Cluster headache: the history of the Cluster Club and a review of recent clinical research

In September 2003, a scientific meeting was held in Rome to revive the International Cluster Headache Research Group (or "Cluster Club") tradition. This group of specialists was originally formed in the late 1970s by Ottar Sjaastad in order to promote research ideas, and to generate papers and other important information in this field. Its meetings, the last of which had taken place in 1994, had been informal events at which there was ample time for lively discussion. The last decade of the 20th century brought a significant increase in clinical and experimental research into cluster headache (CH), and this review summarizes some of the results of this research. The male preponderance of CH has been shown to be progressively decreasing over the years. Revised clinical criteria and a modern classification have been presented. First-degree relatives of probands with CH have been shown to have an increased risk of suffering from CH compared with the general population. Genetic analysis suggests that an autosomal dominant gene plays a role in some families. Functional neuroimaging has contributed to a better understanding of the pathophysiology of the condition. Positron emission tomography during provoked attacks has shown activation of the ipsilateral inferior posterior hypothalamus and it has been suggested that CH might be a functional neurovascular disorder of pacemaker or circadian regions in the hypothalamic grey matter. Subcutaneously administered sumatriptan has emerged as a highly effective acute treatment, but, in our opinion, the emphasis should be on attack prevention. Deep brain stimulation of the inferior posterior hypothalamic grey matter seems to be very promising as a novel treatment targeting the presumed central origin of pain attacks.     

Activation in the anterior left auditory cortex associated with phonological analysis of speech input: localization of the phonological mismatch negativity response with MEG

The spatio-temporal dynamics of cortical activation underlying auditory word recognition, particularly its phonological stage, was studied with whole-head magnetoencephalography (MEG). Subjects performed a visuo-auditory priming task known to evoke the phonological mismatch negativity (PMN) response that is elicited by violations of phonological expectancies. Words and non-words were presented in separate conditions. In each of the 318 trials, the subjects first saw a word/non-word (e.g., 'cat') that was soon followed by a prime letter (e.g., 'h'). Their task was to replace mentally the sound of the first letter of the word/non-word with the prime letter, thus resulting in a new word/non-word (e.g., 'hat'). Finally, an auditory word/non-word either matching or mismatching with the anticipated item was presented. In most subjects, a PMNm followed by a later, N400m-like negativity was obtained in the left hemisphere to the mismatching auditory stimuli. A similar response pattern was obtained in the right hemisphere only in a few subjects. Source localization of the N1m, an index of acoustic analysis, and the PMNm and N400m-like responses was performed using L1 minimum-norm estimation. In the left hemisphere, the PMNm source for the words was significantly more anterior than the source of the N400m-like response; for the non-words, the PMNm source was significantly more anterior than the sources of the N1m and the N400m-like response. These results suggest that the left-hemisphere neuronal networks involved in sub-lexical phonological analysis are at least partly different from those responsible for the earlier (acoustic) and later (whole item) processing of speech input.     

Type 1 diabetes patients with severe non-proliferative retinopathy may benefit from panretinal photocoagulation

