PURPOSE OF REVIEW The review was designed to summarize recent research relevant to the trigeminal autonomic cephalalgias, which include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features (SUNCT/SUNA). Hemicrania continua is included for completeness. RECENT FINDINGS Cluster headache has the longest attack duration and relatively low attack frequency. Paroxysmal hemicrania has intermediate duration and intermediate attack frequency. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing have the shortest attack duration and the highest attack frequency. Hemicrania continua has a continuous pain with exacerbations that can include cranial autonomic symptoms as part of the phenotype. The importance of diagnosing these syndromes resides in their excellent but highly selective response to treatment. SUMMARY Considerable advances have been made in the diagnostic and therapeutic approaches to trigeminal autonomic cephalalgias and these are important for neurologists to consider.

Paroxysmal hemicrania is a rare syndrome characterized by repeated attacks of strictly unilateral, severe, short-lasting pain occurring with cranial autonomic features. The hallmarks of this syndrome are the relatively short attacks and the exquisite response to indometacin. We describe the phenotype of this condition in a series of 31 patients. The mean duration of attack was 17 min. The mean attack frequency was 11. The distribution of the pain was orbital and temporal in 77% of the patients, retro-orbital in 61%, frontal in 55%, occipital in 42%; although pain was also reported in the vertex, second division of trigeminal nerve, neck, nose, jaw, parietal region, ear, teeth, eyebrow, shoulder (ipsilateral and bilateral), arm and third division of trigeminal nerve. Of the cohort, 87% had lacrimation, 68% had conjunctival injection, 58% rhinorrhoea, 54% nasal congestion, ptosis and facial flushing. Other cranial autonomic features include eyelid oedema, forehead/facial sweating, sense of aural fullness and periaural swelling, miosis, mydriasis and swelling of the cheek. The majority of the patients (80%) were agitated or restless, or both, with the pain and 26% were aggressive. All patients had positive placebo control indometacin test (100-200 mg intramuscularly), or a positive oral indometacin trial or both. We suggest the International Headache Society criteria be revised to remove specification of attack site, and to include the full range of cranial autonomic features. Currently, the sine qua non for paroxysmal hemicrania is a response to indometacin. Since there is no reliable clinical marker of that response we recommend an indometacin test, either orally or by injection for any patient with lateralized discrete attacks of head pain with associated cranial autonomic symptoms.

A 54 year-old female has a clinical diagnosis of chronic paroxysmal hemicrania (CPH) according to IHS-criteria (2004) three years ago. Six months after that, she developed symptoms compatible with trigeminal neuralgia (TN) involving the second and third trigeminal territories also at the left side. Cranial and cervical spine resonance magnetic images showed extensive cervical syringomyelia that included nucleus caudalis (C2 level) region and a posterior fossa Chiari I malformation without hydrocephalus. The association between CPH and TN is called chronic paroxysmal hemicrania-tic syndrome (CPH-tic). This is the first clinical description of a secondary cause of CPH-tic syndrome in the literature.

The trigeminal autonomic cephalgias include cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT). The evidence for the current treatment options for each of these syndromes is considered, including oxygen, sumatriptan, and verapamil in cluster headache, indomethacin in paroxysmal hemicrania, and intravenous lidocaine and lamotrigine in SUNCT. Some treatments such as topiramate have an effect in all of these, as well as in migraine and other pain syndromes. The involvement of the hypothalamus in functional imaging studies implies that this may be a substrate for targeting treatment options in the future.

Few cluster-like headaches have been described. Idiopathic intracranial hypertension (IIH) presents with headaches in more than 90% of patients. We describe a male patient with new onset cluster-like headache secondary or related to IIH.

