Angelo Ranieri

Advancement in idiopathic intracranial hypertension pathogenesis: focus on sinus venous stenosis

Idiopathic intracranial hypertension is consistently associated with venous outflow disturbances. Sinus venous stenosis are found at magnetic resonance venography in the large majority of IIH patients and may have various conformations, ranging from functional smooth narrowings of sinus segments associated or not with definite flow gaps, to segmental hypoplasia or aplasia of one or more central venous collectors. Stenosis are currently believed to be a consequence of a primary altered cerebrospinal fluid (CSF) pressure since it may normalize after CSF subtraction with lumbar puncture or shunting procedures. In this paper a “self-sustained venous collapse” is proposed as a crucial causative mechanism in predisposed subjects, leading to a self-sustained intracranial hypertension in presence of a wide range of triggering factors. The proposed mechanisms predict the long-term remission of IIH syndromes frequently observed after a single or few serial CSF subtractions by lumbar puncture.

A clinical comparison of trigeminal neuralgic pain in patients with and without underlying multiple sclerosis.

Despite clinical similitude, there is a tendency to consider trigeminal pain in multiple sclerosis (MS) as a distinct condition. To evaluate clinical differences in trigeminal pain presentation in patients with and without underlying MS, we compared clinical characteristics of facial pain found in 15 consecutive MS patients with those reported by 13 consecutive subjects diagnosed with classical trigeminal neuralgia. The only significant difference between MS and non-MS neuralgic patients was the age of onset of pain (43.4±10.5 in MS vs. 59.6±11.50 in non-MS patients, p=0.000629, unpaired Student’s t-test). No differences were observed for side, duration and quality of pain, trigeminal branches involved, presence of trigger areas or factors, pain refractive period, remitting-relapsing or chronic course. There was only a trend without statistical significance in interval pain and trigeminal hypoesthesia, more frequent in MS population. Only one patient in the MS group presented with long-lasting episodes (45–60 min) of atypical odontalgia. Our findings support the view of a common pathogenetic mechanism underlying TN in the two groups, possibly related to demyelination of the trigeminal entry root in the pons. Typical TN in MS patients should be considered as “symptomatic trigeminal neuralgia”.

Hypnic headache: an update

Hypnic headache (HH) is a rare sleep-associated primary headache disorder, usually affecting aged people, first described by Raskin in 1988. The headache attacks, single or multiple in one night, occur exclusively during sleep and tend to present at a consistent time each night, sometimes during a dream. Compared to the original description, newly reported cases have expanded the clinical spectrum of the disorder to include unilateral forms (about 40%, half of which are side-locked), forms with a longer duration (up to 3 h) and cases with onset in juvenile/adult age. The male predominance found in Raskin’s series has not been confirmed by subsequent observations. To date the reported F/M ratio is 1.7/1. Pain is of severe intensity in less then one-third of cases and mild-moderate in about two-thirds. The location of pain is fronto-temporal in over 40% of cases; headache is throbbing in 38% of cases, dull in 57% and stabbing in less than 5%. Nausea is reported in 19% of cases; photophobia, phonophobia or both are present in 6.8%. Mild autonomic signs (lacrimation, nasal congestion, ptosis) may rarely be present. In 2004, HH was included in Group 4 of the International Classification of Headache Disorders—II (Other primary headaches). Sufficient evidence, mainly from polysomnographic studies, indicates that HH is a primary rapid eye movement (REM) sleep-related headache disorder of chronobiological origin. Lithium, melatonin, indomethacin and caffeine at bedtime are among the most effective therapeutic options. The pathophysiology of HH is still unclear. Available data allow speculation that, in predisposed subjects, an age-related impairment of suprachiasmatic nucleus could cyclically activate a disnociceptive mechanism leading to both a sudden awakening and headache. The mechanism may be precipitated by neurophysiologic events such as the strong reduction of firing occurring in the dorsal raphe nucleus during a REM sleep phase.

Cranial neuralgias: from physiopathology to pharmacological treatment

Cranial neuralgias are paroxysmal painful disorders of the head characterised by some shared features such as unilaterality of symptoms, transience and recurrence of attacks, superficial and “shock-like” quality of pain and the presence of triggering factors. Although rare, these disorders must be promptly recognised as they harbour a relatively high risk for underlying compressive or inflammatory disease. Nevertheless, misdiagnosis is frequent. Trigeminal and glossopharyngeal neuralgias are sustained in most cases by a neurovascular conflict in the posterior fossa resulting in a hyperexcitability state of the trigeminal circuitry. If the aetiology of trigeminal neuralgia (TN) and other typical neuralgias must be brought back to the peripheral injury, their pathogenesis could involve central allodynic mechanisms, which, in patients with inter-critical pain, also engage the nociceptive neurons at the thalamic-cortical level. Currently available medical treatments for TN and other cranial neuralgias are reviewed.