PURPOSE: To examine whether panretinal photocoagulation for severe non-proliferative retinopathy in type 1 diabetes patients could halt the progression of retinopathy with subsequent vitreous haemorrhages and visual impairment. METHODS: During a 10-year follow-up study period of 344 type 1 diabetes patients, 81 subjects went through panretinal photocoagulation. Forty patients were treated for severe non-proliferative retinopathy (age at onset of diabetes 14 +/- 8 years, diabetes duration 18 + 10 years) and 41 for proliferative retinopathy (age at onset 15 +/- 10 years, diabetes duration 22 + 13 years). One randomly selected eye per patient forms the basis for the study. Metabolic control, systolic and diastolic blood pressure, serum creatinine and urinary albumin levels were measured and analysed yearly during the follow-up period. RESULTS: A total of 35% (14/40) of eyes treated for severe non-proliferative retinopathy developed neovascularizations during a mean time of 2.9 +/- 1.5 years. Vitreous haemorrhages were more frequent in eyes with proliferative retinopathy at treatment than in eyes with severe non-proliferative retinopathy (12/41 versus 2/40; p = 0.007). The number of vitrectomies due to vitreous haemorrhages in eyes treated for severe non-proliferative retinopathy tended to be lower (1/40 versus 6/41; p = 0.052). Before photocoagulation, visual acuity (VA) was similar in eyes with severe non-proliferative retinopathy and in those with proliferative retinopathy (1.0, 0.4-1.0 versus 1.0, 0.1-1.0; median and range). Visual impairment and blindness tended to develop more often in eyes treated for proliferative retinopathy compared to those treated for severe non-proliferative retinopathy (10/40 versus 4/40; p = 0.056). Eyes with neovascularizations at follow-up were more often visually impaired (VA < 0.5) than eyes without neovascularizations (15/55 versus 1/26; p = 0.016). CONCLUSION: In type 1 diabetes, panretinal photocoagulation may be beneficial even at the severe non-proliferative retinopathy stage in terms of preventing vitreous haemorrhage, subsequent vitrectomy and visual impairment.     

Epigenetic and genetic alterations of APC and CDH1 genes in lobular breast cancer: relationships with abnormal E-cadherin and catenin expression and microsatellite instability

The causes and functional consequences of E-cadherin (E-CD) loss in breast cancer are poorly understood. E-CD loss might act in concert with alterations in the APC/beta-catenin pathway to permit oncogenic beta-catenin signaling. To test this hypothesis, we have analyzed the presence of genetic and epigenetic alterations affecting E-CD (CDH1), APC and beta-catenin (CTNNB1) genes and the immunohistochemical expression of E-CD, beta- and gamma-catenin in a series of 46 infiltrating lobular breast carcinomas (ILCs). Since 80% of ILCs featured complete loss of E-CD expression, we analyzed the molecular alterations responsible for E-CD inactivation in these tumors. We found that 10 of 46 (22%) cases harbored mutations in CDH1, including 1 case with 2 different mutations (1 of which was germline). CDH1 was also inactivated by loss of heterozygosity (LOH; 30/41, 73%) and promoter hypermethylation (19/46, 41%). Interestingly, LOH and mutations were also detected in the corresponding in situ lesions of the ILCs, implying that these alterations are early events in lobular cancer tumorogenesis. Additionally, the presence of a polymorphism in the CDH1 promoter was found to be inversely correlated with CDH1 mutations, but not with E-CD levels. We next examined whether alterations in the APC/beta-catenin pathway also occurred in the same series of ILCs. Although no CTNNB1 or APC mutations were detected, promoter methylation (25/46, 52%) and LOH (7/30, 23%) of APC were found. Moreover, methylation of APC and CDH1 occurred concordantly. However, beta- and gamma-catenin were severely reduced or absent in 90% of these tumors, implying that alterations in CDH1 and APC genes do not promote beta-catenin accumulation in ILC. These molecular alterations were not associated with microsatellite instability. In summary, several different mechanisms (mutations, LOH, methylation) are involved in the frequent CDH1 inactivation in invasive and in situ lobular breast cancer. The same tumors also show genetic and epigenetic alterations of APC gene. However, altered CDH1 and APC genes do not promote beta-catenin accumulation in this tumor type.     

Cognitive abilities related to post-traumatic symptoms among refugees from the former Yugoslavia in psychiatric treatment

The overall aim was to study the relationship between post-traumatic symptoms and cognitive abilities among traumatized refugees from the former Yugoslavia, in psychiatric treatment. The results showed that a diagnosis of post-traumatic stress disorder (PTSD), as well as a higher level of post-traumatic symptoms, was significantly associated with poorer average cognitive performance. Three of four tests of fluid intelligence, and the Benton Visual Retention Test, assessing episodic memory, were the most discriminating. A specific constellation of PTSD symptoms, dominated by arousal and intrusive symptoms, had a significant overall correlation with intellectual performance. One implication of the study is that assessment of cognitive abilities might be advisable in this patient group, in particular when arousal and re-experiencing symptoms are frequent.     

