peyron R, Mertens P, Costes N, Magnin M, Sindou M, Laurent B, Garcia-Larrea L. Motor cortex stimulation for pain control induces changes in the endogenous opioid system. Neurology. 2007;69:827-834.

Background: Motor cortex stimulation (MCS) for neuropathic pain control induces focal cerebral blood flow changes involving regions with high density of opioid receptors. We studied the possible contribution of the endogenous opioid system to MCS-related pain relief.

Methods: Changes in opioid receptor availability induced by MCS were studied with PET scan and [(11)C]diprenorphine in eight patients with refractory neuropathic pain. Each patient underwent two preoperative (test–retest) PET scans and one postoperative PET scan acquired after 7 months of chronic MCS.

Results: The two preoperative scans, performed at 2 weeks interval, did not show significant differences. Conversely, postoperative compared with preoperative PET scans revealed significant decreases of [(11)C]diprenorphine binding in the anterior middle cingulate cortex (aMCC), periaqueductal gray (PAG), prefrontal cortex, and cerebellum. Binding changes in aMCC and PAG were significantly correlated with pain relief.

Conclusion: The decrease in binding of the exogenous ligand was most likely explained by receptor occupancy due to enhanced secretion of endogenous opioids. Motor cortex stimulation (MCS) may thus induce release of endogenous opioids in brain structures involved in the processing of acute and chronic pain. Correlation of this effect with pain relief in at least two of these structures supports the role of the endogenous opioid system in pain control induced by MCS.

Comment: Since the early 1990s, motor cortex stimulation (MCS) has garnered increasing attention as treatment for refractory pain syndromes, in particular, neuropathic pain disorders. The mechanism explaining its success is not known, and this article attempts to compare opioid receptor availability before and after chronic MCS for the (successful) treatment of chronic refractory neuropathic pain. This study followed the recognition that pain relief after MCS is delayed in relation to the periods of stimulation and is associated with prolonged activation of areas of the brain associated with pain processing (by more than 60 minutes after discontinuation of MCS): the anterior cingulate gyrus (ACG) and the periaqueductal gray matter (PAG). The authors surmised that functional changes (ie, plasticity) may be occurring in the areas known to be well endowed with opioid receptors, and proceeded to study this aspect functionally utilizing PET scanning and a radio-tagged nonselective opioid antagonist. They studied eight patients with central pain syndromes (seven post-stroke and one post-trigeminal injury pain) before and after MCS using epidural stimulating leads and voxel-wise comparison. All patients demonstrated significant clinical relief with MCS and this correlated with reduced opioid receptor binding potential.

The authors found this significantly decreased opioid receptor density in areas of the brain intimately involved in pain processing/modulation: PAG, anterior middle cingulate cortex, prefrontal cortex, and cerebellum. They reasoned this was due to an increase in endogenous opioid release, and the resulting increased occupancy of available opioid receptors left fewer receptors for the radioligand-bound opioid receptor antagonist. In addition, increased endogenous occupancy would likely lead to down-regulation of remaining receptors over time. To the headache research community, these brain areas are the same ones noted by Weiller et al in 1995 when they imaged spontaneous migraine in the PET scanner.1This study also compliments the above study of Obermann et al on the refractoriness of trigeminal neuralgia associated with lingering chronic neuropathic pain.

Weiller C, May A, Limmroth V, Jüptner M, Kaube H, Schayck RV, Coenen HH, Diener HC. Brain stem activation in spontaneous human migraine attacks. Nat Med. 1995;1:658-660.

—Mark J. Stillman, MD

NEUROGENETICS AND CHANNELOPATHIES

  1. Top of page
  2. CLASSIFICATION/CLINICAL SYNDROMES/SEMIOLOGY
  3. CLINICAL TRIALS AND DESIGN
  4. QUALITY OF LIFE AND ITS MEASUREMENT
  5. PATHOPHYSIOLOGY AND BIOLOGY
  6. NEUROGENETICS AND CHANNELOPATHIES
  7. CLUSTER

Thomsen LL, Kirchmann M, Bjornsson A, Stefansson H, Jensen RM, Fasquel AC, Petursson H, Stefansson M, Frigge ML, Kong A, Gulcher J, Stefansson K, Olesen J. The genetic spectrum of a population-based sample of familial hemiplegic migraine. Brain. 2007;130:346-356.

