Testosterone replacement therapy for treatment refractory cluster headache

OBJECTIVES: To describe the clinical characteristics and laboratory findings of cluster headache patients whose headaches responded to testosterone replacement therapy. BACKGROUND: Current evidence points to hypothalamic dysfunction, with increased metabolic hyperactivity in the region of the suprachiasmatic nucleus, as being important in the genesis of cluster headaches. This is clinically borne out in the circadian and diurnal behavior of these headaches. For years it has been recognized that male cluster headache patients appear overmasculinized. Recent neuroendocrine and sleep studies now point to an association between gonadotropin and corticotropin levels and hypothalamically entrained pineal secretion of melatonin. RESULTS: Seven male and 2 female patients, seen between July 2004 and February 2005, and between the ages of 32 and 56, are reported with histories of treatment resistant cluster headaches accompanied by borderline low or low serum testosterone levels. The patients failed to respond to individually tailored medical regimens, including melatonin doses of 12 mg a day or higher, high flow oxygen, maximally tolerated verapamil, antiepileptic agents, and parenteral serotonin agonists. Seven of the 9 patients met 2004 International Classification for the Diagnosis of Headache criteria for chronic cluster headaches; the other 2 patients had episodic cluster headaches of several months duration. After neurological and physical examination all patients had laboratory investigations including fasting lipid panel, PSA (where indicated), LH, FSH, and testosterone levels (both free and total). All 9 patients demonstrated either abnormally low or low, normal testosterone levels. After supplementation with either pure testosterone in 5 of 7 male patients or combination testosterone/estrogen therapy in both female patients, the patients achieved cluster headache freedom for the first 24 hours. Four male chronic cluster patients, all with abnormally low testosterone levels, achieved remission. CONCLUSIONS: Abnormal testosterone levels in patients with episodic or chronic cluster headaches refractory to maximal medical management may predict a therapeutic response to testosterone replacement therapy. In the described cases, diurnal variation of attacks, a seasonal cluster pattern, and previous, transient responsiveness to melatonin therapy pointed to the hypothalamus as the site of neurological dysfunction. Prospective studies pairing hormone levels and polysomnographic data are needed.     

Melatonin versus placebo in the prophylaxis of cluster headache: a double-blind pilot study with parallel groups

A fall in nocturnal plasma melatonin occurs in patients with cluster headache, suggesting that melatonin may play a role in the promotion of attacks. During a cluster period, we administered melatonin to 20 cluster headache patients (2 primary chronic, 18 episodic) in a double-blind placebo-controlled study of oral melatonin 10 mg ( n =10) or placebo ( n =10) for 14 days taken in a single evening dose. Headache frequency was significantly reduced (ANOVA, p <0.03) and there were strong trends towards reduced analgesic consumption (ANOVA, p <0.06) in the treatment group. Five of the 10 treated patients were responders whose attack frequency declined 3–5 days after treatment, and they experienced no further attacks until melatonin was discontinued. The chronic cluster patients did not respond. No patient in the placebo group responded. There were no side effects in either group. Although the response rate is low, melatonin may be suitable for cluster headache prophylaxis in some patients, particularly those who cannot tolerate other drugs.     

Chronic Paroxysmal Headache: Two Cases With Cerebrovascular Disease

Paroxysmal headaches often occur in benign headache disorders such as episodic cluster headache, chronic paroxysmal hemicrania (CPH) and episodic paroxysmal hemicrania. We report 2 patients with paroxysmal headaches occurring in association with cerebrovascular disease. The first patient had paroxysmal headaches from an arteriovenous malformation which resolved following embolization. In the second patient, headache followed a cerebral infarction and responded to treatment with indomethacin. We suggest that vascular disease may cause paroxysmal headaches resembling CPH. Patients with an atypical presentation of CPH warrant a neuroimaging procedure.     

