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Neurology Department. Hospital Universitario Clínico San Carlos, Madrid Faculdad de Medicina, Universidad Complutense de Madrid

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Issue

Article

1:2

Migraine associated recurrent vertigo

1:3

Epileptic seizures in neurodegenerative dementia syndromes

1:4

99m Tc-MIBI muscle imaging and approach to assess functional anatomy of lower limb muscles

1:5

Postural ocular pain due to orbital varix

2:1

Pretectal syndrome caused by multiple sclerosis.

2:2

Blood pressure changes in patients with migraine: Evidences, controversial views and potential mechanisms of comorbidity

2:3

Acute Stroke in a 26 year old male

2:4

Activity of serum Cathepsin D in Alzheimer’s disease

3:1

Inheritance Of Alzheimer´s Disease Investigated By Complex Segregation Analysis

3:2

Clinical and functional description of a new form of autosomal recessive familial parkinson´s disease with late onset

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Migraine associated recurrent vertigo

Jesús Porta-Etessam MD

Neurology Department. Hospital Clínico Universitario San Carlos. Madrid. Correspondence:Jesús Porta-Etessam. C/ Andrés Torrejón, 15, 7º. 28014 Madrid. Spain. E-mail jporta@yahoo.com, mporta@caminos.recol.es Phone: +34 667 062 4

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The relationship between migraine and vertigo is well known. Migraine patients may suffer different types of vertigo: Meniere disease, basilar-type migraine with vertigo as an aura, benign positional vertigo and migraine associated recurrent vertigo (MARV). MARV is one of the most prevalent vertigo in migraine patients, included as a common cause of recurrent spontaneous vertigo in the neurotological lite- rature. MARV is an entity with its own clinical pattern, pathophysiology and treatment. Differential diagnosis should be done with benign positional vertigo, Meniere disease and basilar type migraine. Specific diagnosis criteria could help in its recognition and management.

Introduction:

The International Classification of Headache Disorders is beco- ming the most important reference document for the manage- ment of headache patients (1). Include several migraine related symptoms or syndromes as migraine related seizure or cyclic vomiting syndrome, but not the migraine associated recurrent vertigo (MARV)?

The relationship between vertigo and migraine is well-known since the initial description in 1873 (2). It has gone beyond the scientific field reaching the literature in the exciting Julio Cortaza´s short tale titled “Cefalea” (3). Although migraine pa- tients mayn suffer different types of vertigo (table 1), MARV has its own specific clinical features. It is the third cause of consul- tation for vertigo in a general neurology outpatient clinic (4) and is included as a common cause of recurrent spontaneous vertigo in the neurotological literature (5). MARV is an entity that needs its own place in the International Classification of Headache Disorders.

Delimiting MARV:

MARV differs from other vertigos present in migraine patients and from other types of recurrent vertigos. Most migraine pa- tients experience instability or poor balance sensation during migraine attacks. This multifactor symptom is not vertigo and it differs radically from MARV, where patients suffer motion illu- sion during the episodes.

Table 1. Types of vertigo in migraine patients

Migraine associated recurrent vertigo Basilar type migraine Benign positional vertigo Meniere disease Benign paroxysmal vertigo of the childhood

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The differential diagnosis with benign positional vertigo (BPV), (6) a type of vertigo with an increased incidence in migraine patients (possibly related with utriculus ischemia) (7-8) is ne- cessary. There are two critical differences: MARV attacks last for hours or even days opposed to BPV characterized by short episodes of vertigo lasting seconds or minutes; and BPV is a postural induced vertigo that may be induced by positional- provoked manoeuvres.

The lack of auditory symptoms is crucial to distinguish MARV from Meniere disease (MD). MD uses to have otological symp- toms during the attacks and in the late phase the patients de- velop a sensorineural deafness. An increase incidence of MD in migraine patients has been reported. Even though a genetic

migraine patients has been reported. Even though a genetic relationship between both entities or an induced
migraine patients has been reported. Even though a genetic relationship between both entities or an induced

relationship between both entities or an induced mechanism by lowering the“clinical”threshold could justify this association, it is difficult to explain it from a pathophysiology or biological plausibility approach. It is possible that some MD patients were misdiagnosed cases of MARV.

MARV is not a basilar type migraine (BTM). The aura of BTM, ty- pically precede the migraine attack, opposed to MARV where there is not a temporal relationship with the migraine. Florid aura symptoms of BTM are lacking in MARV that may be also

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AND NEUROSCIENCE 2010 Vol.1 No. 1:2 doi: 10:3823/301 gin of MARV. The duration of the episodes
AND NEUROSCIENCE 2010 Vol.1 No. 1:2 doi: 10:3823/301 gin of MARV. The duration of the episodes

gin of MARV. The duration of the episodes lasting even days without compensation, the lack of hypoacusia, fullness or tinni- tus and the improvement with triptans or migraine-preventive drugs uphold the central-origin hypothesis.

MARV responds to several migraine-preventive drugs (16-20). Topiramate seems to be an option reducing the frequency of the vertigo attacks (18). Flunarizine has shown to be an effec- tive treatment for MARV (16-17). As a personal communication valproic acid also works well in these patients. Acetazolamide a drug effective in familial hemiplegic migraine and episodic ataxia type 2 may be also a useful option in both MARV and mi- graine with aura (11, 21). The vertigo attacks seem to respond to triptans (22).

associated with migraine without aura (1). MARV not only di- ffers from BTM in the clinical spectrum but also in the longer duration of the vertigo attacks.

Assuming the relevance of cortical spreading depression, and trigeminal nociception in the pathophysiology of migraine, it’s well known the trigeminal innervations of the crista ampulla- ris, and there are cortical regions that projects to the brainstem vestibular complex (9-10). The release of neuropeptides into the vestibular peripheral cells or in the vestibular nucleus could precipitate and maintain the vertigo. Even this neuropeptides could sensitized the vestibular system and justify the subclini- cal vestibular alteration shown in migraine patients (11). Other explanation of vertigo in migraine patients is the cortical sprea- ding depression. It has been described vertigo episodes as an epileptic symptom and vertigo is one of the features of BTM (1, 12). And finally both syndromes share some features: Are re- current and chronic, the episodes last from hours to days, and both could be the result of peripheral or/and central neuronal mechanisms.

the result of peripheral or/and central neuronal mechanisms. Neurons in lateral and medial vestibular nucleus respond
the result of peripheral or/and central neuronal mechanisms. Neurons in lateral and medial vestibular nucleus respond

Neurons in lateral and medial vestibular nucleus respond to se- rotonin increasing the firing rate and autoradiographic studies confirm the presence of 5-HT 1 and 5-HT2 receptors in the rat vestibular nucleus (13, 14). There are evidences about the par- ticipation of glutamate and calcitonin gene-related peptide in the vestibular nerve fibres (15). The presence of those receptors and neurotransmitters bring nearer again migraine and MARV. There is some controversy about the peripheral or central ori-

Waking through the diagnostic criteria.

Tables 2, 3 and 4 show the proposed diagnosis criteria divided by definitive, probable and possible.

Conclusions

MARV is an entity that has its own clinical pattern, pathophysio- logy and treatment. Differential diagnosis should be make with benign positional vertigo, Meniere disease and basilar type mi- graine. Specific diagnosis criteria could help in its recognition and management.

References

1) Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders, 2nd ed. Cephalalgia 2004; 24 Suppl 1: 1-160. 2) Kayan A, Hood JD. Neuro-otological manifestations of migra- ine. Brain 1984; 107: 1123–1142. 3) Cortazar J. Cefalea. En: Cortazar J. Cuentos completos. Ma- drid: Alfaguara. 1994; 134-143. 4) Porta-Etessam J, Martinez-Salio A, Berbel-García A, Ramos A, Millán J, Garcia-Ramos R, Gonzalez-Martinez V. Evaluation of neuro-otology patients in a general neurology office. Journal of Neurology 2003; 250 (SII): 105-106. 5) Halmagyi GM, Baloh. Overview of common syndromes of vestibular disease. En: Baloh RW, Halmagyi GM (Eds) Disorders of the Vestibular System. Oxford 1996; 291-299. 6) Porta-Etessam J, Martinez-Salio A, Villarejo A et al. Vértigo po- sicional paroxístico: Un síndrome para detectar, diagnosticar y solucionar. Neurología 2004; 19: 495-496. 7) Olsson JE. Neurotologic findings in basilar migraine. Laryn- goscope 1991; 101 (S52): 1–41. 8) Uneri A. Migraine and benign paroxysmal positional vertigo:

an outcome study of 476 patients. Ear Nose Throat J. 2004; 83:

814-815.

9) Crevits L, Bosman T, Paemeleire K. Migraine related vertigo:

The challenge of the basic science. Clinical Neurology and Neu- rosurgery 2005; 108 :111-112.

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10) Berthoz A How does the cerebral cortex process and utilize vestibular signals?. En: Baloh RW, Halmagyi GM (Eds) Disorders of the Vestibular System. Oxford 1996; 113-125. Neurology. 2000; 55 :1906-1908 11) Harker LA. Migraine-associated Vertigo. En: Baloh RW, Hal- magyi GM (Eds) Disorders of the Vestibular System. Oxford 1996; 407-417. 12) Kluge M, Beyenburg S, Fernandez G, Elger CE. Epileptic ver- tigo: evidence for vestibular representation in human frontal cortex. Neurology. 2000; 55: 1906-1908 13) Licata F, Li Volsi G, Maugeri G, Santagelo F. Excitatory and inhibitory effects of 5-hydroxytryptamine on the firing rate of medial vestibular nucleus in the rat. Neurosci Lett 1993; 154:

195-198.

14) Fonseca MI, Ni YG, Dunning DD, Miledi R. Distribution of se- rotonin 2A, 2C and 3 receptor mRNA in spinal cord and medulla oblongata. Brain Res Mol Brain Res. 2001; 89: 11-19. 15) Wackym PA, Popper P, Micevych PE. Distribution of calcito- nin gene-related peptide mRNA and immunoreactivity in the rat central and peripheral vestibular system. Acta Otolaryngol 1993; 113: 601-608.

16) de Bock GH, Eelhart J, van Marwijk HW, Tromp TP, Springer MP. A postmarketing study of flunarizine in migraine and verti- go. Pharm World Sci. 1997; 19: 269-274. 17) Verspeelt J, De Locht P, Amery WK. Postmarketing study of the use of flunarizine in vestibular vertigo and in migraine. Eur J Clin Pharmacol. 1996; 51: 15-22 18) Porta-Etessam J, Latorre G, Escribano A, López-de-Silanes C, García-Ramos R, Fernández MJ. Neurology 2008:70, S1P05.036 19) Bisdorff AR. Treatment of migraine related vertigo with la- motrigine an observational study. Bull Soc Sci Med Grand Du- che Luxemb. 2004; 2: 103-108. 20) Porta-Etessam J. Migraña y vertigo. In: Pascual J (Ed). Lectu- res in cefalea. Current Medicine Group. London 2006: 26-31. 21) De Simone R, Marano E, Di Stasio E, Bonuso S, Fiorillo C, Bonavita V. Acetazolamide efficacy and tolerability in migraine with aura: a pilot study. Headache. 2005; 45: 385-856. 22) Neuhauser H, Radtke A, von Brevern M, Lempert T. Zolmi- triptan for treatment of migrainous vertigo: a pilot randomized placebo-controlled trial. Neurology. 2003; 60: 882-883. 23) Porta-Etessam J. Vértigo asociado a la migraña. Rev Neurol 2007: 44; 490-493.