Familial hemiplegic migraine (FHM) is a rare subtype of migraine with aura and transient hemiplegia. FHM mutations are known in three genes, the CACNA1A (FHM1) gene, the ATP1A2 (FHM2), and the SCN1A (FHM3) gene and seem to have an autosomal-dominant mode of inheritance. The aim of this study was to search for FHM mutations in FHM families identified through a screen of the Danish population of 5.2 million people. FHM patients were diagnosed according to the International Classification of Headache Disorders and all FHM patients had a physical and neurological examination by a physician. A total of 147 FHM patients from 44 different families were identified; 43 FHM families participated in this study. Linkage analysis of these families shows clear linkage to the FHM locus (FHM1) on chromosome 19, supportive linkage to the FHM2 locus whereas no linkage was found to the FHM3 locus. Furthermore, we sequenced all exons and promoter regions of the CACNA1A and ATP1A2 genes and screened for the Q1489K mutation in the SCN1A gene. CACNA1A gene mutations were identified in three of the FHM families, two known FHM mutations, R583Q and T666M and one novel C1369Y mutation. Three FHM families were identified with novel mutations in the ATP1A2 gene; a family with a V138A mutation, a family with a R202Q mutation and a family with a R763C mutation. None of the Danish FHM families have the Q1489K mutation in the SCN1A gene. Our study shows that only 14% (6/42) of FHM families in the general Danish population have exonic FHM mutations in the CACNA1A or ATP1A2 gene. The families we identified with FHM mutations in the CACNA1A and ATP1A2 genes were extended, multiple affected families whereas the remaining FHM families were smaller. The existence of many small families in the Danish FHM cohort may reflect less bias in FHM family ascertainment and/or more locus heterogeneity than described.

Fertleman CR, Ferrie CD, Aicardi J, Bednarek NA, Eeg-Olofsson O, Elmslie FV, Griesemer DA, Goutières F, Kirkpatrick M, Malmros IN, Pollitzer M, Rossiter M, Roulet-Perez E, Schubert R, Smith VV, Testard H, Wong V, Stephenson JB. Paroxysmal extreme pain disorder (previously familial rectal pain syndrome) Neurology. 2007;69:586-595.

Objective: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SN9A.

Methods: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals.

Results: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete.

Conclusions: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.

Comment: These two neurogenetic studies, the first one from Brain and the second from Neurology, illustrate the importance of genetics in the study of pain. The first study from Denmark related a screening pf the entire Danish population for the three known missense mutations responsible for familial hemiplegic migraine (FHM). Each mutation is responsible for dysfunction of an ion channel: CACNA1A (FHM1); ATP1A2 (FHM2, Na+/K+ ATPase pump); and SCN1A encoding the Nav2.1 Na+ channel (FHM 3). In previous studies, these three mutations accounted for 50-70% of known families of FHM; however, in the above study, no families in Denmark were found with FHM3 and only 14% of FHM families had FHM1 or 2, suggesting much more work needs to be carried out.

The second article is a description of a new missense mutation on yet another voltage gated sodium channel. The mutation in this family takes place in the SCN9A gene encoding the alpha subunit in Nav1.7 voltage gated sodium channel. This missense mutation results in a gain in function and enhanced activity in the neurons (peripheral sensory neurons in the dorsal root ganglia, sympathetic ganglia, and nociceptors.) In the proband's family, the patients get attacks in the perineum, eye region and the jaw associated with autonomic changes. The pain is neuropathic: severe, tic-like and either spontaneous or induced by a maneuver such as touch or defecation. The pain is associated with sudomotor changes many times. The attacks can be associated with leg weakness, somewhat reminiscent of MUMS, autonomic changes of the face similar to the trigeminal autonomic cephalalgias, and sympathetic signs of failure seen in cluster attacks.