Clinical Subtypes of Cluster Headache and Response to Lithium Therapy

SYNOPSIS
Based on clinical features, a group of 31 patients with cluster headache was divided into 1) episodic cluster headache, with months or years of headache free intervals, 2) chronic cluster headache without significant headache free intervals. Chronic type could be subdivided into primary and secondary varieties, secondary being a transformation from episodic cluster headache. A clinical trial of Lithium Carbonate was undertaken. Blood levels of lithium were determined at regular intervals to monitor the therapeutic dosage. Lithium was found to be an effective prophylactic agent in both episodic and chronic cluster headache patients. The percentage of improvement based on headache index was as follows: 55% of patients had more than 90% improvement; 10% of patients showed 60–90% improvement; 15% of patients showed 25–60% improvement; and 20% no improvement. Effectiveness of lithium was evident in less than a week after the initiation of treatment in those who responded. 55% of patients showed mild side effects such as tremor, nausea, diarrhea, abdominal discomfort and lethargy. Only one patient had serious side effects which needed discontinuation of therapy.The beneficial effect of lithium on cluster headaches appear to be independent of its anti-depressant action. Mechanism of action of lithium in cluster headache is not clear.     

Acute and interictal allodynia in patients with different headache forms: an Italian pilot study

OBJECTIVE: To investigate allodynia in patients with different primary headaches. BACKGROUND: Many migraineurs have allodynia during headache attacks; some may have allodynia outside attacks; allodynia may also be associated with other primary headaches. METHODS: A total of 260 consecutive primary headache patients presenting for the first time at a headache center, and 23 nonheadache controls answered written questions (subsequently repeated verbally) to determine the presence of acute and interictal allodynia. RESULTS: We divided the patients into: episodic migraine (N = 177), subdivided into only migraine without aura (N = 114) and those sometimes or always reporting migraine with aura (N = 63); episodic tension-type headache (N = 28); chronic headaches (headache > or = 15 days/month, N = 52), including chronic migraine, chronic tension-type headache, and medication-overuse headache; and other headache forms (N = 3). Acute allodynia was present in 132 (50.7%), significantly more often in patients sometimes or always suffering migraine with aura, and those with chronic headache forms, compared to patients with migraine without aura and episodic tension-type headache. Interictal allodynia was present in 63 (24.2%) patients, with significantly higher frequency in those having migraine with aura attacks than controls and common migraine patients. CONCLUSIONS: Allodynia is not specific to migraine but is frequent in all headache patients: acute allodynia was reported in half those interviewed and in over a third of patients in each headache category; interictal allodynia was reported by nearly 25%.     

Natural History of Cluster Headache

SYNOPSIS
A follow-up study of 123 patients with episodic cluster headaches and of 9 patients with chronic cluster headaches was undertaken after 10–25 years, (mean 14.7 and 13.9 years respectively). This shows a significant but low remission rate for both episodic and chronic cluster headache. It confirms the observation that some patients change from episodic to chronic pattern, and that occasionally chronic clusters may become episodic.     

2. Cluster Headache

Cluster headache is a strictly unilateral headache that is associated with ipsilateral cranial autonomic symptoms and usually has a circadian and circannual pattern. Prevalence is estimated at 0.5 to 1.0/1,000. The diagnosis of cluster headache is made based on the patient's case history. There are two main clinical patterns of cluster headache: the episodic and the chronic. Episodic is the most common pattern of cluster headache. It occurs in periods lasting 7 days to 1 year and is separated by at least a 1-month pain-free interval. The attacks in the chronic form occur for more than 1 year without remission periods or with remission periods lasting less than 1 month.
Conservative therapy consists of abortive and preventative remedies. Ergotamines and sumatriptan injections, sublingual ergotamine tartrate administration, and oxygen inhalation are effective abortive therapies. Verapamil is an effective and the safest prophylactic remedy. When pharmacological and oxygen therapies fail, interventional pain treatment may be considered. The effectiveness of radiofrequency treatment of the ganglion pterygopalatinum and of occipital nerve stimulation is only evaluated in observational studies, resulting in a 2 C+ recommendation.
In conclusion, the primary treatment is medication. Radiofrequency treatment of the ganglion pterygopalatinum should be considered in patients who are resistant to conservative pain therapy. In patients with cluster headache refractory to all other treatments, occipital nerve stimulation may be considered, preferably within the context of a clinical study.     