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Epileptic seizures in neurodegenerative dementia syndromes

AJ Larner

Consultant Neurologist. Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Liverpool, United Kingdom Correspondence: AJ Larner, Cognitive Function Clinic, Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, UK Tel: (44) 151 529 5727 FAX: (44) 151 529 8552 e-mail: a.larner@thewaltoncentre.nhs.uk

Summary Epileptic seizures may be a feature of some neurodegenerative dementia syndromes. There is an increased incidence of seizures in Alzheimer’s disease compared to age-matched controls. Seizures also occur in prion disorders and some frontotemporal lobar degenera- tion syndromes, whereas parkinsonian dementia disorders seem relatively seizure free. Seizure pathogenesis in these conditions is uncer- tain, but may relate to neocortical and hippocampal hyperexcitability and synchronised activity, possibly as a consequence of dysfunctio- nal protein metabolism, neuronal structural changes, and concurrent cerebrovascular disease. Alzheimer’s disease may be a neuronal network disorder, characterised by both cognitive decline and epileptic activity, in which seizures are an integral part of disease phenotype rather than epiphenomena. Treatment of seizures in dementia syndromes currently remains empirical. Greater understanding of demen- tia pathogenesis may shed light on mechanisms of epileptogenesis and facilitate more rational approaches to seizure treatment.

Introduction

In its canonical definition, the dementia syndrome is charac- terised as an acquired impairment of cognitive functions, par- ticularly memory, sufficient to interfere with social and occu- pational functioning (American Psychiatric Association, 2000). In addition to cognitive and functional decline, dementia syn- dromes may also feature other clinical phenomena, including behavioural and psychiatric symptoms, sleep-related disorders, and epileptic seizures.

The differential diagnosis of dementia is broad (Mendez & Cummings, 2003; Larner, 2008), although in clinical practice Alzheimer’s disease (AD) is the most common identified cause. Likewise, the differential diagnosis of cognitive deficits associa- ted with epileptic seizures encompasses various possibilities. Many patients with epilepsy complain of memory problems, which may be multifactorial in origin (Zeman, 2009). They may relate to the underlying brain pathology which causes seizu- res, perhaps leading to impaired memory consolidation (Blake et al., 2000); or to seizures per se, since these may sometimes be sufficient to simulate neurodegenerative disorders such as AD (Høgh et al., 2002); or to the adverse effects of anti-epileptic drugs (Loring et al., 2007); or to concurrent affective disorders; or to any combination of these factors. A population-based in- cidence study of epilepsy in adults found 18% to be demented (Forsgren et al., 1996).

In addition to these situations, neurodegenerative dementia syndromes may be attended by the occurrence of epileptic seizures. However, with the exception of AD (McKhann et al., 1984), widely accepted clinical diagnostic criteria for the com- mon dementia subtypes do not mention epileptic seizures, even as an exclusion criterion (Román et al., 1993; McKeith et

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al., 1996, 1999; Neary et al., 1998; World Health Organisation, 1998; McKhann et al., 2001; Emre et al., 2007). This article brie- fly reviews seizure phenomena which have been reported in association with the common neurodegenerative dementia syndromes, specifically AD, frontotemporal lobar degeneration syndromes, Parkinson’s disease dementia and dementia with Lewy bodies, prion diseases, and Huntington’s disease. Becau- se of the pathological overlap between neurodegenerative di- sease and cerebrovascular changes, especially in AD, seizures in vascular dementia are also considered. Some brief comments on the management of seizures in neurodegenerative demen- tias are appended.

Seizures in Alzheimer’s disease

Epileptic seizures in AD have recently been extensively re- viewed (Palop & Mucke, 2009; Larner, 2010). Epidemiological studies have shown that AD is a risk factor for development of late-onset unprovoked seizures, seizure onset occurring on average more than six years into the course of disease, with 10- 22% of patients having at least one unprovoked seizure during the course of their illness (Mendez & Lim, 2003). A prospective cohort study of mild AD patients found the cumulative inciden- ce of unprovoked seizures to be 8% after 7 years of follow up (Amatniek et al., 2006).

Defining seizure type in AD may be difficult. Generalised seizu- res seem to predominate, presumably secondarily generalised from a partial seizure focus (Mendez & Lim, 2003). Complex partial seizures may also occur, although they may be under- recognised in the context of a progressive dementia (Rao et al.,

2009).

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The widely-accepted NINCDS-ADRDA clinical diagnostic crite- ria for AD state that seizures in advanced disease are consistent with a diagnosis of probable AD, but seizures at disease onset or early in the disease course make the diagnosis of AD uncer- tain or unlikely (McKhann et al., 1984). However, seizure onset may be concurrent with onset of cognitive decline in some AD patients (6%), with no explanation for seizures other than AD identified in about half of these patients (Lozsadi & Larner, 2006). Hence, as a rule of thumb, it is probably advisable to in- vestigate seizures in AD patients in the early stages of cognitive decline to exclude alternative symptomatic causes.

AD may be arbitrarily divided into early- and late-onset disea- se with a threshold of 65 years of age (McKhann et al., 1984), although there is scant evidence to suggest any biological di- fference in these entities. The relative risk of seizures is mar- kedly increased in patients with early-onset AD (Mendez et al., 1994; Amatniek et al., 2006). This may be related, at least in part, to the higher prevalence of deterministic genetic muta- tions in early-onset AD. Seizures have been recorded as part of the phenotype in a number of pedigrees harbouring mutations in the presenilin-1 gene on chromosome 14, the commonest deterministic genetic cause of AD (Larner & Doran, 2009a), and with amyloid precursor protein (APP) gene duplications on chromosome 21 (Cabrejo et al., 2006). Down’s syndrome (tri- somy 21) patients invariably develop AD-type pathology, and late-onset of seizures may correlate with the clinical onset of cognitive decline (Puri et al., 2001).

A number of factors may contribute to the pathogenesis of sei- zures in AD (Palop & Mucke, 2009; Larner 2010). The amyloid hypothesis of AD pathogenesis suggests that altered meta- bolism of APP to produce amyloidogenic amyloid _-peptides (A_) is the ultimate cause of AD. Excessive brain levels of A_ in transgenic mice may result in spontaneous non-convulsive seizure activity in cortical and hippocampal networks, even in the absence of frank neurodegeneration (Palop et al., 2007). Hence it is posited that seizure activity may be an integral com- ponent of the disrupted neuronal networks of the AD brain and may contribute to cognitive decline, rather than being simply an epiphenomenon. Structural alterations in neurones related to tau pathology, the other hallmark change observed in AD brain, including loss of synaptic contacts and aberrant neuro- nal sprouting, may facilitate development of recurrent hypers- ynchronous discharges underpinning seizure activity. Tau defi- cient transgenic mice do not develop aberrant network activity despite excessive A_ (Roberson et al., 2007). Changes in neu- rotransmitter activities and concurrent cerebrovascular disease might also contribute to seizures in AD.

Seizures in frontotemporal lobar degeneration syndromes The frontotemporal lobar degenerations (FTLDs) encompass a heterogeneous group of disorders with respect to both clinical phenotype and neuropathology (Neary et al., 1998; McKhann et al., 2001; Cairns et al., 2007; Mackenzie et al., 2009). Broadly they may be divided clinically into behavioural (behavioural va- riant frontotemporal dementia) and linguistic syndromes, the latter characterised by either non-fluent output with relatively preserved comprehension (progressive non-fluent aphasia) or

fluent output with impaired comprehension (semantic demen- tia). Clinical or subclinical evidence of motor neurone disease may be found in some FTLD cases. Movement disorders asso- ciated with cognitive impairment such as progressive supranu- clear palsy (PSP) and corticobasal degeneration (CBD) may also be included under the FTLD rubric (Kertesz & Munoz, 1998). In terms of neuropathology, FTLDs may be categorized according to the protein abnormality presumed to be pathogenic, such as tau, TDP-43, ubiquitin proteasome system, or intermediate filaments (Mackenzie et al., 2009).

Epileptic seizures do not feature in the diagnostic criteria for FTLDs, either as inclusion or exclusion criteria (Neary et al., 1998). However, a normal conventional EEG despite clinically evident dementia is one of the investigational consensus diagnostic cri- teria (Neary et al., 1998), in contradistinction to AD in which EEG changes, particularly slowing of background rhythms, are com- mon (Stam, 2006), particularly in the later stages of the disea- se. Although the view that the EEG is normal in FTLDs has been challenged (Chan et al., 2004), nonetheless it remains the case that epileptic seizures are rarely reported in FTLDs. An excep- tion may be FTLD with concurrent hippocampal sclerosis (HS). Initially defined by neuropathological appearances of neuronal loss in the hippocampal CA1 region in a distribution similar to that seen in seizure-associated mesial temporal sclerosis (Corey- Bloom et al., 1997), “pure” HS was later reclassified as a subtype of FTLD based on the neuropathological finding of tau-negative ubiquitin-positive inclusions (Hatanpaa et al., 2004) and the overlap of clinical and neuropsychological features with FTLD (Blass et al., 2004). These cases are probably TDP-43 proteinopa- thies (Cairns et al., 2007). They were previously reported to have a similar prevalence of seizures to AD (Leverenz et al., 2002).

Frontotemporal dementia with parkinsonism linked to chro- mosome 17 (FTDP-17) may result from mutations in genes en- coding either the microtubule associated protein tau (MAPT) or progranulin. FTDP-17 resulting from the P301S MAPT gene mutation has been reported with a phenotype including pro- minent early seizures (Sperfeld et al., 1999), but this seems to be an exceptional occurrence in FTDP-17 with tau gene mutations (Larner & Doran, 2009b).

Seizures in Dementia with Lewy bodies, Parkinson’s disease dementia, and other parkin- sonian syndromes

Possibly the second most common form of neurodegenerative dementia, dementia with Lewy bodies (DLB) is not reported to be associated with epileptic seizures, nor is the dementia asso- ciated with Parkinson’s disease which has similar neuropsycho- logical and neuropathological features, both being classified as synucleinopathies. This is perhaps a little surprising since concurrent tau pathology of Alzheimer type is not infrequent in these cases. Although transient loss of consciousness is one of the supportive features in the diagnostic criteria for DLB (Mc- Keith et al., 1996) these are not epileptic seizures, but are more likely to be related to the autonomic dysfunction which is com- mon in this condition (Horimoto et al., 2003).

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In other neurodegenerative parkinsonian syndromes, seizures have been reported in PSP (Nygaard et al., 1989) but do not seem to be a common feature. There seems to be no litera- ture on epileptic seizures in CBD or multiple system atrophy. Although there are clearly areas of overlap between the fields of epilepsy and movement disorders (Guerrini et al., 2002), this does not seem to be relevant in these late-onset movement di- sorders.

Seizures in prion diseases

Prion diseases may be of sporadic, inherited or iatrogenic aetio- logy. Seizures have been reported in sporadic Creutzfeldt-Jakob disease (Cokgor et al., 1999), sometimes as the presenting fea- ture, with focal motor seizures (Aronyk et al., 1984; Yamanouchi et al., 1986), nonconvulsive status epilepticus (Rees et al., 1999; Cohen et al., 2004; Fernandez-Torre et al., 2004; Vaz et al., 2005), and generalised status epilepticus (Neufeld et al., 2003; Kara- tas et al., 2007) all reported. Localization-related seizures have been reported as the first presentation of variant CJD (Silverda- le et al., 2000) but this would seem to be a rare or even excep- tional event (Spencer et al., 2002).