PURPOSE OF REVIEW The new International Classification of Headache Disorders was recently published by the International Headache Society. Several uncommon primary headaches, including some new clinical entities (e.g. hypnic headache), were included in the section on 'Cluster headache and other trigeminal autonomic neuralgias' and 'Other primary headaches'. The recent classification offers an interesting opportunity to evaluate the clinical role and to discuss the mechanisms of some of the more relevant uncommon primary headaches. RECENT FINDINGS Due to the low incidence of these uncommon headache forms, their diagnostic criteria, pathogenetic mechanisms and therapy are still debated. Differential diagnosis versus secondary headaches is also a crucial issue. In this review, some of the most important uncommon primary headaches are discussed in light of the most recent contributions to the literature. SUMMARY The review focuses on the update of the main uncommon primary headaches, intending to clarify some controversial points and to indicate some headlines for further research.

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders characterized by unilateral pain in the somatic distribution of the trigeminal nerve and ipsilateral autonomic signs, which reflect activation of the cranial parasympathetic pathway. The group includes cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache with conjunctival injection and tearing. Hemicrania continua was previously classified as one of the TACs. Despite their common elements, individually these headaches differ with respect to attack duration, frequency, and response to indomethacin.

We present a prospective study of 240 patients with medication overuse headache (MOH) treated with drug withdrawal and prophylactic medications. At 1-year follow-up, 137 (57.1%) patients were without chronic headache and without medication overuse, eight (3.3%) patients did not improve after withdrawal and 95 (39.6%) relapsed developing recurrent overuse. Age at time of MOH diagnosis, regular use of benzodiazepines, frequency and Migraine Disability Assessment (MIDAS) score of chronic headache, age at onset of primary headache, frequency and MIDAS score of primary headache, ergotamine compound overuse and daily drug intake were significantly different between successfully and unsuccessfully treated patients. Multivariate analysis determined the frequency of primary headache disorder, ergotamine overuse and disability of chronic headache estimated by MIDAS as independent predictors of treatment efficacy at 1-year follow-up.

OBJECTIVE Elevated plasma total homocysteine (tHcy) is an independent risk factor for ischemic stroke and has been linked to cerebral small vessel disease (SVD), in particular. Controversy persists as to whether increased tHcy is associated with functional status and cognitive decline in these patients. METHODS Plasma tHcy, MTHFR polymorphism, vascular risk factors, functional and cognitive status and severity of lesions on MRI, assessed with the Age-Related White Matter Changes (ARWMC) visual grading scale, were analyzed in 95 patients with SVD and 41 healthy control subjects. RESULTS Plasma tHcy levels were higher in patients with SVD (14.4±5.0 μmol/L) compared to healthy SVD-free controls (8.9±3.9 μmol/L). In SVD patients, tHcy levels strongly correlated with cognitive status (age-adjusted risk 5.8, 95% CI 1.3-25.3, p=0.015), functional status (age-adjusted risk 3.2, 95% CI 1.2-8.8, p=0.022) and severity of MRI lesions (age-adjusted risk 1.2, 95% CI 1.1-1.4; p=0.004). Only total ARWMC score was independently associated with increased tHcy levels (OR 1.2, 95%CI 1.1-1.4, p=0.004). Independent predictors of WMC occurrence were tHcy levels (OR 1.2, 95%CI 1.1-1.3, p=0.003) and mRS score (OR 2.2, 95%CI 1.2-4.1, p=0.017). CONCLUSIONS In patients with cerebral SVD there is a positive association of increased plasma tHcy levels with clinical status and severity of WMC.

There is an increase in the number of patients with systemic lupus erythematosus (SLE) reported as developing progressive multifocal leukoencephalopathy (PML) while on intensive immunosuppressive therapy. A 39-year-old HIV-negative woman with a 10-year history of SLE presented with progressive left-side weakness while on maintenance therapy with oral prednisone and mycophenolate mofetil (MMF). On several occasions low CD4+ T-lymphocyte counts were found (68/µL). Brain magnetic resonance imaging (MRI) revealed a large lesion in the right subcortical fronto-parietal region and a smaller one in the left frontal subcortex, corresponding to the PML. In cerebrospinal fluid, polymerase chain reaction (PCR) for JC virus (JCV) was negative, but anti-JCV antibodies were highly positive. Diagnosis of probable PML was made and MMF was withdrawn. The patient's condition improved with marked reduction of left-side weakness and an increase in CD4(+) T-lymphocyte count (141/µL). Follow-up MRI showed regression of lesions and over the next 6 months the patient remained stable. In spite of the grave prognosis associated with PML, SLE patients can have an excellent outcome if immunosuppressants are discontinued as soon as the correct diagnosis is made. SLE patients with associated low CD4(+) T-lymphocyte counts should be monitored for the development of PML during immunosuppressive therapy in particular.