Acupuncture for chronic headaches--an epidemiological study

OBJECTIVE: To investigate the characteristics and outcomes of patients undergoing acupuncture treatment for chronic headaches under conditions of routine care provided within the framework of statutory health insurance in Germany. Furthermore, we investigated correlations between different outcomes. PATIENTS AND METHODS: Patients with migraine, episodic or chronic tension-type headache (TTH), or several other forms of chronic headache (cluster, vascular, drug-induced headache; other specific headaches) treated with acupuncture (mean number of sessions 8.6 +/- 3.0) were included into an observational study. Detailed questionnaires including questions on headache days and instruments measuring disability (Pain Disability Index) and quality of life (SF-36) were completed before treatment, after treatment, and at 6 months after inclusion. RESULTS: A total of 2,022 patients (732 with migraine, 351 with episodic and 440 with chronic TTHs, and 499 with other diagnoses) treated by 1,418 physicians were included in the main analysis. Sociodemographic and baseline characteristics differed considerably in the four diagnostic groups. Statistically highly significant and clinically relevant improvements were seen for all clinical outcome measures in all diagnostic groups. In 52.6% of patients headache frequency decreased by at least 50% compared to baseline. The comparison of headache frequency, pain intensity, and generic outcome measures showed that some of these outcomes correlate only weakly. CONCLUSIONS: In this epidemiological study, headache patients reported clinically relevant improvements after receiving acupuncture. Randomized trials performed in parallel to this study confirm the relevant overall effect, however, the effect may largely be due to potent unspecific needling and placebo effects.     

Childhood Onset Cluster Headaches

Cluster headaches are rare in childhood. We identified 35 patients with cluster headaches starting at or before 18 years of age, including 7 patients with onset prior to age 10. All patients met the criteria of the International Headache Society for episodic or chronic cluster headaches. Patients experienced cluster headaches for as long as 20 years before seeking medical attention and required many medical contacts to establish the correct diagnosis. The clinical features of cluster headaches during childhood were similar to those which typically occur in adult life. Cluster headache patterns changed over 18 years of follow up. The frequency and duration of cluster periods increased in 14 subjects. The frequency of single headache attacks during cluster periods also increased in a similar number of subjects. We conclude that cluster headaches starting in childhood or adolescence closely resemble the adult form of the disease. In many patients, the frequency and duration of cluster periods and the frequency of the individual headache episodes increased over time. Cluster headache represent a treatable under-recognized cause of severe headaches in childhood and adolescence.     

Treatment of patients with chronic headaches in a hospital for traditional Chinese medicine in Germany. A randomised, waiting list controlled trial

OBJECTIVE: To investigate the effectiveness of a clinical treatment program with traditional Chinese medicine for migraine and tension-type headache. METHODS: Ninety-one patients with migraine, episodic or chronic tension-type headache according to the criteria of the International Headache Society were randomised into an experimental or a waiting list control group. Patients in the experimental group were treated 4 weeks in a hospital for traditional Chinese medicine after a baseline period of one month. Patients in the waiting list group continued their previous headache treatment. Main outcome measure was the difference in the number of days with headache of at least moderate intensity during baseline (month 1) and month 7. RESULTS: The difference in the number of days with headache of at least moderate intensity was 5.6 (S.D., 6.1) days in the experimental group and 1.2 (S.D., 4.5) days in the waiting list group (P <0.001). A reduction of more than 50% in headache days was observed in 52% of the patients in the experimental group and 16% in the waiting list group. Patients with migraine and a combination of migraine and episodic tension-type headaches improved more than patients with other headaches. CONCLUSION: The results of this study indicate that treatment in the hospital for traditional Chinese medicine in Kotzting is associated with lasting improvements in the majority of patients.     

Zolmitriptan Nasal Spray in the Acute Treatment of Cluster Headache: A Meta-Analysis of Two Studies