Since loss of the cellular prion protein has been reported to be associated with enhanced sensitivity to seizures, with neocor- tical and hippocampal hyperexcitability and synchronised ac- tivity (Walz et al., 2002), it is possible that prion disorders may resemble AD as neuronal network disorders clinically characte- rised by both cognitive decline and epileptic activity.

tients with dementia submitted to autopsy have a combination of both AD and cerebrovascular pathology (MRC CFAS, 2001). Vascular dementia and vascular cognitive impairment are re- cognised to be heterogeneous entities with respect to both pathology and pathogenesis (Wahlund et al., 2009), including vasculopathic and thrombotic disorders.

Patients with stroke who have epileptic seizures may be at in- creased risk of dementia. In a cohort of stroke patients without pre-existing dementia, the occurrence of epileptic seizures was an independent predictor of new-onset dementia within 3 years of stroke (Cordonnier et al., 2007). It is possible that some of these patients harboured AD pathology pre-stroke, with clinical expression emerging after the stroke. Certainly an interaction between AD and CVD to lower clinical threshold for expression of AD pathology is recognised (Snowdon et al., 1997). Pre-existing dementia typical of AD has been reported to increase the risk of late (>7 days) post-stroke seizures (Cor- donnier et al., 2005).

Because of the common neuropathological overlap of CVD and AD, it may be difficult to ascertain the specific contribution of CVD to seizure pathogenesis in mixed cases. In order to stu- dy the effects of CVD per se, relatively pure vascular dementias should be studied. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) resulting from mutations in the Notch3 gene may be associated with seizures as part of encephalopathic episodes (Schon et al.,

2003).

Seizures in Huntington’s disease

Chorea and a subcortical dementia are the classic features of Huntington’s disease (HD) associated with trinucleotide repeat expansions in the IT15 gene on chromosome 4. Epileptic seizu- res may be a feature of HD, particularly in early-onset disease which is more often associated with the finding of parkinsonian rigidity. Seizure frequencies of 30-40% are cited for juvenile HD, defined as onset before age 21 years, as compared to 1-2% in adult-onset cases (Barker & Squitieri, 2009).

Prominent seizures in an adult patient with a HD-like pheno- type should prompt consideration of the diagnosis of denta- torubral-pallidoluysian atrophy, in which condition seizures are much more common than in HD (Egawa et al., 2008).

Seizures in vascular dementias and vascular cog- nitive impairment

Although it might be objected that cerebrovascular disease (CVD) is not a cause of neurodegeneration per se, nonetheless CVD is a recognised risk factor for late-onset epileptic seizu- res, presumably resulting, at least in part, from disruption of neuronal interconnections. Moreover, there is clearly overlap between CVD and other causes of dementia: most elderly pa-

Management of seizures in dementia syndromes

There is essentially no evidence base upon which to formulate judgements about seizure management in neurodegenerative dementias. Hence management remains empirical, based on seizure type and risk:benefit analysis for each individual pa- tient.

In AD, the neurodegenerative dementia most likely to be com- plicated with epileptic seizures, anti-epileptic drug (AED) the- rapy may not necessarily be required since isolated seizures are common (Mendez & Lim, 2003). Moroever, other, treatable, symptomatic causes for seizures may be identified (Lozsadi & Larner, 2006). If AED therapy is indicated, because seizures are frequent or risk of seizure recurrence is thought to be high (as in the presence of fixed or post-ictal focal neurological signs, abnormal EEG, or early age of AD onset), drug choice may be influenced by seizure semiology. However, seizure type in de- mented individuals is often uncertain, although partial onset seizures with or without secondary generalisation are probably the most common (Mendez & Lim, 2003). Since AD prevalen- ce increases with age, factors influencing drug clearance and protein binding such as renal and hepatic function also need to be considered, as does polypharmacy and the risk of drug in- teractions. Use of AEDs with known cognitive and behavioural adverse effects (e.g. phenobarbitone, primidone, phenytoin, topiramate) may be considered undesirable in dementia syn- dromes.

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The response to AED therapy in dementia is not well known.

A 79% response rate was reported in a retrospective study of

dementia patients with epilepsy although one third of patients had dose-related side effects (Rao et al., 2009). A prospective observational study of levetiracetam in 25 patients with advan- ced AD and new onset seizures reported good seizure control,

with 72% of patients seizure free for at least one year, but 16%

of

patients discontinued medication because of poor tolerabili-

ty

(Belcastro et al., 2007).

Discussion

Although the clinical observation of seizures in dementia syn- dromes, particularly AD, is long established, there have been few systematic studies of seizures in these conditions. Mecha- nisms underlying seizure pathogenesis are unresolved, but re-

cent studies raise the possibility, particularly in AD and possibly

in prion disease, that seizures are related to the same pathoge-

netic processes responsible for cognitive decline, and hence are an integral part of disease phenotype, rather than being simply epiphenomena consequent upon non-specific neuronal loss. Treatment of seizures in dementia syndromes remains entirely empirical. However, future classification of dementia disorders according to pathogenesis (e.g. amyloidopathy, tauopathy, synucleinopathy, TDP-43 proteinopathy, prionopathy) may fa- cilitate understanding of seizure pathogenesis and ultimately

guide treatment decisions. Since epileptic seizures may be regarded as part of the AD phenotype, randomised controlled trials of AEDs which might address both symptomatic seizure control and modify pathogenic pathways, such as sodium val- proate (Qing et al., 2008) and lacosamide (Larner, 2009), might be considered.

Declaration: No funding was received for the preparation of this article. The author has no conflict of interest to declare.

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99m Tc-MIBI muscle imaging and approach to assess functional anatomy of lower limb muscles

José A. Arias a,b , Susana García c , María L. Cuadrado d , Carlos Pardo c , Gregoria Lapeña c , José L. Carreras e

a Nuclear Medicine Department, Hospital Ramón y Cajal, Madrid, Spain. b School of Medicine, Universidad Alfonso X el Sabio, Villanueva de la Cañada, Madrid, Spain. c Nuclear Medicine Department, Fundación Jiménez Díaz, Madrid, Spain. d Neurology Department, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain. e Nuclear Medicine Department, Hospital Clínico San Carlos, Universidad Complutense, Madrid, Spain. Institution where the study was performed:

Fundación Jiménez Díaz, Madrid, Spain.

Correspondence to:

Jose A. Arias, School of Medicine, Universidad Alfonso X el Sabio, Avda de la Universidad, 1 28691 Villanueva de la Cañada (Madrid) Spain

E-mail: josari@uax.es

Tel.: +34 9181099975 Fax: +34 918105289

ABSTRACT: 99m Tc hexakis-2-methoxyisobutyl-isonitrile ( 99m Tc-MIBI) has been seldom used as a skeletal muscle tracer, and exercise changes of radionuclide uptake in different muscle groups have not been explored. The image pattern of 99m Tc-MIBI uptake in the lower extremities was studied in 15 subjects (14 men, one woman; mean age: 59.9 ± 12.6 years) with no evidence of muscle or peripheral vascular disease, both at rest and during treadmill exercise. Several muscles could be identified in the scanned regions. No association was found between the intensity of uptake and some cardiovascular and metabolic parameters, but as a whole exercise increased radionuclide uptake in the calves. 99m Tc-MIBI scintigraphic imaging might be a useful technique to assess the functional anatomy of lower limb muscles.

Introduction

99m Tc hexakis-2-methoxyisobutyl isonitrile ( 99m Tc-MIBI) is a ra- diopharmaceutical which has been widely used for in vivo ima- ging of myocardial perfusion [1,2] and, less frequently, for eva- luation of tumor processes[3,4]. 99m Tc-MIBI is a lipophilic cation that behaves like Na+ and uses the Na+/H+ antiport system to enter the heart cell [5]. It eventually goes through the outer and inner membranes of mitochondria, and accumulates into the mitochondrial matrix [6] by a mechanism that largely depends on the transmembrane potential [7]. As might be expected, this radiotracer settles not only in the myocardium, but also in ske- letal muscles.

A few studies have investigated the potential role of skeletal

muscle imaging with 99m Tc-MIBI in the assessment of periphe- ral vascular disease [8-13], compartment syndrome [14], uremic [15] and statin induced [16] myopathies, systemic sclerosis [17], Duchenne muscular dystrophy [18], and the paralytic phase of thyrotoxic periodic paralysis [19]. Muscular response to propion-

yl-L-carnitine [20] and neuromuscular electrical stimulation [21] has also been explored with this imaging technique. However, no one of these studies has focused on the muscular response

to exercise and the feasibility to depict muscular anatomy. Besi-

des, technical limitations of former devices -i.e. insufficient spa- tial resolution- might have restricted the use of 99m Tc-MIBI as a skeletal muscle tracer. In the present study, we test: 1) whether muscular morphological data can be obtained from 99m Tc-MIBI scintigraphic images, and 2) the association between 99m c-MIBI muscular uptake and some physiological parameters obtained during exercise.

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Materials and methods

Subjects

Fifteen patients (14 men, one woman; mean age: 59.9 ± 12.6 years, range: 26 to 77 years) were included. They had been sent to the nuclear medicine department for myocardial single pho- ton emission computed tomographic (SPECT) study with 99m Tc- MIBI in order to discard ischemic heart disease. None of the subjects had any complaints referred to the lower extremities. Specifically, they did not show any clinical evidence of either peripheral vascular disease or muscle disease. Those patients who had any systemic disease that could affect muscular meta- bolism, such as diabetes mellitus, were excluded. Subclinical or masked effects of cardiovascular disease in the lower extremi- ties could not be ruled out, but they would have not changed the validity of our study as for the established purposes.

The study protocol was approved by the local ethical committee, and written informed consent was given by all the patients. Radiopharmaceutical and imaging protocol.

Each patient underwent a two days protocol for scintigraphic study of ischemic heart disease. The details can be found el- sewhere [22]. Briefly, conventional rest and post stress (tread- mill exercise) SPECT studies were acquired after an intravenous administration of 740-925 MBq of 99m Tc-MIBI (Cardiolite®, Bris- tol-Myers Pharma, Brussels, Belgium) prepared according to the manufacturer’s instructions. Ten minutes after conventional myocardial tomographic studies, planar images were obtained from the lower extremities with a dual head whole-body ga- mma camera (DST-Xli, Sopha Medical Vision International, Buc, France) equipped with a low-energy high-resolution collimator. Anterior and posterior images of thighs and calves were ob- tained for 5 minutes in 256 x 256 pixel matrices, with the pixel

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width being 2.1 mm. Close to the surface of the patient, theore- tical intrinsic spatial resolution (RI) was 3.5 mm and collimator spatial resolution (RC) was 2.5 mm. Overall system resolution (RS) is given by the formula [23]

R S

and it equals 4.3 mm.

