Homocarnosinosis: A historical update and findings in the SPG11 gene.

OBJECTIVES: A family with homocarnosinosis was reported in the literature in 1976. Three affected siblings had spastic paraplegia, retinitis pigmentosa, mental retardation, and cerebrospinal fluid (CSF) homocarnosine concentrations 20 times higher than in controls. Based on the clinical findings and new genetic techniques, we have been able to establish a precise genetic diagnosis. METHOD: The medical records were re-evaluated, and genetic analyses were performed post-mortem in this original family. SNP array-based whole genome homozygosity mapping and Sanger sequencing of the SPG11 gene were performed. Seven additional Norwegian SPG11 patients and their disease-causing variants and clinical findings were evaluated. Homocarnosine levels in CSF were measured in four of these seven patients. RESULTS: A homozygous pathogenic splice-site variant in the SPG11 gene, c.2316 + 1G>A, was found. The clinical findings in the original family correlate with the heterogeneous SPG11 phenotype. The same variant was found in seven other Norwegian SPG11 patients, unrelated to the original family, either as homozygous or compound heterozygous constellation. Normal homocarnosine levels were found in the CSF of all unrelated SPG11 patients. CONCLUSIONS: A re-evaluation of the clinical symptoms and findings in the original family correlates with the SPG11 phenotype. The increased levels of homocarnosine do not seem to be a biomarker for SPG11 in our patients. Homocarnosinosis is still a biochemical aberration with unknown clinical significance.

Indomethacin responsive headache syndromes: chronic paroxysmal hemicrania and Hemicrania continua. How they were discovered and what we have learned since.

In the indomethacin responsive headaches (IRHs), chronic paroxysmal hemicrania (CPH) and Hemicrania continua (HC), the indomethacin (INDO) response is swift, absolute, and permanent, with moderate doses. Traditionally, CPH has been linked to cluster headache (CH) due to clinical similarities: unilaterality, intensity, and some autonomic phenomena. However, other clinical features differ essentially between these two headaches: sex ratio, mean attack frequency (CPH: 13.6 versus CH: 1.7 attacks/day), and duration of attacks. The therapeutic profile in CPH (indomethacin effect: ++; triptan effect: generally non-existent) is reversed in CH. The autonomic phenomena also differ clearly, a forehead supersensitivity sweating pattern and Horner-like pupil being present only in CH. The chronic/non-chronic stage ratio is 3.9 in CPH, against 0.14 in CH, a >25 times difference. Conversely, CPH and HC are very similar, clinically speaking. Accordingly, we should probably sever the link between CH and CPH and favour, instead, a linking together of CPH and HC, the two principal IRHs.

Electrical stimulation in headache treatment. For separate headache(s) or for headache generally?

Two cases of unilateral, severe headache were treated with epidural/epicranial electrical stimulation, with an immediate and most favorable response. One patient suffered from cervicogenic headache (CEH), while the headache in the other one showed some similarity to Hemicrania continua (HC): unilaterality and some localized, ipsilateral autonomic phenomena. But, there were also sufficient features to alienate this picture decisively from HC: poor response to indomethacin and, frequently, excruciatingly severe pain. In the CEH patient, the electrode was anchored at the posterior, bony end of the foramen magnum. In case 2, it was placed above and anterior to the symptomatic side ear, i.e. at the point of maximal pain. The headache in the latter patient may be termed: "non-indomethacinresponsive chronic hemicrania", which may not be a rare headache. In both patients, the spectacular improvement has continued for the whole post-operative period, i.e. for around five years and 11 months, respectively.

Comorbidity of migraine and epilepsy in a Norwegian community.

BACKGROUND AND PURPOSE: Studies on the comorbidity of migraine and epilepsy have shown conflicting results. We wanted to explore the epidemiological association between migraine and seizure disorders in a population-based material where case ascertainment was enhanced by individual specialist assessments. METHODS: Information concerning migraine and seizure disorders was collected from 1793 participants in an interview-based survey in a circumscribed community. Mixed headache, with features both of migraine without aura and tension-type headache, was excluded from further analyses because of its ambiguous character (n = 137). Thus, data from 1656 participants were included in the study. RESULTS: The number of subjects with epilepsy was small, and a statistically significant association between migraine and the diagnosis of epilepsy was not found. There was a tendency to more active epilepsy in subjects with migraine (1.0%, 5/524), particularly for migraine with aura (1.8%, 3/168), compared with subjects without migraine (0.5%, 6/1132). Migraine was present in five of 11 subjects with active epilepsy (45%) and in four of 28 (14%) with epilepsy in remission (P = 0.09). CONCLUSIONS: An overall association between migraine and seizure disorders could not be demonstrated, but there was a tendency to more migraine in individuals with active epilepsy.