Objective.— To conduct an individual subject meta‐analysis of available controlled studies of zolmitriptan nasal spray in the acute treatment of cluster headache. Background.— Two double‐blind, placebo‐controlled, randomized, crossover studies of zolmitriptan nasal spray in the acute treatment of cluster headache, with similar patient populations, protocol designs, doses, and clinical endpoints have been published. Methods.— In both double‐blind studies, each patient was to treat 3 attacks, 1 with placebo, 1 with zolmitriptan 5 mg, and 1 with zolmitriptan 10 mg in a randomized, crossover manner. Headache intensity was rated on a 5‐point scale (none to very severe). The primary endpoint was headache relief at 30 minutes post dose: reduction from moderate, severe, or very severe pain to mild or none. A multilevel, random‐effects, logistic regression model was used to analyze the data. Results.— A total of 121 patients (100 male; 64.5% with episodic cluster headache) provided efficacy data for at least 1 attack. Zolmitriptan 5 mg and 10 mg were significantly more effective at providing headache relief at 30 minutes post treatment than placebo (odds ratio 3.48; 95% confidence interval 1.49‐8.10 and odds ratio 8.68; 95% confidence interval: 3.35‐22.5, respectively). For episodic cluster headache, response rates were 35.6%, 51.7%, and 73.7% for placebo, zolmitriptan 5 mg (odds ratio 2.5; P = .06 vs placebo), and 10 mg (odds ratio 9.9; P < .001 vs placebo), respectively. For chronic cluster headache, response rates were 17.2%, 41.9%, and 40.7% for placebo, zolmitriptan 5 mg (odds ratio 8.1; P = .035), and 10 mg (odds ratio 7.6; P = .046), respectively. Zolmitriptan was well tolerated in both studies with no serious adverse events reported. Conclusion.— Zolmitriptan nasal spray at a dose of 5 mg and 10 mg is efficacious in the acute treatment of episodic and chronic cluster headache.     

The differential diagnosis of chronic daily headaches: an algorithm-based approach

Chronic daily headaches (CDHs) refers to primary headaches that happen on at least 15 days per month, for 4 or more hours per day, for at least three consecutive months. The differential diagnosis of CDHs is challenging and should proceed in an orderly fashion. The approach begins with a search for "red flags" that suggest the possibility of a secondary headache. If secondary headaches that mimic CDHs are excluded, either on clinical grounds or through investigation, the next step is to classify the headaches based on the duration of attacks. If the attacks last less than 4 hours per day, a trigeminal autonomic cephalalgia (TAC) is likely. TACs include episodic and chronic cluster headache, episodic and chronic paroxysmal hemicrania, SUNCT, and hypnic headache. If the duration is > or =4 h, a CDH is likely and the differential diagnosis encompasses chronic migraine, chronic tension-type headache, new daily persistent headache and hemicrania continua. The clinical approach to diagnosing CDH is the scope of this review.     

Treating chronic tension-type headache not responding to amitriptyline hydrochloride with paroxetine hydrochloride: a pilot evaluation

CONTEXT: In some individuals, chronic tension-type headache fails to respond to tricyclic antidepressant medications that often serve as first-line therapy. OBJECTIVE: To evaluate the clinical efficacy of paroxetine hydrochloride for chronic tension-type headache not responding to amitriptyline hydrochloride. DESIGN AND SETTING: Open-label trial of paroxetine conducted at 2 outpatient sites in Ohio. PARTICIPANTS AND INTERVENTION: Thirty-one adults (mean age, 37 years; 20 women) with chronic tension-type headache (mean, 25 headache days per month) who had failed to respond (less than 30% improvement) to treatment with either amitriptyline (n = 13) or matched placebo (n = 18). All participants were treated with paroxetine (up to 40 mg per day) in a 9-month protocol. OUTCOME MEASURES: Monthly headache index calculated as the mean of pain ratings (0 to 10 scale) recorded by participants in a diary 4 times per day, number of days per month with at least moderate pain (pain rating of 5 or greater), and analgesic medication use. RESULTS: In patients who had not responded to amitriptyline, paroxetine failed to reduce chronic tension-type headaches or analgesic medication use. In patients who had not responded to placebo, paroxetine produced modest reductions in chronic tension-type headaches and analgesic use. CONCLUSIONS: We found no evidence that chronic tension-type headaches that failed to respond to tricyclic antidepressant therapy with amitriptyline improved when subsequently treated with paroxetine. More support was found for the efficacy of paroxetine in patients with chronic tension-type headaches who had failed to respond to placebo.     