=

2 2 R + R C I
2
2
R
+
R
C
I

Image analysis and interpretation Visual evaluation was performed comparing scintigraphic ima- ges with corresponding pictures on a standard atlas of human anatomy [24], and muscles were depicted according to them. Images were evaluated by both a neurologist (MLC) and a spe- cialist in nuclear medicine (JAA), and a consensus on anatomi- cal correspondence was reached. To assess muscular activity, rectangular regions of interest that comprised the whole thigh over the anterior view and the whole calf over the posterior view were drawn on each side. Mean counts per pixel within the selected regions were calculated. Since no significant differen- ce was found between right and left activities, data for further analysis were derived from the average of right and left values. Knee areas without muscular tissue were taken as control, and results were expressed semiquantitatively as the percentage of uptake with respect to the uptake in the knees.

of uptake with respect to the uptake in the knees. Figure 1 . 99mTc-MIBI muscle scintigraphy

Figure 1. 99mTc-MIBI muscle scintigraphy obtained from a 55 year-old man after treadmill exercise. (A) Anterior view of the thighs: Pt+Ad, pectineus and adductors (superimposed); Sr, sartorius; Qf, quadriceps femoris. (B) Posterior view of the thighs: Gm, glutaeus maximus; Am+St, adductor magnus and semitendinosus (superimposed); Sm, semimembranosus; Bf, biceps femoris; Vl, vastus lateralis of quadriceps femoris.

Other clinical measurements Body weight and height of all the patients were registered at the time of assessment. In addition, maximum systolic blood pressure, maximum heart rate, and oxygen comsumption as the metabolic equivalent of the task (MET) were measured du- ring exercise.

Statistical analysis For each region of interest, values of uptake at rest and exercise were compared making use of the one-tailed paired Student’s t-test. Correlation between variables was analyzed by means of the Pearson coefficient.

Results

Though superimposed muscles contributed to planar images, the following individual muscles and/or muscular groups could be identified in all the patients: 1) in the thighs (Fig. 1), adduc- tors, sartorius, quadriceps femoris, glutaeus maximus, semiten- dinosus, semimembranosus, and biceps femoris, and 2) in the calves (Fig. 2), tibialis anterior, and triceps surae, with the two heads of gastrocnemius and the belly of soleus being recogni- zable.

From a qualitative point of view, the muscles were more visibly depicted after exercise, specially in the calves. From a quanti- tative point of view, muscle exercise significantly increased 99m Tc-sestamibi uptake with respect to rest uptake in the calves (210.3 % vs. 185.2 %, p<0.01), but not in the thighs (265.8 % vs. 267.8 %, n.s.). Otherwise, no correlation was found between the intensity of uptake and any of the clinical measurements that were taken during exercise testing. Discussion

99m Tc-MIBI is generally used to evaluate myocardial perfusion or tumor activity, but it has also proved to be an adequate tracer for skeletal muscle. Some technical limitations might have restricted the use of 99m Tc-MIBI muscle scintigraphy with former devices, but current equipment has allowed us to get rather sharp images of skeletal muscles. Moreover, 99m Tc-MIBI muscle imaging could be further improved by increasing the time of acquisition of pla- nar images or by getting tomographic images with SPECT.

We have made use of 99m Tc-MIBI muscle scintigraphy in a group of patients who were free of muscle disease. In this setting, 99m Tc-MIBI has provided us with anatomical information, as ma- jor muscle groups and even some individual muscles could be located on scintigraphic images. In addition, it has given some functional information, as there was a qualitative and quantita- tive change of 99m Tc-MIBI uptake during exercise. The muscles that showed a significant increase of uptake were those most implicated in walking and running, i.e. the muscles of the calves [25]. Presumably the effects of muscle activity on 99m Tc-MIBI up- take would have been different with another type of exercise. On the other hand, even with running the analysis of smaller regions of interest restricted to individual muscles might have shown an increase of uptake in additional locations.

To date, muscle imaging with 99m Tc-MIBI has focused mainly on the vascular properties of this tracer [8-13], but only marginal attention has been paid to the possibility of tracing muscular disorders [17-19]. Furthermore, the effect of muscle activity on 99m Tc-MIBI scintigraphy has not been thoroughly investigated for clinical purposes. Due to the pharmacokinetical properties of 99m Tc-MIBI, this technique might be particularly suitable for the assessment of mitochondrial diseases. In fact, a cardiac decrease of 99m Tc-MIBI-uptake has already been demonstrated when the heart is involved in some mitochondrial gene ab- normalities [26-28]. It would be worth exploring any potential applications of rest and exercise 99m Tc-MIBI imaging in the eva- luation of different myopathies.

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AND NEUROSCIENCE 2010 Vol.1 No. 1:2 doi: 10:3823/301 Figure 2 . 99m Tc-MIBI muscle scintigraphy obtained

Figure 2. 99m Tc-MIBI muscle scintigraphy obtained from a 55 year-old man after treadmill exercise. (A) Anterior view of the thighs: Ta, tibialis anterior; Cm, caput mediale of gastrocne- mius. (B) Posterior view of the calves: Gt, gastrocnemius (caput mediale and caput laterale); Sl, soleus.

99m Tc-MIBI scintigraphic imaging might be a useful technique to assess the functional anatomy of skeletal muscles in both health and disease conditions. Undoubtedly, this technique cannot compete with positron emission tomography (PET) as the gold standard in metabolic imaging [29-33]. However, it offers some advantages over PET: 1) the procedure is more sim- ple; 2) it has much lower cost, and 3) it provides different meta- bolic information, since 99m Tc-MIBI is a mitochondrial tracer and does not follow the route of 18F-fluoro-deoxy-glucose, i.e. the usual tracer in PET.

Conclusion

99m Tc-MIBI scintigraphic imaging is a simple procedure that pro- vides both anatomical and functional information about ske- letal muscles. Further research is needed to ascertain any po-

99m Tc-MIBI for tracing muscular

tential clinical applications of disorders.

Abbreviations

MBq: megabecquerel PET: positron emission tomography SPECT: single photon emission computed tomography 99m Tc-MIBI: 99m Tc hexakis-2-methoxyisobutyl isonitrile RI: intrinsic spatial resolution RC: collimator spatial resolution RS: overall system resolution

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Postural ocular pain due to orbital varix

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Casanova-Peño I, Gómez-Vicente L, Cuadrado ML, Porta-Etessam J Neurology Department. Hospital Clínico San Carlos. Madrid. Spain.

Correspondence to: Jesús Porta-Etessam C/ Andrés Torrejón, 15, 7º 28014 Madrid e-mail: jporta@yahoo.com Phone: +34 667 062 490 e-mail: a.larner@thewaltoncentre.nhs.uk

Abstract:

Primary orbital varices are infrequent congenital vascular abnormalities resulting from the pathological enlargement of one or more ve- nous channels of the orbit. We report a patient suffering ocular pain that appeared when the patient was bending over or lying. A 68 years-old woman consulted in our office because of an ocular pain that appeared when the patient was bending over or lying. There was no proptosis and neuro-ophthalmological examination including pupils’ reflexes, ocular mobility and visual acuity was normal. The patient was evaluated by computed tomography examination which revealed a faintly, enhancing lesion in the left inferomedial retrobul- bar area.

The clinical presentation of primary orbital varices typical presents with exophthalmos that becomes evanescent in dependent positions and in certain situations that increase intraorbital pressure. However, in patients suffering from bending over and lying ocular pain we must suspect orbital varices even without positional exophthalmos

Key words:

Orbital varix, postural headache, ocular pain, bending over, intracranial hypotension.

Introduction

Primary orbital varices are infrequent congenital vascular ab- normalities resulting from the pathological enlargement of one or more venous channels of the orbit (1, 2). The clinical syndro- me is usually characterized by intermittent filling and emptying of the varix, resulting in variable proptosis. In infants, eye bul- ging during crying or orbital ecchymoses should raise this diag- nostic possibility (3). We report a patient suffering ocular pain that appeared when the patient was bending over or lying.

Case reports

A 68 year-old woman consulted in our office because of a 3-mon- th history of ocular pain with a characteristic postural pattern. It appeared when lying flat or bending over, and was relieved by standing. The patient denied any autonomic feature, or the as- sociation with dizziness, vertigo, visual or auditory disturbances. There was no proptosis and physical, neurological and neuro- ophthalmological examination including pupils’ reflexes, ocular movility and visual acuity was normal. There was not fatigability or ocular bruit. The patient was evaluated by orbital computed tomography examination (figure 1a-b) which revealed an en- hancing lesion in the left inferomedial retrobulbar area and an MR angiogram ruled out caroid-cavernous fistulas.

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Discussion:

We present a case of postural headache. Postural headaches are usually related to low pressure organic fluid physic changes. The most common postural headache is intracranial hypoten- sion headache. In these patients the headache usually worsens within 15 minutes after sitting or standing and improves upon lying over (4-5). The traction of pain sensitive intracranial and meningeal structures and bridging veins is thought to cause headache and other related symptoms. Paradoxical postural headaches have also been described with cerebrospinal fluid leaks, with the head pain occurring in horizontal positions and fading when the patient is upright. The pathophysiology of the- se latter headaches could be related to congestion and dilation of cerebral venous sinuses and large veins (6).

We present a postural headache related to an orbital varix. Usually the clinical presentation of primary orbital varices in- cludes exophthalmos that becomes evanescent in dependent positions. Our patient did not have exophthalmos at the time of consultation and the only symptom was a postural pain. The pain could be due to an increase of intravenous and intraorbital pressure when the patient was lying over. However, in patients suffering from bending over and lying ocular pain we must sus- pect orbital varices even without positional exophthalmos.

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References:

1) Weill A, Cognard C, Castaings L, Robert G, Moret J. Emboliza- tion of an orbital varix after surgical exposure. Am J Neuroradiol

1998;19:921-3.

2) Secil M, Soylev M, Ada E, Saatci AO. Computerized Medical Imaging and Graphics 2001; 25: 243-247. 3) Orbital disease in neuro-ophthalmology. In: LiuGT, Volpe NJ, Galetta SL (eds). Neuroophthalmology: diagnosis and manage- ment. Pp 651-697. Philadelphia. WB Saunders Company. 2001. 4) Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders, 2nd edn. Cephalalgia 2004; 24 Suppl 1:1–160. 5) Garcia-Morales I, Porta-Etessam J, Galán L, Lagares A, Molina JA. Recurrent subdural haematomas in a patient with sponta- neous intracranial hypotension. Cephalalgia 2001; 21: 703-705. 6) Mokri B, Aksamit AJ, Atkinson JLD. Paradoxical postural hea- daches in cerebrospinal fluid leaks. Cephalalgia 2004; 24: 883.

Figure 1. Contrast enhanced orbital computed tomography examination, showing an enhancing lesion in the left inferomedial retrobulbar area.

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Pretectal syndrome caused by multiple sclerosis.

Porta-Etessam J (1, 2), García-Ramos R (2), Ruiz-Giménez J (3), Moreno T (3), Ruiz-Morales-J (3)

1) Headache and Neuroophthalmology Unit. 2) Neurology Department. Hospital Universitario Clínico San Carlos. 3) Neurology department. Hospital Universitario “12 de octubre”. Madrid. Spain.

Correspondence: Jesús Porta-Etessam MD C/ Andrés Torrejón, 15, 7º. 28014 Madrid Spain. E-mail: jporta@yahoo.com

Pretectal syndrome refers to a complex clínical elements and symptoms secundary to damage of the pretectum structures. The two most important pretectal areas are the rostral intersti- cial nucleus of the medial longitudinal fasciculus (riRLF) and in- terstitial nucleus of Cajal. This syndrome is highlighted by supra- nuclear vertical upgaze paresis, pupillary, eyelid and converge- gence retraction nystagmus 1,2 . We report a 35-years-old woman who present pretectal syndrome due to a multiple sclerosis.