AIM The aim of this study was to evaluate and analyze the incidence and features of headaches in patients undergoing hemodialysis. MATERIAL AND METHODS In this prospective study 318 patients, 119 women and 199 men, undergoing chronic HD in four hemodialysis centers in Serbia, were questioned about their problems with headaches using a questionary designed according to the diagnostic criteria of the International Headache Classification of Headache Disorders (ICHD) from 2004. Patients were distributed in two groups according to the presence of hemodialysis headaches (HDH). The groups were compared regarding sex, age, duration of HD, primary diseases that lead to ESRD, arterial systolic and diastolic blood pressure (BP) and serum levels of hemoglobin, urea nitrogen, creatinine, sodium, potassium, calcium, phosphates, albumin, glucose and calcium-phosphate product. We also analyzed features of HDH. The results were statistically compared. RESULTS Patients with HDH had significantly lower serum glucose, but higher serum phosphates and albumin than patients without headaches. Furthermore, HDH patients had higher calcium phosphate product and systolic blood pressure than non-HDH patients. Out of 318 patients included in the study, 21 (6.6%) patients had HDH. According to our results, HDH appeared more frequently in men, during the 3rd hour of HD in more than a half of the patients and lasted less then 4 h in the majority of HDH patients. In the majority of patients HDH was bilateral, non-pulsating, without associated symptoms and it appeared mostly during HD. Personal history was negative for primary headaches in all patients with HDH. CONCLUSION We believe that the results of our investigation of more than 300 HD patients pointed to some biochemical changes, possibly implicated by pathophysiology of HDH and disclose some specific HDH features that might contribute to a better understanding of this secondary headache disorder.

In this open study, the therapeutic effect of moclobemide, a reversible selective monoamine oxidase A inhibitor, was tested in 20 patients with Parkinson's disease who developed levodopa-induced motor response complications. Moclobemide as adjunct therapy reduced "off" time duration for 27%, without an overall motor and functional improvement during their "on" periods. Since it was well tolerated, moclobemide may be specially indicated in elderly or depressed fluctuating parkinsonian patients.

Hemiballism is a relatively rare hyperkinetic disorder; treatment is based mainly on neuroleptics and drugs that decrease release of dopamine. We report the cases of two patients with hemiballism. After a period of 1 month of nonresponsiveness to haloperidol, amelioration of ballistic movements was observed only a few days after the initiation of clozapine therapy (50 mg/day). Our report suggests that clozapine may be a valuable alternative for patients with hemiballism.

Sleep patterns of two consecutive nights were analyzed in 26 drug-free patients with Parkinson's disease (PD), who were clinically divided into depressed (n = 8) and nondepressed (n = 18) groups. Sleep electroencephalographic (EEG) recording showed significantly shorter rapid eye movement (REM) latency in depressed PD patients (41.1 +/- 21.7 min) compared to nondepressed PD patients (129.0 +/- 84.9 min, p less than 0.002). Furthermore, shortened REM latency (less than or equal to 65.0 min) was observed with significantly more frequency in depressed PD patients (6 out of 8) compared to nondepressed PD patients (4 out of 18, p less than 0.02). The other sleep parameters studied did not differ significantly between the two groups of patients. Because shortened REM latency is one of the most reliably documented biological features of major depression, these findings may be of some importance for understanding the nature of depression in the course of PD.