Treatment of chronic daily posttraumatic headache with divalproex sodium

OBJECTIVE: To determine the effectiveness of divalproex sodium in the treatment of chronic daily posttraumatic headaches. BACKGROUND: Divalproex sodium has been found to be useful for the treatment of migraine and chronic daily headache. No studies have been done to evaluate effectiveness in posttraumatic headache. METHODS: A retrospective review was done of 100 patients treated with divalproex for chronic daily posttraumatic headache of 2 months or longer. RESULTS: Sixty percent of patients with chronic posttraumatic headache had mild to moderate improvement in their headaches after at least 1 month of divalproex sodium. Forty percent either showed no response (26%) or discontinued treatment because of side effects (14%). Fifty-eight percent of patients showing improvement had a change in headache pattern from daily to episodic. CONCLUSIONS: Divalproex sodium appears to be safe and effective for treatment of patients with persistent, chronic daily posttraumatic headaches.     

Steroid hormones in cluster headaches

For decades, glucocorticoid therapy has been a well-recognized abortive treatment for cluster headaches. However, the role of steroid hormones, including both glucocorticoids and sex steroids, in the pathophysiology and therapy of cluster headaches has been a topic of much debate and speculation. Current research now points to the importance of cortisol and testosterone in the pathogenesis of cluster headaches, and they appear to be linked mechanistically to another hormone, melatonin. Melatonin, unlike cortisol or testosterone, is not a product of the hypothalamic pituitary axis but of the retinohypothalamic pineal axis, and is the major biomarker of circadian rhythms. The regulation of steroids and melatonin in the pathogenesis of cluster headaches in turn depends on the sympathetic nervous system. Accumulated evidence suggests sympathetic dysfunction —embodied in the Horner sign so commonly seen in the cluster headache—as a necessary ingredient in the inception of the cluster headache. Sympathetic dysfunction now is thought to be associated with the hypercortisolism, hypotestosteronism, and lower-than-normal melatonin levels in the active cluster patient. Future research may hold the key to a fuller explanation of the complex interaction of hormonal systems in the cluster headache.     

Osmophobia in primary headaches

This study evaluates osmophobia (defined as an unpleasant perception, during a headache attack, of odours that are non–aversive or even pleasurable outside the attacks) in connection with the diagnosis of primary headaches. We recruited 775 patients from our Headache Centre (566 females, 209 males; age 38±12 years), of whom 477 were migraineurs without aura (MO), 92 with aura (MA), 135 had episodic tension–type headache (ETTH), 44 episodic cluster headache (ECH), 2 chronic paroxysmal hemicrania (CPH) and 25 other primary headaches (OPHs: 12 primary stabbing headaches, 2 primary cough headaches, 3 primary exertional headaches, 2 primary headaches associated with sexual activity, 3 hypnic headaches, 2 primary thunderclap headaches and 1 hemicrania continua). Among them, 43% with MO (205/477), 39% with MA (36/92), and 7% with CH (3/44) reported osmophobia during the attacks; none of the 135 ETTH and 25 OPH patients suffered this symptom. We conclude that osmophobia is a very specific marker to discriminate adequately between migraine (MO and MA) and ETTH; moreover, from this limited series it seems to be a good discriminant also for OPHs, and for CH patients not sharing neurovegetative symptoms with migraine. Therefore, osmophobia should be considered a good candidate as a new criterion for the diagnosis of migraine.     

Impaired circadian rhythmicity of nociceptive reflex threshold in cluster headache

BACKGROUND: Alteration of circadian rhythmicity involving several endocrinologic and autonomic parameters has been observed in cluster headache. OBJECTIVES: To explore whether circadian failure of the pain control system may exist in cluster headache. METHODS: The nociceptive flexion reflex threshold was studied in 25 patients with episodic cluster headache (14 active, 11 in remission) and 6 patients with chronic cluster headache, along with 10 normal volunteers throughout a 24-hour period. The reflex response was evoked at the level of the biceps femoris by stimulating the sural nerve at the ankle. Single and population mean cosinor methods were used to detect the circadian rhythmicity. RESULTS: In the patients with episodic cluster headache, a significant reduction in the nociceptive flexion reflex threshold was observed in both the active subgroup and the subgroup in remission (P < .05). In these patients, persistence of a significant 24-hour rhythm during both the active period and remission was observed, but a shift of the phase was observed during clinical activity when compared with the remission period. A lack of circadian nociceptive flexion reflex threshold rhythmicity was found in the patients with chronic cluster headache. CONCLUSIONS: Our findings suggest that in cluster headache there may be impairment of the pain control system that is associated with periodic failure of the mechanisms involved in the organization of biological rhythms.     