She complains about diplopia and blurred vision at near. Gen- eral examination was normal and on neurological examination, she showed supranuclear gaze restriction affecting both ver- tical saccades and pursuit, but the saccades deficit was more prominent. When she attempted upwards saccades the eyes jerk inward and the left eye had an abduction deficit which easily overcome by horizontal oculocephalic movements (fig 1-3). There was no pupillary anormalities, lid retraction or con- vergence insufficience.

anormalities, lid retraction or con- vergence insufficience. Figure 1. Right thalamic esotropia and order saccadic

Figure 1. Right thalamic esotropia and order saccadic superior gaze limitation

esotropia and order saccadic superior gaze limitation Figure 2. Slight limitation in superior smooth movement ©

Figure 2. Slight limitation in superior smooth movement

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© Under License of Creative Commons Attribution 3.0 License Figure 3. Normal oculo-vestibular reflexes. A cranial

Figure 3. Normal oculo-vestibular reflexes.

A cranial CT scan revealed no abnormality. An oligoclonal band was detected in CSF. An MRI using General Electric revealed an abnormal high signal intensity lesion on T2-weigted imaginng at the ventral area of the midbrain aqueduct whith gadolinium- enhanced ,another small lesion in the temporal white matter on the left and T2-hyperintense lesion traversing the corpus cal- losum on 1.5-mm thick, T2-weighted imaging.

The most common causes of pretectal syndrome are hydro- cephalus, tumours and cerebrovascular disorders; however multiple sclerosis is really rare 3 Problems associated with the similar terminologies including Parinaud’s syndrome, sylvian aqueductsyndromeordorsalmidbrainsyndromewerediscussed. The eponym is attributed to Henri Parinaud, an ophthalmologist who worked under Charcot at the Salpetriere in Paris in the late 19 th century and wrote two landmarks articles describing vari- ous types of conjugate gaze palsies and paralyses of convergen- ce 4 . Nowadays, the syndrome includes pupillary and eyelid abnormalities, as well as convergence retraction nystagmus, for this reason the term pretectal syndrome are more popular 4,5 . The supranuclear vertical gaze restriction in this syndrome re- sults from involment of the posterior commisure, intersticial nucleus of Cajal or riMLF. Upgaze deficits may be seen alone as in our case, or in combination wit downgaze paresis, lesions affecting posterior commisure usually produce greater invol- ment of upgaze while those located more ventrally are associ- ated with greater downgaze paresis 5 . Fibers mediating the up- ward gaze originate in the rostral interstitial MLF (riMLF) project

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ipsilateraly to ipsilateral oculomotor complex, cross through the posterior commissure, and terminate in the contralateral ocu- lomotor complex . On the other hand, fibbers from interstitial nucleus of Cajal cross within the posterior commisure before reaching the oculomotor complex and the superior rectus and inferior oblique subnuclei. However, for downgaze each riFLM supplies the ipsilateral inferior nucleus and the fourth nucleus. This may be a reason for the dissociation of the upward and downward gaze palsy, and the different topography for upward and downward gaze. And MS should be considering in the dif- ferential diagnosis in a patient with a pretectal syndrome.

Reference List

1. Keane JR. The pretectal syndrome: 206 patients. Neurology 1990;

40(4):684-690.

2. Keane JR, Davis RL. Pretectal syndrome with metastatic malignant

melanoma to the posterior commissure. Am J Ophthalmol 1976;

82(6):910-914.

3. Keane JR. The pretectal syndrome: 206 patients. Neurology 1990;

40(4):684-690.

4. Liu GT VNGSL. Neuro-ophthalmology. Liu GT VNGS, editor. 1est, 584-

626. 2004. Philadelphia, WB Saunders company. Ref Type: Serial (Book,Monograph)

5. Corbett JJ, Schatz NJ, Shults WT, Behrens M, Berry RG. Slowly

alternating skew deviation: description of a pretectal syndrome in three patients. Ann Neurol 1981; 10(6):540-546.

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Blood pressure changes in patients with migraine:

Evidences, controversial views and potential mechanisms of comorbidity

Sherifa Ahmed Hamed (M.D.)

Department of Neurology and Psychiatry, Assiut University Hospital, Assiut, Egypt

Running title:

Blood pressure changes with migraine

Corresponding author: Dr. Sherifa Ahmed Hamed (M.D.) Consultant Neurologist Associate Professor Assiut University Hospital Department of Neurology and Psychiatry, Floor # 4, Room # 4, Assiut, Egypt P.O.Box 71516 Telephone: +2 088 237490 Fax : +2 088 2333327 +2 088 2332278 Email: hamed_sherifa@yahoo.com

Abstract:

Migraine and hypertension are common complaints and both have high prevalence worldwide. The comorbidity of migraine with hyperten- sion is a common issue since 1913. Recent epidemiologic and population-based studies put some doubt regarding the association between migraine and hypertension, no association or even negative association was found by some authors. Authors who supported the positive association suggested that rennin-angiotensin system as a biological link between hypertension and CNS activities that are relevant for migraine pathogenesis. Authors who denied the association suggested a coincidental existence since any association between two preva- lent health conditions is likely to be detected in large series. Authors who supported the negative association suggested a central regulatory and homeostatic process resulting in reduction of sensitivity to pain (a phenomenon called hypertension-associated hypalgesia). Baroreflex stimulation, endogenous opioids, catecholamines and calcitonin peptide may influence blood pressure and pain sensitivity in patients with migraine and lowers the number of migraine attacks in hypertensives. Despite the uncertainty still present in this field, a unifying view among most recent studies suggests that migraine is positively correlated with diastolic blood pressure but negatively correlated with systolic blood pressure and pulse pressure. Similar vascular risk profile and the abnormal properties of systemic as well as cranial arterial vessels exist in subjects with migraine and hypertension. On the other hand poor control of blood pressure may exacerbate the frequency and severity of migraine and other headaches. These evidences may suggest that both conditions may coexist as part of a systemic disease. Thus estab- lishing the blood pressure should be a routine task in the assessment of all headache patients and the control of hypertension in migraine patients is an important factor for the success of migraine treatment and to lower cardio- and cerebro-vascular risks.

Introduction:

Migraine is a common chronic presenting complaint encoun- tered in Neurology and Internal Medicine clinics. A series of po- pulation-based studies based on the new operational Interna- tional Headache Society (IHS) criteria, has found that migraine, although common, has a variable prevalence worldwide. In European and American studies the one-year period prevalence of migraine in adults is estimated at 10-15%, significantly more women are affected than men, in a ratio of 2-3:l (1); in Japan, the reported prevalence is 8.4% (2). In Africa, crude prevalence rate is estimated at 19 %, and specific rates of 26.8 % for women versus 9.4 % for men (3). In Arab countries, the migraine preva- lence was 2.6–5% in Saudi Arabia and 7.9% in Qatar, while the 1-year migraine prevalence was 10.1% in Oman (4). In a study of Egyptian school children in Assiut, the prevalence of migraine

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is 16.6% (female to male ratio: 1.33) (5). Overall, migraine preva- lence varies by age, gender, race, and income. Before puberty, migraine prevalence is approximately 4%. As adolescence ap- proaches, prevalence increases more rapidly in girls than in boys. Migraine is most common in the third decade of life and in lower socioeconomic groups. It increases until approximately age 40, and then declines. Migraine is more frequent in women than men (1,6). Few studies of migraine incidence have been performed. A population-based study conducted by Rasmussen (6) showed that the annual incidence of migraine is 3.7 per 1,000 person years (women 5.8; men 1.6).

Hypertension and migraine are very prevalent disorders in gen- eral population and many old and recent studies suggested a relevant comorbidity between headache, migraine and arterial hypertension (7-11). However, in some recent studies and text-

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books, the relationship between migraine and hypertension is poorly characterized. Epidemiologic and population-based studies found no (12,13) or even negative (14) correlation be- tween the two diseases.

In general, the relation between two disease states may be due to (15) 1) an artifact of diagnostic uncertainty when symptom profiles overlap or when diagnosis is not based on objective markers, 2) chance association or coincidental, 3) unidirectional causality, such as migraine resulting in blood pressure changes due to headache-specific treatment, 4) bidirectional causal as- sociation i.e. one disorder causes the other, 5) a shared environ- mental or genetic risk for the two disease states that increase the risk of both conditions. In such cases, understanding these shared risk factors may lead to greater understanding of the fundamental mechanisms of migraine, or 6) both conditions are manifestations of one systemic disease. However, the term comorbidity is used to refer to the greater than coincidental as- sociation of two conditions in the same individual (16).

The present article serves as an overview of the blood pre- ssure changes encountered in patients with migraine. Studies in migraine literatures present in pubmed which highlighted migraine and blood pressure, migraine and hypertension, head- ache and blood pressure (publications till 2010) were checked. The reference lists of retrieved studies for additional reports of relevant studies were also checked. In this review, the eviden- ces of comorbidity between migraine and high, low or normal blood pressure and the potential mechanisms of controversial views were discussed. It will be clear that despite the uncertain- ties regarding the presence of interictal blood pressure changes in patients with migraine, whether one condition leads to the other or both conditions are expression of similar systemic ill- ness, both hypertension and migraine have to be carefully treated to avoid the development of cardio- and cerebrovascu- lar complications.

Evidences of blood pressure changes in migraine:

A) Evidences that hypertension is positively associated with migraine:

Since several decades, the comorbidity of migraine with hyper- tension is a widely accepted issue despite the absence of confir- mation by well-designed studies. In general, headache, particu- larly early-morning pulsating headache, is usually considered a symptom of hypertension and poor control of blood pressure may exacerbate the frequency and severity of migraine (17).

In 1913, Janeway (18) noted that migraine was common in sub- jects with arterial hypertension and since then the relation

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between blood pressure and headache has been examined in many studies (8-11,19-26). A higher prevalence of headache (27-30) and migraine (31,32) has been reported in hypertensive patients than among normo-tensive controls. On the other hand, a higher prevalence of hypertension has been reported in patients with headache (24,33-35); or migraine (36-38); than among headache free people.

Grebe et al. (39) retrospectively analyzed 64 files of headache outpatient clinic (Coimbra, Portugal), chosen randomly among patients suffering from migraine or tension headache. The au- thors found that the prevalence of hypertension was 35,9% among all patients (migrainous and non-migrainous head- ache), 28,5% among migraine patients and 44,8% among pa- tients with tension headache. The prevalence of resistance to treatment was 39,8%, 34,3% and 41,3%, respectively. Of the pa- tients resistant to treatment 60% were hypertensive and 62,5% of the hypertensive patients showed resistance to therapy. In the study of Prudenzano et al. (40), the authors found higher prevalence of hypertension in patients with tension headache. In 2005, Pietrini et al. (17) examined a total of 1486 consecutive outpatients with headache recruited from the department of Internal Medicine, Italy. In all headache groups, the prevalence of hypertension was higher than in general population. Hyper- tension was present in 28% of the patients, and was particularly common in medication-overuse headache (60.6%), chronic ten- sion headache (55.3%), cluster headache (35%), episodic tension headache (31.4%), but less common in migraine without aura (23%) and migraine with aura (16.9%). In the preliminary case control study done by Hamed et al. (11) on 63 adult patients with migraine (n = 44) and tension headache (n = 19), the authors found higher systolic blood pressure in migraine without aura, transformed migraine compared to control subjects (p<0.045, p<0.002), while diastolic blood pressure was higher in patients with migraine with aura, transformed headache and tension headache (p<0.041, p<0.002, p<0.002) and in patients with ten- sion headache than migraine with aura (p<0.024).