Is idiopathic intracranial hypertension without papilledema a risk factor for migraine progression

The association of chronic migraine (CM) with an idiopathic intracranial hypertension without papilledema (IIHWOP), although much more prevalent than expected in clinical series of CM sufferers, is not included among the risk factors for migraine progression. We discuss the available evidence supporting the existence of a pathogenetic link between CM and idiopathic intracranial hypertensive disorders and suggest a causative role for IIHWOP in migraine progression.

High prevalence of bilateral transverse sinus stenosis-associated IIHWOP in unresponsive chronic headache sufferers: pathogenetic implications in primary headache progression.

Dear Sir We read with great interest the paper ‘‘Abnormal pressure waves in headache sufferers with bilateral transverse sinus stenosis’’ by Bono et al. (1). The study replicates the findings of a previous study by Torbey et al. entitled ‘‘Utility of CSF pressure monitoring to identify idiopathic intracranial hypertension without papilledema in patients with chronic daily headache’’ (2), providing an independent confirmation that the diagnosis of idiopathic intracranial hypertension without papilledema (IIHWOP) may be overlooked even in the case of direct opening pressure (OP) measurement by lumbar puncture (LP). In fact, in most such cases the intracranial hypertensive status presents large intra-day fluctuations so that prolonged intracranial pressure (ICP) monitoring is crucial in recognizing the condition. However, the study design of Bono et al. presents a number of important differences from that of Torbey, four of which are of major relevance:

Sinus Venous Stenosis–Associated Idiopathic Intracranial Hypertension Without Papilledema as a Powerful Risk Factor for Progression and Refractoriness of Headache

Data from two recent studies strongly support the hypothesis that idiopathic intracranial hypertension without papilledema (IIHWOP) could represent a powerful risk factor for the progression of pain in primary headache individuals. The first study highlights that an asymptomatic IIHWOP is much more prevalent than believed in the general population and occurs only in central venous stenosis carriers. In the second study, about one half of a large consecutive series of unresponsive primary chronic headache patients shows significant sinus venous stenosis. A continuous or intermittent IIHWOP was detectable in 91% of this subgroup and in no patient with normal venography. Moreover, after the lumbar puncture, a 2- to 4-week improvement in headache frequency was observed in most of the intracranial hypertensive patients. These findings strongly suggest that patients prone to primary headache who carry central venous outflow abnormalities are at high risk of developing a comorbid IIHWOP, which in turn is responsible for the progression and the unresponsiveness of the pain. Based on the available literature data, we propose that central sinus stenosis–related IIHWOP, although highly prevalent among otherwise healthy people, represents an important modifiable risk factor for the progression and refractoriness of pain in patients predisposed to primary headache. The mechanism could refer to up to one half of the primary chronic headache patients with minimal response to treatments referring to specialized headache clinics. Due to the clinical and taxonomic relevance of this hypothesis further studies are urgently needed.

Clinical progression of SYNJ1-related early onset atypical parkinsonism: 3-year follow up of the original Italian family