Tension-type headache: comparison with migraine without aura and cervicogenic headache. The Vågå study of headache epidemiology.

The aim of the present study was to describe the prevalence of tension-type headache (T-TH) in rural Norway, and 1838 citizens aged 18-65 years were included. Features indicating neck involvement were also looked for. T-TH was compared with migraine without aura and with cervicogenic headache (CEH) considering both these features and typical migraine traits. Face-to-face interviews were carried out, based on an elaborate questionnaire. The IHS criteria, first version, were used for T-TH diagnosis. A T-TH prevalence of 34% was found. In T-TH and migraine without aura, typical CEH features, such as reduced range of motion in the neck and mechanical provocation of pain, were far less prominent than in CEH. Typical migraine traits, e.g. photophobia, were much less frequently present in T-TH and CEH than in migraine without aura. T-TH is, in all probability, not a CEH variant and vice versa.

Cervicogenic headache: comparison with migraine without aura; Vågå study.

The prevalence of cervicogenic headache (CEH) is only vaguely known. Furthermore, it is a common belief that in migraine without aura (MwoA), neck symptoms frequently occur and that MwoA and CEH may pathogenetically be intimately related. In the Vågå study, 1838 18-65-year-old citizens (88.6% of that age group) were studied with face-to-face interviews and a thorough neck examination. For CEH, the Cervicogenic Headache International Study Group criteria were used, and for MwoA, the IHS criteria. The extent of cervical involvement was assessed by the 'CF' ('features indicative of cervical abnormality'). CEH prevalence was 4.1%. 'CF' was 2.37 in CEH vs 0.93 in M-A. CEH criteria, e.g. mechanical attack provocation, were present many times more frequently in CEH than in MwoA. Conversely, migraine criteria, e.g. photophobia, were >/= 2.6 times higher in MwoA than in CEH. CEH is unlikely to be a subgroup of MwoA.

Migraine without aura: comparison with cervicogenic headache. Vågå study of headache epidemiology.

OBJECTIVES: To study migraine without aura (MwoA) prevalence in the commune of Vågå, Norway; 1838 (18- to 65-year-old) individuals were included. A special search was made for cervicogenic characteristics in MwoA, as it has been claimed that such characteristics may frequently be present. A comparison with cervicogenic headache (CEH) was made. METHODS: The MwoA and tension-type headache (T-TH) diagnosis was based on IHS criteria. CEH diagnosis was based on the principles of The Cervicogenic Headache International Study Group. RESULTS: There were 562 cases of MwoA; prevalence: 31%. There were 425 cases of 'pure' MwoA, i.e. without coexisting T-TH. These 'pure' cases were used for extracting MwoA symptoms. The female/male ratio was 1.69, the corresponding ratio in CEH being 0.71. Typical MwoA symptoms such as nausea/photophobia were most frequently found in migraine. This difference amounted to a factor of > or =2.6. On the other hand, typical CEH traits, like mechanical pain provocation and 'posterior' onset of exacerbations, occurred more frequently in CEH than in MwoA. The difference amounted to a factor of two or more. CONCLUSIONS: MwoA and CEH have clearly different characteristics. The differences between MwoA and CEH are staggering. It is unlikely that migraine and CEH are linked in a nosological sense.

Prevalence of cervicogenic headache: Vågå study of headache epidemiology.

OBJECTIVES: To describe the prevalence and various clinical characteristics of cervicogenic headache (CEH) in the population at large. METHODS: CEH was searched for in Vågå, Norway, where 1838 18 to 65-year-old citizens, i.e. 88.6% of this age group, underwent an interview/clinical examination. The Cervicogenic Headache International Study Group criteria include: (I) unilaterality of head pain, (II) reduction, range of movement, neck, (III/IV) ipsilateral shoulder/arm discomfort, (V/VI) mechanical provocation of similar pain, objectively or subjectively. RESULTS: A prevalence of 4.1% was found. In 41 cases with the highest number of CEH criteria ('core' cases), there was a male preponderance (F/M: 0.71). While cervicogenic traits (mechanical precipitation etc.) were frequently present in CEH, 'migraine traits', like nausea, vomiting, and throbbing seemed to be rarely present. In 97% of the cases, pain exacerbations began in the neck/occipital region. CONCLUSIONS: CEH may be one of the three large, recurrent headaches. In this series, there was no female preponderance. Nuchal onset of pain is a characteristic trait.