Information about the comorbidity of migraine and hyperten- sion or hypertension frequency in migraine patients was also shown in large population based studies. In 2005, Scher et al. (41) studied 5,755 subjects from the Genetic Epidemiology of Migraine Study in the Netherlands and found higher blood pre- ssure (systolic BP >140 mm Hg or diastolic BP >90 mm Hg) in individuals with migraine compared to those without migraine. In the population based study done by Gudmundsson et al. (42) evaluated 10,366 men and 11,171 women with migraine in a population-based study, the authors found that patients with migraine had higher diastolic blood pressure and lower systolic blood pressure and pulse pressure compared to controls. They also found that one standard deviation (1-SD) increase in dia- stolic blood pressure significantly increased the probability of migraine by 30% of women compared to 14% of men, while one standard deviation (1-SD) increase in systolic blood pressure

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and pulse pressure significantly decreased the probability of mi- graine by 19% and 13% of men and 25% and 14% of women, respectively.

The possible mechanisms of comorbidity of migraine with hypertension:

Shared biological mechanisms have been suggested as a link between migraine and hypertension. One such mechanism may be the rennin-angiotensin system, which is certainly involved in hypertension and has activities in the CNS that may be rel- evant for migraine pathogenesis (43-45). In support: a) attacks of migraine without aura and higher angiotensin converting enzyme activity are more frequent in subjects with angioten- sin converting enzyme DD gene, and b) clinical trials indicated that angiotensin-converting enzyme inhibitors as captobril and angiotensin II receptor blockers as Lisinopril are effective in the prophylactic treatment of migraine. In addition to their action on angiotensin-converting system, they alter sympathetic activ- ity, inhibit free radical activity, increase prostacyclin synthesis and block the degradation of bradykinin, encephalin and sub- stance P. All are implicated in the pathophysiology of migraine

(44,45).

B) Evidences that hypertension is not associated with headache:

Most cross-sectional studies performed in unselected popula- tions did not report significant association (negative or positive) between blood pressure and the prevalence of Headache. Chen et al. (46) found no association between migraine and hyperten- sion in 508 young women with migraine and 3902 without mi- graine. In a cross sectional study of Wiehe et al. (12), the authors studied 1174 individuals older than 17 years, representative of in- habitants of Porto Alegre, RS, Brazil and complained of migraine or tension headache. The authors found that i) individuals with optimal or normal blood pressure complained of migraine more frequently than participants with high-normal blood pressure or hypertension, ii) episodic and chronic tension headache was not associated with hypertension in lifetime in the last year, and iii) individuals with migraine-like episodes of headache may have lower blood pressure than individuals without headache. In a cross-sectional study conducted in the hypertension clinic of a tertiary care University hospital in Brazil, Fuchs et al. (47), in- vestigated 1763 subjects for the association between hyperten- sion classified at moderate to severe stages and headache. The authors found that headache and hypertension was not associ- ated. In addition, they found that pulse pressure and headache were inversely associated. In the large prospective study done by Hagen et al. (48), the authors estimated the relative risk of headache (migraine or non-migrainous headache) in relation to blood pressure at baseline in a total of 22 685 adults not likely to have headache, had their baseline blood pressure measured

in 1984-6, and responded to a headache questionnaire at fol- low up 11 years later (1995-7). The authors found that subjects with a systolic blood pressure of 150 mm Hg or higher had 30% lower risk (risk ratio (RR) = 0.7, 95% CI 0.6-0.8) of having non- migrainous headache at follow up compared with those with systolic pressure lower than 140 mm Hg. For diastolic blood pressure, the risk of non-migrainous headache decreased with increasing values, and these findings were similar for both sexes, and were not influenced by use of antihypertensive medication. For migraine, there was no clear association with blood pres- sure. In the randomized sample of the Vobarno population done by Muiesan et al. (13) (Brescia, Italy), the authors evaluated the prevalence of headache in a general population sample (n = 301, 126 males, 175 females with age range 35-50 years) to deter- mine its relationship to hypertension (diagnosed by office and/ or 24 hours blood pressure). The authors found no differences in headache prevalence (58% vs 55%), migraine prevalence (32% vs 28%) and use of analgesic drugs in the presence of headache (82% vs 78%) between hypertensive (93.5% newly diagnosed, 6.5% treated) and normo-tensive subjects. The first popula- tion based study that uses International Headache Society (IHS) criteria for classification of headache found 11 % hypertension in 974 subjects (49). However, the study did not report any dif- ference on incidence of headache between hypertensives and non-hypertensives.

In addition to the above, there is a consensus agreement within the International Headache Society that chronic arterial hyper- tension of mild to moderate degree does not cause headache but this may not be the case in patients with hypertension clas- sified at more severe stages. Severe hypertension in the setting of new acute headache may indicate a serious underlying cause and requires urgent investigation (50).

The possible factors or reasons for the denied association between migraine and hypertension:

The authors who found no association between migraine and arterial hypertension consider that the frequency rates of some common vascular risks (as hypertension) might be increased among patients with migraine which is also common (coinci- dental or chance association). Hypertension is also a common and consistent health problem in both developed and devel- oping countries and its prevalence is currently rising steadily (51). In general population, the prevalence of hypertension is 28.7% (52). In economically developed countries, the prevalence of hypertension ranged between 20 and 50%. The prevalence of hypertension varies widely among different populations, with rates as low as 3.4% in rural Indian men and as high as 72.5% in Polish women (53). The estimated prevalence of hypertension in Egypt was 26.3%. Hypertension was slightly more common in women than in men (26.9% versus 25.7%, respectively) (54). Since both hypertension and migraine are frequent in popula-

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tion, any association between them is likely to be detected in

large series. In fact individuals seeking medical care often show

a high rate of association between two medical conditions

which may be independent in the general population i.e., due

to a Berkson’s bias. In 10-20% of the population migraine and

hypertension can be found together.

C) Evidences that hypertension is negatively associated with headache:

Recent large-sample prospective and population-based studies showed a negative correlation between migraine and hyper- tension (12,48,55) with lower systolic pressure levels in migraine patients than in controls. Another indirect indication of this paradoxical link is suggested by the positive results of ACE inhibitors and sartans for migraine prophylaxis (56,57).

Hegan et al. (48) and Wiehe et al. (12) showed that migraine patients had lower values of blood pressure. Tzourio’s et al. (55) found lower blood pressure and reduced carotid-intima media thickness (evidence of hypertension) in migraine patients. Re- cently, Tronvik and his colleagues (14), looked at the association between migraine and non-migrainous headache and various measures of blood pressure: systolic, diastolic, mean arterial pressure (average of diastolic and systolic), and pulse pressure (systolic minus diastolic). The authors used both cross-sectional and prospective data from two large epidemiologic studies covering 51,353 men and women over the age of 20 living in Trondheim, Norway. The reason for the study was to explore the link between blood pressure and headache frequency, and how blood pressure medication affects that relationship. The two large studies were called HUNT1 (Nord-Trøndelag Health Survey 1984-1986) and HUNT2 (Nord-Trøndelag Health Survey 1995-1997). The main topics of HUNT-1 included blood pres-

sure, diabetes mellitus, and health related quality of life (58,59). While HUNT-2 was more extensive than HUNT-1, and among several topics, HUNT-2 included 13 questions related to head- ache (58). In HUNT study, Tronvik and his colleagues observed that: i) increasing systolic pressure was linked with decreasing prevalence of migraine and non-migrainous headache (people with higher systolic blood pressure were up to 40 per cent less likely to have headaches), ii) The most robust and consistent association was the link between increasing pulse pressure and decreasing prevalence of both migraine and non-migrainous headache, iii) This link was present for both men and women,

in both studies, and iv) The finding was less clear in cases where

people were also taking blood pressure medication.

The possible mechanisms of the negative association between migraine and hypertension:

Researchers in Norway have shown that high blood pressure is linked to fewer headaches, possibly due to having stiffer artery

walls which affects a homeostatic process that regulates blood pressure and decreases sensitivity to pain, i.e. a phenomenon called “hypertension-associated hypalgesia” (blood pressure

linked reduction in pain sensitivity). In support: a) an inverse relationship between blood pressure levels and sensitivity to painful stimuli extends into the normo-tensive range (60), b) low pain sensitivity has been reported in hypertensive ani- mals and humans and in groups deemed to be at an increased risk for the development of hypertension (61-63), and c) previ- ous studies confirmed that increasing blood pressure was linked

to decreasing amounts of chronic musculoskeletal pain in diffe-

rent parts of the body. In 2005, Hegan et al. (64) observed that

individuals with a high blood pressure had a lower prevalence of chronic musculoskeletal complaints than individuals with a nor- mal blood pressure. The authors also found that among 46 901 adults who participated in HUNT1 and HUNT 2 surveys, there was a strong linear trend of decreasing prevalence of chronic musculoskeletal complaints with increasing BP values (systolic and diastolic BP). The authors suggested that the phenomenon

of hypertension-associated hypalgesia, may be one explanation

for the negative association between migraine and musculos- keletal pains.

The mechanism for hypertension-associated hypalgesia is not clear. but data from humans and rats suggest an interaction be- tween the cardiovascular and pain regulatory systems.

A role for baroreceptors in mediating the blood pressure-pain

sensitivity relationship has received some experimental and clinical support. Stimulation of the baroreflex arch (a homeo-

static process that helps to maintain blood pressure) in response

to increased blood pressure is assumed to inhibit pain transmis-

sion at both spinal and supraspinal levels, possibly because of an interaction of the centers modulating nociception and car- diovascular reflexes in the brainstem (65). The presence of the

inverse association between blood pressure and pain sensitivity

in the absence of clinical hypertension also support the view

that some common central mechanism is underlying the anti- nociception and cardiovascular regulation rather than a specific effect of hypertension itself. Sanya et al. (66) assessed the baro- reflex stimulations in 30 migraine patients in a headache-free phase. The authors applied oscillatory neck suction at 0.1 Hz (to assess the sympathetic modulation of the heart and blood vessels) and at 0.2 Hz (to assess the effect of parasympathetic stimulation on the heart) to assess the changes in power of the RR-interval and blood pressure fluctuations at the relevant stim- ulating frequency from the baseline values. The authors found that 0.1 Hz neck suction pressure were not significantly different between the patients and controls but the RR-interval oscilla- tory response to 0.2 Hz neck suction was significantly less in the migraine patients compared with the controls. This confirms that central autonomic changes are associated with the patho-

physiology of migraine related blood pressure changes.

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Although endogenous opioids are necessary for full expression of the relationship between resting blood pressure and pain sensitivity (60,61), however, the absence of the effect of opioid blockade on the blood pressure pain sensitivity relationship, leaves a doubtful role of endogenous opioid as explanation to the relationship between resting blood pressure and pain sensitivity in migraine (60). Other neurotransmitters, like cat- echolamines, may also be involved (61). It has been found that a polymorphism of catechol-O-methyltransferase (COMT) gene, of which its protein product is an important enzyme for the me- tabolism of catecholamines, may influence the response to pain (67) and may also be important also for blood pressure regula- tion (68). In support, antihypertensive medications may have an influence on blood pressure-pain sensitivity relationship.

Hypotension and headache:

is there a relationship?