Obesity is among the greatest health burden worldwide, then again there is a certain lack in regard to objective evidence-based clinical therapeutic algorithms. Relative share of advanced classes of obesity in adult and childhood population shows increment. Treating of those grades by means of conservative therapy (lifestyle change, pharmacotherapy) mostly fails to attain clinically significant weight lost or any effect on the obesity related comorbidities. For this reason, more effective forms of treatment were developed in terms of bariatric surgery and newly emerging field of endoscopic devices within gastroenterology. Bariatric surgery has showed tremendous growth, with couples-hundred-thousand operations a year. However, due to relatively narrowly stated indication parameters (body mass index and comorbidity), study population selection, randomization and representation in part did not meet the evidence based guided principles. Conversely, emerging field of endoscopic methods showed promising results in weight loss, within satisfying safety profiles. Although there are no clear defined positions of endoscopic devices in treating of obesity, tens thousands were implanted worldwide. Endoscopic treatment seems to be especially interesting prior to bariatric or as an alternative to surgery; reducing elective surgical risks, or better control of diabetes. Studies on the minimal invasive devices similarly showed lack in the evidence based principles, particularly in regard to treatment sustainability, effect on the obesity related comorbidities. This review presents analyses on the position and bases of invasive treatments, with aim to identify challenging key points in order to develop systematic bases on how to treat obesity more efficiently.

Introduction: Data on clinical differences between episodic (eCH) and chronic cluster headache (cCH) and accompanying migraine features are limited. Methods: History and clinical features of 209 consecutive cluster headache patients (144 eCH, 65 cCH; male:female ratio 3.4 : 1) were obtained in a tertiary headache centre by face-to-face interviews. Relationship between occurrence of accompanying symptoms, pain intensity, comorbid migraine, and circannual and circadian rhythmicity was analysed. Results: 99.5% of patients reported a minimum of one ipsilateral cranial autonomic symptom (CAS); 80% showed at least three CAS. A seasonal rhythmicity was observed in both eCH and cCH. A comorbid headache disorder occurred in 25%. No significant difference was detected between patients with comorbid migraine and without regarding occurrence of phonophobia, photophobia or nausea during cluster attacks. Patients with comorbid migraine reported allodynia significantly (p = 0.022) more often during cluster attacks than patients without comorbid migraine. Conclusion: Occurrence of CAS and attack frequency, as well as periodic patterns of attacks, are relatively uniform in eCH and cCH. Multiple CAS are not related to pain intensity. Allodynia during cluster attacks is a frequent symptom. The unexpectedly high rate of accompanying migrainous features during cluster attacks cannot be explained by comorbid migraine.

The majority of previous studies on unilateral headaches beyond migraine and cluster headache have focussed on certain disorders such as paroxysmal hemicrania, SUNCT and primary stabbing headache. We assessed headache characteristics, importance of neuroimaging and response to indomethacin in an unselected series of uncommon unilateral headaches. We investigated all consecutive patients presented with unilateral headaches not fulfilling ICHD-II criteria of migraine and cluster headache. Patients underwent cranial magnetic resonance imaging or computed tomography as well as an indo-test, i.e. oral indomethacin 75 mg b.i.d. for 3 days. Among 63 patients we diagnosed primary stabbing headache in 12 patients,(probable) paroxysmal hemicrania in 6 and tension-type headache in 3 patients. One patient each had probable SUNCT, new daily persistent headache and nasociliary neuralgia. Eight patients had a secondary headache and 31 could not be classified according to ICDH-II. Imaging revealed lesions causally related to the headache in 8 patients. Indo-test achieved full remission of headache in 13 of 51 patients. At follow-up 11 ± 3 months after the first visit 29% of the patients were headache-free for ≥3 months. In conclusion, almost half of the patients presented with unilateral headaches beyond migraine and cluster headache cannot be classified according to ICHD-II. Among classifiable headaches primary stabbing headache was the most common. Imaging should be considered to rule out secondary headaches. The course is favourable in one third of the patients.