During the past few years, several Mendelian forms of human parkinsonism have been identified [1]. As regards autosomal recessive forms of early-onset parkinsonism, mutations in PRKN (PARK2), PINK1 (PARK6), and DJ1 (PARK7) may cause a typical parkinsonism with no additional clinical signs, while mutations in ATP13A2, PLA2G6, and FBX07 (PARK9, PARK14, and PARK15) are responsible for atypical parkinsonism, with pyramidal signs and cognitive decline, as well as a variable response to dopaminergic treatment and a more severe progression of disease. Recently, a homozygous mutation (c.773G [A; p.Arg258Gln) in the polyphosphoinositide phosphatase synaptojanin 1 (SYNJ1) was found to be associated with early-onset atypical parkinsonism in an Italian consanguineous family from Sicily, and in an Iranian family [2, 3]. This form has been designated as PARK20 (Online Mendelian Inheritance in Man, OMIM 615530). A clinical variability was observed across the two families. Indeed, the Italian siblings presented cognitive impairment and no seizures compared to the Iranian siblings. However, the clinical progression over time of the clinical features of this novel form of autosomal recessive, early-onset atypical parkinsonism has not been evaluated or documented to date. We report a 3-year follow-up of the affected Italian siblings. Details of the onset and our first examination have been described elsewhere [2]. The first proband was a 50-year-old man who was untreated as previous administration of dopaminergic treatment yielded no relevant benefit but induced marked dystonias and hypotension [2]. On examination, 28 years after the onset of disease, his clinical picture was relatively stable. The Unified Parkinson’s Disease Rating Scale part III (UPDRS-III) score was 82. Compared to our previous examination some features, such as gait and ocular movement, even seemed slightly improved, possibly suggesting a spontaneous fluctuation (Video 1). The second proband was a 34-year-old woman who was still untreated. Like her brother, she could not tolerate dopaminergic therapy [2]. On examination six years after the onset of disease, she presented a worsening of both gait and posture. Axial rigidity and both facial and upper limb dystonic postures had worsened. High-frequency, wideamplitude tremors were evident at the level of the facial muscles and the upper limbs. Her dysarthria had also worsened but some words were still intelligible. Her UPDRS-III was 68 (Video 2). Cognitive decline was detected, as the Mini-Mental State Examination (MMSE) score had decreased to 24/30 (2 points less than the evaluation at baseline, 3 years earlier). This is the first video report of the clinical progression of SYNJ1-related early onset parkinsonism. The clinical course of the untreated Italian siblings over a 3-year Electronic supplementary material The online version of this article (doi:10.1007/s00415-014-7270-6) contains supplementary material, which is available to authorized users.

Sinus venous stenosis-associated IIHWOP is a powerful risk factor for progression and refractoriness of pain in primary headache patients: a review of supporting evidences.

Reported prevalence of idiopathic intracranial hypertension without papilledema (IIHWOP) in series of patients with chronic or transformed migraine is significantly higher than expected; yet, IIHWOP is not included among the risk factors for migraine progression. However, several studies provided evidences suggesting that IIHWOP could represent a possible, largely underestimated, risk factor for progression of pain in migraine and, possibly, in other primary headaches. Data from two recent studies, albeit aimed to different end-points, strongly support this hypothesis. In the first study, conducted on a large series of neurological patients without any sign or symptom of raised intracranial pressure (ICP), including chronic headache, the prevalence of bilateral central venous stenosis at magnetic resonance venography (MRV) was 23% and an IIHWOP at opening pressure was found in 48% of this subgroup (11% of the whole sample) while it was not detected in any of the subjects with normal MRV. This indicates that IIHWOP may be much more prevalent than believed in general population and that it can run without any symptom or sign of raised ICP in most of affected subjects. In the second paper, sinus venous stenosis-associated IIHWOP has been found in about one half of a large chronic primary headache patients series with poor response to treatments and in none of those with normal MRV. Moreover, after the diagnostic lumbar puncture, a transient improvement of headache frequency has been observed in the majority of intracranial hypertensive chronic headache subjects. Taken together, the data of these two recent papers rise the following hypothesis: (1) asymptomatic IIHWOP is much more prevalent than expected in general population; (2) IIHWOP is a powerful and largely unrecognized risk factor for progression of pain in primary headache patients; (3) sinus venous stenosis at MRV is a reliable predictor of raised intracranial hypertension also in asymptomatic patients; (4) sinus venous stenosis has a causative role in IIH pathophysiology. These assumptions share a potential high clinical impact and need to be urgently tested in adequately designed controlled studies.

Cortical spreading depression and central pain networks in trigeminal nuclei modulation: time for an integrated migraine pathogenesis perspective

The role of the cortical spreading depression (CSD)-dependent trigeminovascular activation in migraine etiopathogenesis, long considered paradigmatic, has remained substantially unproven in humans. The parallel advancement of functional neuroimaging techniques promoted the extensive exploration of the brain networks involved in pain processing in search of a possible central migraine generator. However, despite initial enthusiasms, it has not been possible to clarify whether the functional central “markers” of pain observed in primary headaches could be considered as causative or just the neural correlates of the ongoing pain. Nonetheless, our knowledge on the complex interactions between CSD, neurogenic inflammation, peripheral trigeminovascular input, central cortico-trigeminal nuclei direct modulation and pain processing and limbic system networks has enormously grown, allowing the reconceptualisation of migraine from a neurovascular to a pure neurolimbic pain disorder, therefore relocating it in the much broader frame of the brain and whole organism homeostatic control. In this work, the available evidences currently supporting the relevance of CSD, of peripheral trigeminovascular input and of direct cortico-trigeminal nuclei modulation in migraine pathogenesis are reviewed in the light of a possible integrated migraine etiopathogenetic perspective.