Vestibular and oculomotor changes in subjects treated with cisplatin

Cisplatin is an agent used in the treatment of distinct oncologic diseases. We present the electrooculographic (EOG) findings of 6 patients which were seen at our Department under the diagnosis of chronic toxicity for cisplatin and associated vestibular alterations. Mean of age was 45 years. Three subjects were female (50%). The most frequent pathologic finding was ataxic pursuit tracking (100%). Additionally, spontaneous nystagmus, alterations in positional test, and vestibulo-ocular reflex suppression were also found. These results are discussed and the main literature concerning this matter is reviewed.     

Tetanus toxin modulates serotonin transport in rat-brain neuronal cultures

As has been previously described, tetanus toxin (TeTx) and its H_C fragment inhibit the sodium-dependent 5-hydroxytryptamine (5-HT) uptake in rat-brain synaptosomes, probably through a kinase mechanism affecting the 5-HT transporter. Now, the inhibition of 5-HT uptake in neurons in primary culture by TeTx in a dose-dependent manner is described in this work. This effect is also produced by the nontoxic C-terminal fragment of the TeTx heavy chain (Hc-fragment), indicating that 5-HT uptake inhibition is a consequence of the toxin binding to the plasmatic membrane and not to its catalytic activity. This conclusion is supported by the fact that the 5-HT accumulation was not inhibited by the light chain of TeTx or the toxoid, and was even potentiated by botulinum neurotoxin A. These results correlate with the activation of phosphoinositide-phospholipase C activity in the cultures used in this study, this activity only being enhanced by TeTx and by its Hc-fragment. On the other hand, the use of tyrosine phosphorylation modulators indicates that both Na₃VO₄ and basic fibroblast growth factor (bFGF) produce an enhancement of 5-HT uptake in this system, which is also sensitive to TeTx inhibition. On the other hand, genistein alone is able to reduce the 5-HT transport in cultured neurons, and this effect did not appear to be additive to that elicited by TeTx. This result suggests that TeTx and genistein may share some events in their respective mechanisms of action. Furthermore, the incubation at different concentrations of 12-0-tetradecanoylphorbol 13-acetate (TPA) confirms the involvement of protein kinase C (PKC) in 5-HT transport modulation in rat-brain neuronal primary cultures. In summary, we shall demonstrate in this work that TeTx induces, through its Hc fragment, an inhibition of both basal and stimulated serotonin uptakes in primary neuronal cultures, in parallel to the activation of phosphoinositide-phospholipase C activity and PKC activation.     

Parental perception of cold extremities and other accompanying symptoms in children with cerebral palsy.

Cold extremities have been noted in non-walking children with cerebral damage compared with healthy controls. Whether this is a general problem in children with cerebral palsy (CP) and associated with other symptoms is unknown. This study describes accompanying symptoms such as cold extremities, constipation, pain, sleeping disorders and impaired well-being in children with CP as well as treatment the children have undergone. Associations between cold extremities and other symptoms borne by the children were analysed and discussed. From information in postal surveys received from parents of children with CP, 107 children (60 boys and 47 girls) aged 5-13 years, mean 11 years 8 months (SD 2 years 11 months), were described and analysed. Besides neurological impairments, many children had cold extremities and pain, sleeping disorders, constipation, and impaired well-being. Most children had had one or more of these symptoms for over 1 year but the symptoms were largely untreated. Non-walkers generally had more symptoms than walkers. Although pain, constipation, and sleeping disorders may have different underlying causes in children with CP, these symptoms might also be mediated or aggravated by dysfunction in the autonomic nervous system. To improve the child's well-being, early recognition and treatment of accompanying symptoms is important.