Epicrania fugax (EF) is a novel syndrome, described as a paroxysmal and brief head pain, starting in posterior cranial regions and rapidly spreading forward ipsilateral eye, nose or forehead. Two patients with comparable clinical features stemming from frontal scalp to ipsilateral posterior regions have been recently described and proposed as backward radiation epicrania fugax (BREF). We report a new series of nine BREF and compare their clinical characteristics with 18 forward radiation EF (FREF). Since first description of BREF in February 2010 we have assessed nine patients (four males, five females) with this clinical picture at an outpatient headache office in a Tertiary Hospital. Comparison is established with 18 FREF patients (6 males, 12 females), attended since the publication of first series of EF in March 2008. We found no differences between BREF and FREF, respectively, in age at onset (43.4 ± 13.1 vs. 42.5 ± 17.7 years), female/male ratio (5/4 vs. 12/6), pain intensity (6.9 ± 2.1 vs. 6.8 ± 2.1 in a 0-10 visual analogical scale), duration (7.1 ± 4.9 vs. 5.7 ± 4.3 s) and frequency of episodes per day (7 ± 8.4 vs. 9.9 ± 15.4). Patients in BREF group presented less frequently interictal pain in stemming point (22.2 vs. 55.5%) and accompanying autonomic signs (33.3 vs. 55.5%), but without statistical significance in both the cases. This series reinforces the proposal of EF as a new headache variant or a new headache syndrome. Clinical picture of brief pain paroxysms starting in the anterior scalp and radiating backwards does not fit known headaches or neuralgias and might correspond to a reverse variant of EF, clinical characteristics of which are comparable to FREF.

The proposed title "Pain as an evolutionary necessity" could lead to a broad debate with implications covering many chapters of the medicine and particularly of clinical neurology. In the present perspective, the discussion will focus on migraine and cluster headache chosen as elective examples of biological and not only clinical conditions, that unveil the bond between pain and necessity. Migraine, cluster headache, and perhaps other primary headaches begin to be depicted in terms of recurrent activation of innate bio-behavioral specific patterns, with a crucial and highly conserved evolutionarily adaptive significance. The pan-mammalian sickness behavior and the fight or flight response, selectively activated by different kinds of pain, are here proposed as paradigmatic of migraine and cluster headache attacks associated behaviors, allowing to reformulate these forms as the inappropriate recurrent presentation of coordinated allostatic processes, modeled along million of years of natural evolution. In this light, all the multifaceted characteristics of migraine and cluster headache attacks can be reinterpreted as complex and integrated allostatic defensive reactions to an inescapable or to an escapable pain, respectively aimed to the restoration of biologic homeostasis through a temporary disengagement from active interaction with environment (migraine associated sickness behavior) or, on the contrary, to promote the coordinated biological changes preparatory to emergency and defensive behaviors (cluster headache-related fight or flight response).

The trigeminal autonomic cephalalgias (TACs), including cluster headache, paroxysmal hemicrania and SUNCT, are characterized by the cardinal combination of short-lasting unilateral pain and autonomic phenomena affecting the head. Hemicrania continua (HC) shares many clinical characteristics with TACs, including unilateral pain and ipsilateral autonomic features. Nevertheless, HC is separately classified in the revised International Classification of Headache Disorders (ICHD-II). Here, we describe the case of a 45-year-old man presenting an unusual concurrence of different forms of primary headaches associated with autonomic signs, including subsequently ipsilateral cluster headache, SUNCT and HC. This report supports the theory that common mechanisms could be involved in pathophysiology of different primary headache syndromes.

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache disorders that include cluster headache (CH), paroxysmal hemicrania (PH), and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing/cranial autonomic features (SUNCT/SUNA). Hemicrania continua (HC) is often included with this group, although the second edition of The International Classification of Headache Disorders did not link the entities. Trigeminal autonomic cephalalgias are generally characterized by relatively short-lasting attacks of severe pain and lateralized associated features including the pain, cranial autonomic symptoms, and where present, migrainous symptoms, such as photophobia. Paroxysmal hemicrania has intermediate duration and intermediate attack frequency. Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing has the shortest attack duration and the highest attack frequency. Hemicrania continua has a continuous pain with exacerbations that can include cranial autonomic symptoms as part of the phenotype. The syndromes share much in their pathophysiology and investigation paths; however, their treatment is distinct, so that the accurate differentiation is important for optimal management.