Cervicogenic headache: long-term prognosis after neck surgery.

OBJECTIVES: To evaluate the postoperative fate of chronic, hard-to-treat and partly suicidal cervicogenic headache (CEH) patients (n = 32), diagnosed according to the CHISG criteria and treated with a decompression/stabilization operation in the cervical spine: the Smith/Robinson operation. METHODS: The cervical levels of affection, singled out by magnetic resonance, anaesthetic blockades and X-ray examinations were mainly at the C4-5, C5-6, C6-7 levels; one or two discs were removed. The study was prospective and controlled. RESULTS: During the 1- to 3-month-long postoperative period of collar-wearing, there generally was pain freedom. The mean time of follow-up was 19.8 months: pain recurrence, known to the authors, appeared after 1-58 months (n = 12). The mean time of improvement was: 14.8 months (range 1-58 months). Five patients stayed well > or =3 years. This is certainly a minimum figure. The patients ultimately were lost to follow-up. CONCLUSIONS: For the time being, this operation should preferably be used in selected, chronic, severely afflicted, preferably elderly CEH patients, when other therapeutic approaches are exhausted.

Neck pain and associated head pain: persistent neck complaint with subsequent, transient, posterior headache.

BACKGROUND: During the Vågå headache epidemiology study, there were indications that various types of work, such as carpentry and hairdressing, frequently seemed to be linked to a combination of neckache and headache. OBJECTIVES: A post hoc study was conducted among 1838, 18- to 65-year-old Vågå citizens, looking for patients with combined neck/headache. DESIGN: Face-to-face interview was conducted. RESULTS: Combined neckache and headache were detected in 121 (6.6%) individuals. The bilateral headache originated in the neck; it was mild/moderate, symptom-poor, and frequently provoked by awkward neck positions. No such headache occurred without a neckache. Headache in this group of patients resembles tractor drivers' headache, except for the provoking factor itself. CONCLUSIONS: This headache is not listed in headache classification systems/textbooks on headache. This headache must be distinguished from the unilateral cervicogenic headache proper because of the different treatment perspectives.

Hemicrania with massive autonomic manifestations and circumscribed eyelid erythema.

OBJECTIVES: To describe a unilateral headache that in addition to the typical shortlasting unilateral neuralgiform headache attacks with conjunctival injection, tearing, sweating and rhinorrhea (SUNCT) syndrome - traits with excessive and ipsilateral autonomic phenomena - had circumscribed eyelid erythema and adjacent ocular redness. OBSERVATIONS: A 60-year-old female had excessive, right-sided lacrimation and local pain at 15 years of age. Due to steadily increasing discomfort, with lacrimation and swelling over the outer part of the upper eyelid, the right lacrimal gland was removed at 20 years of age, with a suspicion of lacrimal gland adenoma. Preoperatively, symptomatic side mild-degree eyelid erythema/rhinorrhea were integral parts of the attack. After years with minor complaints, she, in the mid-twenties, experienced more long-lasting pain attacks, and pain soon became the main problem. A marked, distinct erythema on the lateral part of the right-sided eyelids and marked, localized 'eye redness' in the adjacent area were main ingredients of the attacks together with eyelid edema and viscous rhinorrhea. There were visible vessels below the eye, and telangiectasia of the upper eyelid. CONCLUSIONS: This headache has many similarities with SUNCT - but has several, grossly deviating traits: the temporal aspects, excruciatingly intense pain attacks, and above all marked, lateral eye-lid erythema, and adjacent, massive ocular reddening. This constellation probably alienates it from SUNCT.

Hydrogen sulphide headache and other rare, global headaches: Vågå study.

One aim of the Vågå study of headache epidemiology was to depict the total panorama of headaches in a small-sized, Norwegian community at the end of the 20th century. In the present part of the study, a search was made for the rare, global headaches. Various, relatively unknown headache categories were observed, such as hydrogen sulphide intoxication (n = 2) after exposure to H(2)S ambient air concentrations of >or=100 p.p.m. In Vågå, nitroglycerine headache ('dynamite headache') proved to be a relatively frequent disorder (n = 13). This represents approximately 0.7% of the study group. A main reason for this, in all probability unusually high frequency is that there previously have been soapstone mines within the precincts of the parish. Another relatively frequently occurring headache followed exposure to wind (n = 7; 0.38%). Ice-cream headache was rare (n = 3; 0.16%), when only the general question was asked: 'other headaches?'. Approximately 7 years later, an ad hoc procedure was adopted: 50 parishioners who did not answer positively concerning ice-cream headache on the first examination were asked specific questions concerning ice-cream headache. Four had had such an experience, i.e. prevalence of 8%, which is 50 times higher than the original result, but still a rather low prevalence when compared with the mean prevalence from other studies: 39%. This demonstrates that the result as regards prevalence, even for a headache such as ice-cream headache, to a large degree depends upon the interview technique used.