One last thing. The involved voltage gated sodium channel is also the site of a mutation in inherited insensitivity to pain, a severely deforming and morbid disorder, and erythromelalgia, a condition of the extremities associated with allodynic type discomfort of the distal extremities.

Catalina Cleves-Bayon, MD (Pediatric Headache Fellow); Mark J. Stillman, MD

Brennan KC, Romero Reyes M, López Valdés HE, Arnold AP, Charles AC. Reduced threshold for cortical spreading depression in female mice. Ann Neurol. 2007;61:603-606.

The prevalence of migraine is much greater in female than male individuals. Cortical spreading depression (CSD) is thought to be a fundamental mechanism of migraine, and CSD in rodents is used as a model for migraine. We used optical intrinsic signal imaging and electrophysiological techniques to investigate CSD in C57Bl/6 mice. Using two different methods for induction of CSD, we found that female mice had a significantly reduced threshold for induction of CSD compared with male mice. These results suggest an increased cortical excitability in female mice that may be independent of the estrous cycle.

Comment: While we were on the issue of cortical spreading depression, channelopathies, and FHM, I thought this study by Dr. Andy Charles' group was worth passing on!

Stewart J. Tepper, MD

CLUSTER

  1. Top of page
  2. CLASSIFICATION/CLINICAL SYNDROMES/SEMIOLOGY
  3. CLINICAL TRIALS AND DESIGN
  4. QUALITY OF LIFE AND ITS MEASUREMENT
  5. PATHOPHYSIOLOGY AND BIOLOGY
  6. NEUROGENETICS AND CHANNELOPATHIES
  7. CLUSTER

Rapoport AM, Mathew NT, Silberstein SD, Dodick D, Tepper SJ, Sheftell FD, Bigal ME. Zolmitriptan nasal spray in the acute treatment of cluster headache: A double-blind study. Neurology. 2007;69:821-826.

Objective: To evaluate the efficacy and tolerability of zolmitriptan 5-mg and 10-mg nasal spray (ZNS) vs placebo in the acute treatment of cluster headache.

Design/Methods: We conducted a multicenter, double-blind, randomized, three-period crossover study using ZNS 5 mg, ZNS 10 mg, and placebo. Headache intensity was rated by a 5-point scale: none, mild, moderate, severe, or very severe. The primary efficacy measure was headache response (pain reduced from moderate, severe, or very severe at baseline, to mild or none) at 30 minutes. Logistic regression was used to account for treatment period effect as well as for cluster headache subtype effect.

Results: A total of 52 adult patients treated 151 attacks. For the primary endpoint, both doses reached significance at 30 minutes (placebo = 30%, ZNS 5 mg = 50%, ZNS 10 mg = 63.3%). For headache relief, ZNS 10 mg separated from placebo at 10 minutes (24.5% vs 10%). Zolmitriptan 5 mg separated from placebo at 20 minutes (38.5% vs 20%). For pain-free status, ZNS 10 mg was superior to placebo at 15 minutes (22.0% vs 6%). Both doses had higher pain-free rates than placebo at 30 minutes (placebo = 20%, ZNS 5 mg = 38.5%, ZNS 10 mg = 46.9%). Side effects were mild and seen in 16% of those attacks treated with placebo, 25% of attacks treated with ZNS 5 mg, and 32.7% treated with ZNS 10 mg.

Conclusions/Relevance: Zolmitriptan nasal spray, at doses of 5 and 10 mg, is effective and tolerable for the acute treatment of cluster headache.

Comment: This study should not be a surprise as sumatriptan nasal spray has demonstrated efficacy in the treatment of cluster headache.1The pharmacokinetics of nasal zolmitriptan are such that blood levels arising from nasal mucosal absorption are clearly seen at 15 minutes. And speed of onset is the name of the game in cluster treatment!

With that in mind – as well as the knowledge that inhaled absorption of medications can be very rapid and complete – one cannot help but wonder what role inhaled DHE might someday play in cluster treatment.

Ekbom K; The Sumatriptan Cluster Headache Study Group. Treatment of acute cluster headache with sumatriptan. N Engl J Med. 1991;325:322-326.

—Mark J. Stillman, MD