(Headache 2010;**:**-**) The trigeminal autonomic cephalalgias (TACs) and hemicrania continua (HC) share many clinical characteristics including unilateral pain and ipsilateral autonomic features. We report a patient with a history of migraine without aura who developed cluster headache and HC simultaneously. The distinctive clinical features and differential response profiles to various treatments indicates that they are distinct disorders. We then review previous reports of patients with coexisting TACs and HC and discuss the relationship between these families of primary headache disorders.

The trigeminal autonomic cephalalgias (TACs) are a group of primary headache syndromes all marked by headache and associated autonomic features. The TACs include cluster headache, paroxysmal hemicrania, hemicrania continua, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing syndrome. Diagnosis is made after looking at headache frequency, duration, and accompanying symptoms. Each TAC has its own unique treatment modality, which is discussed in depth.

Neurophysiological methods used in the diagnosis of headache, especially migraine are: electroencephalography (EEG), evoked cortical potentials (VEP, BAER, ERP), reflex responses, autonomic tests and transcranial magnetic stimulation (TMS). Interpretation of EEG can be important for the differential diagnosis of some disorders with headache as a presenting symptom. Noninvasiveness, accessibility and ability to repeat the test due to exposure to harmful ionization are the main advantages of EEG. The role of thorough medical history and clinical assessment in patients with headache should not be underestimated. Interictal EEG (between headache attacks) is not significant in routine evaluation of these patients, but can be useful in patients with unusual symptoms suggesting epilepsy or migraine. It is indicated in patients with an abrupt onset of headache, in patients with migraine followed by neurological signs, in basilar migraine, migraine with extended duration of aura and in cases where epilepsy is suspected. Headache as a symptom is present in various brain and systemic diseases and metabolic disorders. EEG changes seen in headache patients are not specific for a particular disorder, but can suggest additional evaluation and accelerate accurate diagnosis and earlier treatment. Visual evoked cortical potentials (VEP) and cognitive evoked potentials (ERP) in patients with migraine in interictal periods have shown differences in sensory processing between patients with headache and healthy controls. Neurophysiological methods (VEP, ERP) between migraine attacks show cortical hyperactivity and predisposition for further attacks. Brainstem auditory evoked responses (BAER) are a sensitive method for the detection of central nervous system damage. Activation of the brainstem during the migraine attack results in an amplitude increment seen soon after the end of the attack. According to recent studies, R2 component of the blink reflex was six times longer during migraine attack as compared to interictal values. This is thought to be a response to sensitization of the skin nociceptive afferent arch or other neurons in the trigeminal nucleus. In patients with cluster headache, autonomic tests generate cardiovascular and pupillary response suggesting systemic sympathetic hyperactivation connected to concurrent pupillary sympathetic hypofunction and modified opioid modulation. TMS is shown to be very useful for the detection of pathophysiological changes of numerous disorders including migraine, due to its excitatory and inhibitory effects. Recent studies have shown changes in motor and occipital cortex during TMS interictal excitability. Neurophysiological tests are used in differential diagnosis of headache, follow up of possible complications in patients with symptomatic headache as well as in neurorehabilitation. In addition, electrophysiological diagnostic test can contribute to better understand the headache pathophysiology.

--Trigeminal autonomic cephalalgias (TACs) include cluster headache, paroxysmal hemicranias and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCTs).--Because they are rare, it is often difficult to recognise TACs in practice. Hallmarks of TACs include the strictly unilateral pain near the eye or temple, the accompanying autonomic symptoms, and the specific pattern in the timing of the attacks.--The TAC subtypes differ in the duration and frequency of attacks. Differentiating TAC subtypes is important because it affects the treatment approach.--In rare cases, TAC results from an underlying structural disorder. Neuroimaging (cerebral MRI) is advised in all patients with TAC.