Neck-tongue syndrome and related (?) conditions.

A search has been made for the neck-tongue syndrome. It started out with a systematic inquiry during the Vågå study of headache epidemiology during the years 1995-97. Two cases were detected relatively early during the study. This led to a scrutiny of such cases also in our hospital headache practice. The origin - and the basis of the study, nevertheless, was the Vågå study. In the Vågå study, where 1838 18-65-year-old parishioners were examined, there were four neck-tongue syndrome cases (N-TS), i.e. a prevalence of approximately 0.22%. N-TS may be more frequent than hitherto surmised. A variant was observed in one case; a young male: instead of numbness, a 'spasm' seemed to occur in the tongue. None of the four had at any time consulted their physician for their complaints. In our regular headache practice, two new cases were detected. In one of them and in one of the Vågå cases, there was a combination with ipsilateral cervicogenic headache (CEH). In N-TS, there may be both ipsilateral headache and upper extremity sensory phenomena, a constellation reminiscent of CEH. The possible pathogenetic relationship between N-TS and CEH is therefore discussed in some detail.

Ontogeny of erythropoietin receptor mRNA expression in various tissues of the foetal and the neonatal pig.

Erythropoietin receptor (EPOR) mRNA expression in liver, spleen, bone marrow and testes of foetal and neonatal pigs was analysed using a real-time RT-PCR assay. The results showed that early in the foetal life, EPOR expression is greatest in the liver. Later in foetal life, the spleen has the greatest expression of EPOR, whereas at 2 weeks after birth, the main expression of EPOR is found in the bone marrow. These findings contradict our earlier hypothesis that erythropoietin (EPO) acting in a paracrine fashion can account for an extensive erythropoiesis at birth, a point of time when plasma EPO concentrations are low. Results presented in the present paper suggest that the spleen or, alternatively, the bone marrow is able to respond to very low concentrations of circulating EPO around the time of birth. The testes were found to express significant amounts of EPOR. Since EPO mRNA has previously been found in the testes, a paracrine function of EPO may exist in this organ.

Long-lasting cephalic jabs (?) The Vågå study of headache epidemiology.

Jabs (stabs) usually last < or = 3 s and are located in the skull area, mostly anteriorly. In many cases, there are only a few jabs during lifetime. With this definition, jabs are frequent, thus at 35.2% in the Vågå study of headache epidemiology. Long-lasting jabs (?), i.e. paroxysms lasting 10-120 s, were present in six out of 1779 parishioners. These pain paroxysms seemed mainly to be side-locked, but could not be provoked. Possibly, these long-lasting jabs after all mainly are regular jabs. To include the < or = 2-minute-long paroxysms among the jabs will necessitate a rather drastic change of criteria. This group of jabs may, nevertheless, be heterogeneous. In two parishioners, the paroxysms were associated with a migraine-like pain. The paroxysms occasionally became most intense (2-10 times the basal pain), and then, and only then, were they combined with stark, visual phenomena: wave-like movements ('undulation'), anopsia, but also: immense dizziness, nausea/vomiting. The nature of the side-locked basal pain, although migraine-like, remains unsolved.

Single high-dose steroid treatment in episodic cluster headache.

Corticosteroids appear to be the most rapid-acting of the prophylactic drugs used in the treatment of cluster headache (CH). These agents are frequently employed as a short-term regimen to induce clinical remission. In this study, we assessed in an open fashion the effect of high dose methylprednisolone (MPD) in a group of 13 patients with episodic CH (3 females and 10 males). On the 8th day of the active period, MPD was administered intravenously at the dose of 30 mg/kg body weight, as a 3-h infusion in saline. The attack frequency was followed for 7 days. The mean daily attack frequency before MPD administration was statistically different from that reported after treatment (respectively: 1.38 +/- 0.42 and 0.83 +/- 0.78; P = 0.05 Student's t-test). The mean interval between MPD administration and the occurrence of the first subsequent attack was 3.8 +/- 2.2 days (range: 2-7 days). Only 3 (23%) of 13 patients experienced a complete headache remission. No significant side-effects were noted after MPD administration. These data further demonstrate that in most patients with episodic CH, high-dose systemic steroid administration may invariably interrupt attack recurrence for a few days, but is ineffective in maintaining complete clinical remission. This study also suggests that MPD administered as a solitary dose does not provide any advantage above prednisone in CH treatment.