No studies reported hypotension in the inter-ictal period. Howev- er, hypotension is not excluded as comorbid with migraine. In fact, with hypotension, a painful headache is commonly experienced when one bend over and suddenly move upright his/her head. This is also called orthostatic and occurs with dramatic changes in cranial blood pressure. Once triggered, hypotensive headache presents itself just like migraine and most other headaches.

Ictal hypotension has been reported by some authors. Recently, Seçil et al. (69), recorded blood pressure at 3 times in 62 normo- tensive patients with migraine: (1) just before or very early, (2) during (when headache peaks), and (3) 1 hour after the attack. The authors detected diastolic hypotension in a considerable number of patients before or very early, during, and after mi- graine attack (5.1%). The authors hypothesized that pathophysi- ological mechanisms (as autonomic dysfunction) are involved in migraine, which are still largely unknown, could lead to a decrease in blood pressure. Autonomic dysfunction is also re- ported in many functional neuroimaging studies (fMRI and PET) with migraine (49). It has been found that during migraine at- tacks, some substances are released especially calcitonin gene- related peptide (CGRP) (which is the main vasodilator) due to activation of contralateral locus ceruleus, dorsal pontine area and dorsal raphe nucleus. This peptide could be the reason of diastolic and systolic hypotension during the entire attack (70).

The current opinion of the comorbidity between blood pressure changes and migraine:

Recent evidences suggest that during attacks of migraine and in the interictal period, migraine patients have changes in the properties of the systemic as well as cranial vasculature, includ- ing: generalized peripheral vasoconstriction (71), increased diameter and/or decreased distensibility of peripheral blood

vessels (72), decreased brachial artery flow-mediated dilatation and increased nitrate-mediated response (73), increased bra- chial artery intima-media thickness (72), presence of microvas- cular retinal abnormalities (74) and reduced number and func- tion of circulating endothelial progenitor cells (EPC) which are surrogate biologic markers of impaired vascular function and higher cardiovascular risk (75). Nagai et al. (76) reported signifi- cant association between enhanced radial augmentation index and migraine. Augmentation index (AI) is a parameter of arterial stiffness that can be obtained from the central arterial waveform as the ratio of augmentation pressure by the reflection pressure wave to the pulse pressure. It has been reported that central AI is closely related to several risk factors for atherosclerosis and future cardiovascular events. AI can also be obtained from the radial arterial waveform. Since radial AI is closely associated with aortic AI, radial AI itself could provide information on vascular properties (77). In the study of Hamed et al. (11), the authors found that brachial artery flow mediated dilatation was lower in patients with transformed headache and is inversely corre- lated with systolic and diastolic blood pressure and carotid ar- tery intima-media thickness of all groups of headache patients (migrainous and non-migrainous).

Previous studies confirmed that hypertension is associated with modification of the physical properties of large arteries which are concerned the geometry, wall elasticity, and wall viscosity of cranial and peripheral vessels vessel (78). These properties are shared in patients with migraine and hypertension. Together with the evidences for the presence of vascular risk profile in some patients with migraine which include: high blood pres- sure (35), disturbed lipid profile (79), elevated body mass index (BMI) (80), insulin resistance (81), metabolic syndrome (82), hy- perhomocysteinemia (83), ischemic cerebrovascular stroke (84) and coronary heart disease (85), all indicate the possibility of migraine being a local manifestation of a systemic vascular ab- normality rather than a primary cerebral phenomenon.

Clinical implications:

1) Based on the above information and despite the fact that there is still uncertainity regarding the comorbidity of blood pressure changes with migraine, establishing the blood pres- sure should be a routine task in the assessment of all headache patients and the control of hypertension in migraine patients is an important factor for the success of migraine treatment and to lower cerebrovascular risk (86,87). A unifying view among most recent studies suggests that migraine is positively cor- related with diastolic blood pressure but negatively correlated with systolic blood pressure and pulse pressure (42,87,88). Some evidence suggests that poor control of blood pressure may exacerbate the frequency and severity of migraine and other headaches (17).

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2) Careful consideration of the therapeutic options is important for both migraine and hypertension. At present, acute treatment of migraine includes the use of non-steroidal anti-inflammato- ry drugs (NSAIDS) and triptans (5-HT agonists). However, some agents used to treat migraine can exacerbate hypertension and many of the drugs used to treat hypertension may cause headache. Triptans are vasoconstrictive and cannot be used in patients with cardiovascular diseases. A promising option is the use of antihypertensive drugs in migraine prophylactics. Re- cently, angiotensin converting enzyme inhibitors and blockers of angiotensin II provide beneficial results in migraine prophy- laxis (44). A very recent progress for migraine therapy includes the introduction of CGRP antagonist (MK-0974 or telcagepant) which shows high efficacy in treatment of migraine attacks with no adverse cardiovascular risk (89).

3) Addressing the vascular comorbidities with vascular risk pro- file with migraine in experimentally large sample sized studies could be a big step towards understanding vascular component of migraine attacks as well as systemic end points of attacks. It is important to point that the bidirectional association between migraine, hypertension and vascular risk factors may increase the risk of arterial endothelial damage resulting in cardio- and cerebrovascular complications (11).

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Acute Stroke in a 26 year old male

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Gaurav Patel, MD; Nicholas Pantaleo, MD; Alireza Eghtedar, MD; Thambirajan Nandakumar, MD; Akash Ferdaus, MD; Maritza Jerome, DO

Department of Medicine, Jamaica Hospital Medical Center, New York 11418

E-mail: npantal1@jhmc.org

Abstract

This case report identifies a young patient who initially presented to a New York City hospital complaining of weakness and incidentally found to have a cervical spine lesion. An extensive workup diagnosed the lesion as a non-caseating granuloma, consistent with neurosar- coidosis. The patient had also been suspected to have TB meningitis given his unclear history of a past untreated positive PPD test. Before final discharge, the patient’s condition had some improvement with steroid treatment and rehabilitation.

Introduction

Acute stroke in a 26 year old patient is a rare finding. In such cases, physicians usually assume an underlying medical pro- blem to account for the symptoms. In this case, the patient underwent an extensive workup revealing no outright cause. Then, one brain scan identified an incidental upper cervical

spine lesion. This case discusses the initial patient work-up and

a rare presentation of neurosarcoidosis.

Case

A 26 year old Hispanic male presented to the emergency room

with complaints of sudden onset of right sided weakness. The prior day he was in his normal state of health without any mo- tor or sensory deficits. Upon waking that morning, the patient noticed difficulty speaking and was unable to move the right side of his body. The patient denied any fevers, chills, neck pain, visual changes, seizures, headache, or nausea.

Three months prior to this ER visit, the patient had a prolonged stay at another hospital. At that time he presented with a two day history of an elevated temperature to 105ºF, occipital head- ache, neck pain and stiffness, dizziness, nausea and vomiting, and anorexia. When that admitting team pried further, they dis- covered that the patient was from Mexico and had only been in this country for five years. In addition, the patient stated that he had a non-productive cough for nine months and a vague history of an untreated positive PPD.

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While hospitalized, the team suspected meningitis and pro- ceeded with the proper work-up. The patient experienced one episode of hallucinations and complained of pain in his poste- rior thighs that was not associated with any weakness.

Several lumbar punctures performed were all consistent with chronic meningitis, showing lymphocyte predominance and low glucose levels. Due to these findings, history of an untreat- ed positive PPD, and while cultures were growing, the patient began anti-tuberculosis RIPE regimen (Rifampin, Isoniazid, Pyra- zinamide, Ethambutol, and Pyridex) and oral steroids.

Although all cultures remained negative (blood, fungal, AFB), the patient’s headache resolved. He also began tolerating oral feeds, and he became more alert and oriented. Therefore, the patient was discharged and was complaint with a medication regimen that included RIPE and oral prednisone.

On presentation at this hospital, physical examination portrayed an afebrile patient in no acute distress. Neurologic exam identi- fied slurred speech, right facial droop, brisk lower extremity re- flexes, and 1/5 strength in the upper and lower right extremities.

Imaging studies illustrated several findings. Initial brain MRI showed an acute stroke in the left coronal radiate, a 4-mm enhancement in the left temporal lobe without surrounding edema, and an incidental upper c-spine lesion likely within the spinal cord. For further clarification, a cervical MRI identified an enhancing, intra-medullary lesion in the right posterolateral cer- vical spinal cord extending from C3 to C4-5 level, containing a

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AND NEUROSCIENCE 2010 Vol.1 No. 2:3 doi: 10:3823/307 5-mm cystic component with adjacent dorsal spinal cord

5-mm cystic component with adjacent dorsal spinal cord edema or non-enhancing infiltrative changes extending from the skull base to T7 and adjacent syrinx. Brain MRA did not identify any vascular abnormalities.

This patient had a workup aimed to identify the cause of his stroke. All vasculitis investigations proved negative.

Due to limited services at the presenting hospital, the patient was transferred to a larger facility for further workup of the cer- vical spinal lesion.

On presentation, neurological exam showed right facial droop, sustained clonus of the right ankle, and increased muscle tone, decreased muscle strength, and increased reflexes in the right upper and lower extremities. The patient was able to stand and could walk only with assistance.

This patient underwent repeat imaging, cultures, and lumbar puncture, and since they yielded little additional information, the patient underwent both a brain and cervical spine biopsy. The brain biopsy from the left corona radiata showed findings consistent with a stroke and no evidence of neoplasm, demye- linated lesions, or infection. The pathology from the spinal biop- sy identified lympho-plasmacytic infiltrates and non-caseating granulomas, consistent with neurosarcoidosis.

After these findings, RIPE therapy was discontinued and a slow prednisone taper was started. The patient continued to receive physical and occupational therapy, and he was transferred back to this hospital for discharge planning.

Discussion

The exact etiology of sarcoidosis is unknown, but proposed causes include infectious agents, occupational and environ- mental factors, genetic factors, and autoimmune disorders. 1 Sarcoid lesions can occur anywhere in the body but there is a predominance in the lungs, skin, and lymph nodes. 1 Neurosar- coidosis presents in less than five percent of individuals with sarcoidosis, and it usually occurs only after other systemic symp- toms are found. 1 About 1% of sarcoidosis cases present with CNS problems alone. 2

While sarcoidosis usually presents with remitting and relapsing episodes, neurosarcoidosis usually presents as a monophasic self-limiting illness. 1 Presentation will also vary in individuals depending on the location of the lesion with manifestations involving cranial nerves, parenchymal brain tissue, pituitary- hypothalamic axis, the spinal cord, and peripheral nerves. 1 Typical presentation include affects of the cranial nerves includ- ing facial palsy, visual loss, double vision, hearing loss, vertigo, swallowing problem, shoulder and tongue weakness. 2 Other presentations include grand mal seizures, meningitis, severe headaches caused increased ICP, and hydrocephalus. 2

Although few cases have presented with symptoms of acute or subacute CNS ischemic events, the majority of these cases occurred in patients with known sarcoidosis including patients who were on treatment. Proposed mechanisms responsible for the cerebrovascular even include small vessel granulomatous vasculitis, large vessel inflammation leading to occlusion or ste- nosis, and embolism. 3,4

As in this case, when systemic manifestations are absent, imag- ing and then biopsy are necessary to confirm the diagnosis. 1 Biopsy of lesions should identify non-caseating epithelioid-cell granulomas that over time should resolve or convert to hyaline connective tissue. 1 Although lumbar puncture may demonstrate an elevated protein level, pleiocytosis, and oligoclonal bands, about 30% of cases show no cerebral spinal fluid abnormality. 2 Various other tests (e.g. ACE level in CSF) have little added value in neurosarcoidosis. 2

Mainstay treatment involves corticosteroids, immunosuppres- sants, and possible surgical excision of lesions. 1 Corticosteroids like prednisone are the main therapeutic agent in the manage- ment of neurosarcoidosis. 2 Small studies have found resistant cases to respond to immunosuppressants, including metho- trexate, hydroxychloroquine, cyclophosphamide, pentoxifylline, thalidomide, and infliximab. 2 Radiotherapy and neurosurgical interventions are usually considered with obstruction or mass effect. 2 In one case of neurosarcoidosis that presented with acute stroke, surgeons performed left middle cerebral artery angioplasty with successful results. 5

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Since few cases of acute stroke caused by neurosarcoidosis have been reported, neurosarcoidosis as a cause of unexplained acute CNS ischemic event should be considered in a relatively young patient when other common etiologies have been ruled out. Diagnostic work-up should include routine laboratory studies, CSF analysis, imaging studies, and biopsy of abnormal lesions to develop a correct diagnosis in order to satisfactorily treat the patient.