Treatment and management of cluster headache

Cluster headache is an uncommon yet well-defined neurovascular syndrome occurring in both episodic and chronic varieties. The most striking feature of cluster headache is the unmistakable circadian and circannual periodicity. Inheritance may play a role in some families. The attacks are of extreme intensity, of short duration, occur unilaterally, and are accompanied by signs and symptoms of autonomic dysfunction. In contrast to migraine, during an attack the cluster patient prefers to pace about. Attacks frequently occur at night. Although the pathophysiology of cluster headache remains to be fully elucidated, several seminal observations have recently been made. The medical treatment of cluster headache includes both acute therapy aimed at aborting individual attacks and prophylactic therapy aimed at preventing recurrent attacks during the cluster period. Agents used for acute therapy include inhalation of oxygen, sumatriptan, and dihydroergotamine. Transitional prophylaxis involves the short-term use of either corticosteroids or ergotamine derivatives. The cornerstone of maintenance prophylaxis is verapamil, yet methysergide, lithium, and divalproex sodium may also be employed. In some patients, melatonin or topiramate may be useful adjunctive therapies.     

Behavioral sleep modification may revert transformed migraine to episodic migraine

BACKGROUND: Sleep problems have been linked with headaches for more than a century, but whether the headaches are the cause or the result of the disrupted sleep is unknown. OBJECTIVES: We previously reported that nonrestorative sleep and poor sleep habits are almost universal in a referral population of women with transformed migraine (TM). Since cognitive behavioral therapy is effective in improving sleep quality in individuals with poor sleep hygiene, we designed a randomized, placebo-controlled study to assess the impact of such treatment on TM. We hypothesized that behavioral sleep modification (BSM) would be associated with improvement in headache frequency and intensity and with reversion to episodic migraine. METHODS: Subjects were 43 women with TM referred to an academic headache center. After obtaining informed consent, patients were randomized to receive either behavioral sleep instructions or placebo behavioral instructions in addition to usual medical care. Subjects recorded headaches in standardized diaries. The first postintervention visit was scheduled at 6 weeks. At that visit, the blind was broken and all subjects received BSM instructions. A final visit was scheduled 6 weeks later. RESULTS: Compared to the placebo behavioral group, the BSM group reported statistically significant reduction in headache frequency [F (1, 33 = 12.42, P=.001)] and headache intensity [F(1, 33 = 14.39, P= .01)]. They were more likely to revert to episodic migraine chi2 (2, n = 43) = 7.06, P= .029. No member of the control group reverted to episodic migraine by the first postintervention visit. By the final visit, 48.5% of those who had received BSM instructions had reverted to episodic migraine. CONCLUSIONS: In this pilot study of women with TM, we found that a targeted behavioral sleep invention was associated with improvement in headache frequency, headache index, and with reversion to episodic migraine.     

Primary headaches in HIV-infected patients

Headache in patients with human immunodeficiency virus (HIV) infection may indicate life-threatening illnesses such as opportunistic infections or neoplasms. Alternatively, such patients may develop benign self-limiting headaches. Hence, defining the various types of headache in these patients is essential for proper management. This study describes the clinical characteristics of primary headaches occurring in a group of HIV-infected patients. Of 115 patients seen from 1990 to 1996, 44 (38%) had headaches. Primary headaches were present in 29 (66%) patients and secondary causes were identified in 15 (34%). Among those with primary headaches, migraine occurred in 22 (76%), tension-type headache in 4 (14%), and cluster headache in 3 (10%) patients. Half of those with migraine (n=ll), 1 patient with tension-type headache, and 1 patient with cluster headache developed chronic daily headaches which were severe and refractory to conventional headache or antiretroviral therapy. We conclude that primary headaches in patients with HIV infection are: (1) the commonest type of headache; (2) may present for the first time in individuals with severe immunosuppression; (3) usually bear no relationship to antiretroviral drug therapy; (4) polypharmacy, depression, anxiety, and insomnia are commonly associated comorbidities; (5) frequently do not respond to conventional management and carry a poor prognosis; and (6) do not require neuroradiological and/or cerebrospinal fluid evaluations.