Supraorbital neuralgia. Vågå study of headache epidemiology.

In a recent, hospital-based report, we described a small series of 5 patients with unilateral, more or less chronic, severe forehead pain, that could be transitorily abated by anaesthetic blockade of the supraorbital nerve and more permanently abated by 'liberation' operation directed towards the nerve exit area at the supraorbital notch. However, epidemiological data on supraorbital neuralgia are lacking. Among 1838 18-65-year-old inhabitants in Vågå (88.6% of the eligible ones), there were 10 who presented the following clinical picture: (1) Unilateral forehead/ocular pain, not diagnosed or diagnosable as any other, particular, unilateral headache; (2) Steadfast unilaterality; (3) Increased tenderness upon pressure over the exit site of the supraorbital nerve (incisura frontalis) on that side--in those who were in an active phase; (4) Foregoing trauma in the forehead/supraorbital rim area, ipsilaterally. In approximately half the cases, there was a moderate, ipsilateral sensory loss. A striking finding was the occurrence of jabs in the symptomatic area, and in synchrony with the neuralgia pain. These 10 inhabitants correspond to a prevalence of 0.5% (or 0.65% if two nontrauma cases are included).

Caffeine-withdrawal headache. The Vågå study of headache epidemiology.

In connection with the Vågå study of headache epidemiology, a search was made for caffeine-withdrawal headache in 1741 parishioners. Female to male ratio 1.05; mean age 44.2 years (range 18-65 years). A face-to-face interview technique was used. The mean consumption of coffee was 4.7 cups a day. Males on an average consumed more coffee (5.1 +/- 3.3 cups/day) than females (4.4 +/- 3.1 cups/day). Neither in those with a high consumption of coffee: > or =10 cups a day (n = 134), nor in those with a considerable variation in consumption: > or =10 cups/day (n = 31) did there seem to be a definite increase in headache resembling caffeine-withdrawal headache, for instance during weekends. In seven parishioners, however, there did seem to be such a headache, and in two of them, the evidence was rather convincing. This headache generally seemed to be mild and global and occurred mainly in the morning hours on weekends. There was no nausea, no throbbing quality of the pain, and no reported use of analgesics. Coffee seemed to abate the headache. This frequency (0.4%) should, clearly, be regarded as a minimum figure. Caffeine-withdrawal headache at the grassroots level may be a rather rare, generally vague, symptom-poor headache.

Exertional headache--II. Clinical features Vågå study of headache epidemiology.

In connection with a large-scale study of headache epidemiology in the parish of Vågå, Norway (n = 1838), a prevalence of exertional headache (EH) of 12.3% was recently reported (n = 202). The principal aim of the present report is to have a closer look at various clinical features: particular attention has been given to the coexistence of EH and migraine. EH seemed to coexist with migraine in 46% of the cases. In spite of that finding, there was generally no plentitude of 'migraine features' in the EH attacks per se. The predominant 'migraine feature' in EH attacks was throbbing. EH attacks were generally more short-lasting and seemed to be more lenient than the corresponding migraine attacks. Nausea/vomiting, and unilaterality of pain were generally not inherent features of EH attacks. EH attacks in all probability are not abortive migraine attacks--rather, they seem to be 'migraine-like'.

Cluster headache prevalence. Vågå study of headache epidemiology.

In the Vågå study of headache epidemiology, a search was made also for cluster headache. Of the available 18-65-year-old dalesmen, 1838 (88.6%) could be examined personally (O.S.) - 51.3% females and 48.7% males. Based on current International Headache Society criteria, cluster headache seemed to be present in seven dalesmen, one female and six males (corresponding to a total prevalence of 381 per 100 000; 95% confidence interval (CI) 153-783 per 100 000). Except for the female gender, the female case was fairly typical. In one case, there were short-lasting bouts ('minibouts'). It was felt that this also was a genuine case of cluster headache. If one excluded the latter case, there would be one female and five males [a prevalence of 106 per 100 000 for females, and 558 per 100 000 for males, giving a prevalence in the total population of 326 per 100 000 (95% CI 120-709 per 100 000)]. The confidence interval was considerable. This study therefore does not give a clear indication as to prevalence.