References

1. Vinas FC, Rengachary S. Diagnosis and management of neurosar-

coidosis. Journal of Clinical Neuroscience. 2001;8(6):505-513.

2. Joseph FG, Scolding NJ. Sarcoidosis of the nervous system. Practical

neurology. 2007; 7(4):234-244.

3. Younger DS, Hays AP, Brust JC, Rowland LP. Granulomatous angiitis

of the brain: an inflammatory reaction of diverse etiology. Arch Neurol. 1988; 45:514-518.

4. Raske-Nielsen E, Harmsen A: Periangiitis as a manifestation of sar-

coidosis of the brain: report of a case. J Nerv Ment Dis. 1962; 135:399-412.

5. Brisman JL, Hinduja A, Mckinney JS, Gerthardstein B. Successful

emergent angioplasty of neurosarcoid vasculitis presenting with strokes. Surgical Neuro. 2006; 66(4):402-404.

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Activity of serum Cathepsin D in Alzheimer’s disease

Manuel Menéndez-González 1,2 , Ana Suárez 3 , Patricia López 3 , María Teresa Calatayud 4 , Marta Martínez-Rivera 1 , Renée Ribacoba 4 , Alfonso López-Muñiz 2

1 Neurología, Hospital Álvarez-Buylla, Mieres

2 Departamento de Morfología y Biología Celular, Universidad de Oviedo

3 Departamento de Biología Funcional, Universidad de Oviedo

4 Neurología, Hospital Universitario Central de Asturias, Oviedo

E-mail: manuelmenendez@gmail.com

Abstract

Growing evidence support the hypothesis that cathepsin D (catD) is related to AD but the activity of serum catD had never been assessed in patients with dementia. We studied the activity of serum catD in different stages of AD as well as in patients with Mild Cognitive Impairment (MCI) and Vascular Dementia (VD). Results do not support catD activity as a useful biomarker for dementias since we found no significant differences between AD stages or between AD and MCI or VD. Surprisingly we found a relation between ApoE genotype, gender and catD activity that reaffirm the possibility that catD might be involved in the pathogenesis of AD specifically in men carriers of ApoE4.

Introduction

Sporadic, late-onset Alzheimer’s disease (AD) is a complex dis- ease influenced by both genetic and environmental factors. Many of these factors have been identified during last decades. However, little is known about how these factors interact.

Growing evidence point the lysosomal aspartyl protease ca- thepsin D (catD) in AD-related processes as the activation of the endosomal/lysosomal system (1, 2) and the cleavage of the amyloid precursor protein into amyloidogenic components (3). Neuropathological changes in Alzheimer’s disease (AD) are also associated with increased expression of Apolipoprotein E (ApoE) and catD in astrocytes (4).

Additional evidence of the involvement of catD in AD comes from genetics: a non-synonymous polymorphism in the catD gene has been proposed to be a major risk factor for AD. Exonic polymorphisms of the catD gene possibly influences pro-catD secretion and intracellular maturation of the enzyme, was associated with the risk for the development of AD (5, 6, 7, 8) although this result was not replicated in some populations (9, 10). Others suggest that there might be a synergistic interaction between the the CatD T allele and the APOEepsilon4 allele in increasing the risk for developing AD (11, 12). Strikingly gender differences were found recently (13) supporting the idea that this polymorphism confers an increased risk for AD in men but not in women.

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Nevertheless, the enzymatic activity of serum catD had never been assessed in patients with dementia. We aimed to study the activity of serum catD in different stages of AD as well as in patients with Mild Cognitive Impairment (MCI) and Vascular Dementia (VD) in order to evaluate if this parameter could be considered a potential biomarker for AD.

Subjects and Methods

This project has been approved by the Research and Ethics Committees of the Hospital Universitario Central de Asturias (HUCA). Informed consent was obtained from all individuals or their guardians.

All individuals assessed at the HUCA-Dementia Unit from Janu- ary 2003 to December 2005 meeting the inclusion criteria were invited to join the study.

Patients

Inclusion criteria

Patients suffering from one of the next conditions: MCI accord- ing to Petersen’s criteria (14), AD according to the NINDS-ADRA criteria (15), and VD according to the NINDS-AIREN criteria (16).

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Exclusion criteria

Patients suffering from other conditions causative of cognitive impairment including cancer, hydrocephalus, infectious, meta- bolic or toxic disease. Patients with renal or hepatic dysfunction (often associated with abnormal levels of plasmatic proteins).

Controls

Individuals without any central nervous system disorder and ageing more than 60 years old were included as controls. Con- trols were recruited among healthy people matching the age of patients, mainly the spouses of the patients included, or pa- tients studied in our department for peripheral nervous system diseases.

Clinical Assessment

All patients were studied with neuroimaging and full neuro- psychological assessment following the AAN recommenda- tions (17). Neuropsychological assessment included the “Test Barcelona Abreviado” (18) in all patients as well as other tests depending on each patient’s profile. The Barthel Index (19) was also performed in all patients.

ApoE genotype was determined in all cases of AD: genomic DNA was obtained from blood following a salting-out method (20) and ApoE genotyping was performed as previously de- scribed (21).

The staging of the disease was performed following the GDS- FAST criteria (22): mild AD: GDS4, moderate AD: GDS5 and severe AD: GDS6.

Immunoassay

Plasma sample acquisition, storage and laboratory conditions were identical for all specimens used in the study. We used the MBL kit for cathepsin-D activity (Woburn, MA) which is a fluorescence-based assay that measures the free AFC (amino- 4-trifluoromethyl coumarin) released after cleavage of the pre- ferred cathepsin-D substrate sequence RGFFP labelled with AFC. To this end serum samples were added to the synthetic sub- strate in fluorescence validate black 96-wells microtiter plates (BD Falcon TM , Becton Dickinson) and incubated at 37ºC for 2 hours. Fluorescence was quantified in a Cary Eclipse Fluores- cence Spectrophotometer (Varian Ibérica S.A., Madrid) using a 328 nm excitation filter and 460 nm emission filter. Results were expressed by the relative fluorescence units (RFU) per ml of serum.

Statistics

A Chi-square test was performed to study gender distribution

differences between controls and patients. A T-Student test was performed to assess differences in age between controls and patients. ANOVA tests were performed to asses the differences

in catD activity between groups. Chi-square tests were applied

to assess whether catD activity is associated to the fact of be- ing carrier of the E4 allele. Finally, the Mann–Whitney U test was used for assessing differences related both to gender and ApoE genotype.

Results

Sample description

We studied 40 controls and 149 patients. Sixteen patients suf- fered from MCI, 25 from VD and 108 from AD. Patients with AD were in different stages: 52 mild AD, 38 moderate AD and 18 severe AD. The mean age was 77,04 (std. dev.: 8,38) and there were no significant differences between groups (p=0.744). One hundred and 2 subjects were female and 47 male; there were no significant differences between groups (p=0.216), although

in patients with AD there were a higher rate of female subjects

than in other groups. Finally, 38% of patients with AD were car- rier of the ApoE4 allele.

CatD activity

The activity of catD was similar in all groups (Table 1). The mean activity in controls was 659,83 units/ml. There were no signifi- cant differences between groups (p=0.252).The higher activity was found in patients with VD (706,99 units/ml) and the lower in patients with severe AD (587,35 units/ml) though this difference was not significant (p=0.105). There is no correlation between the severity of disease in AD and the catD activit

Table 1. CatD activity (units/ml) measured by relative fluorescence in units/ml.

Diagnostic

 

Mean

N

Std. Dev.

groups

Control

659,84

40

401,35

mild AD

648,92

52

435,04

moderate AD

674,44

38

358,31

severe AD

587,36

18

107,40

MCI

676,14

16

277,59

VD

706,99

25

379,45

Total

660,48

189

369,45

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Relation ApoE genotype-catD activity

When we studied the activity in patients with AD, those who were carriers of one E4 allele had lower activity (596,78 units/ ml) than those without E4 allele (702,95 units/ml), though this difference did not reach statistical significance (p=0.126). This trend was present for all disease stages, as shown in table 2.

Table 2. CatD activity (units/ml) in the three AD stages in E4 and no E4 carriers.

 

No E4

E4

mild AD

704

585

moderate AD

730

652

severe AD

582

547

On the other hand being carrier of two E4 allele did not associ- ate with lower activity than being carrier of just one E4 allele

(p=0,416).

Relation gender-catD activity

When we specifically compared the catD activity by gender, in both ApoE4-carriers and not carriers, we found a significant difference (p=0,037) only in the group of ApoE4 carriers: men showed a lower activity (mean: 542,27 units/ml – SD: ± 74,51) than women (mean: 639,36 units/ml – SD: ± 103,84) (Figure 1).

women (mean: 639,36 units/ml – SD: ± 103,84) (Figure 1). Figure 1. Comparison of catD activity

Figure 1. Comparison of catD activity (units/ml) in men and women in carriers and not carriers of ApoE4.

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Discussion

Lysosomal impairment is involved in AD pathogenesis and can be detected not only in the CNS but also at a peripheral level (1, 23). This involvement may happen through catD. In fact catD seems to be involved in the proteolysis of ApoE and probably contributes to the generation of ApoE fragments previously im- plicated in AD pathology (24). One of the studies presented at the 5th General Meeting of the International Proteolysis Society that address enzymatic mechanisms for producing neurotoxic beta-amyloid (Abeta) peptides describes the poor kinetics of BACE 1 for cleaving the wild-type (WT) beta-secretase site of APP found in most AD patients. They showed that cathepsin D displays BACE 1-like specificity and cathepsin D is 280-fold more abundant in human brain than BACE 1 (25).

We assessed the activity of serum catD in controls, AD, MCI and VD and did not found any significant association with the diag- nosis of AD. However, there is a correlation with the genotype E4: at the three stages of the disease the activity is lower (not to the point of statistical significance) in those patients carriers of at least one apoE4 allele. This suggests that the ApoE genotype influences the activity of serum catD and in turn it can be more or less amyloidogenic. This finding is supported by genetic stud- ies (11, 12). As the risk of AD in population is higher between E4 carriers one may infer that low catD activity might contribute to amyolidogenic deposits. In this line, Cathepsin D was found to be involved in the intracellular clearance of aggregatable Aβ

(26).

Surprisingly, we also found a significant lower activity in men carriers of ApoE4, than in women or men who were not ApoE4 carriers. This finding also links with the results of genetic studies since the single nucleotide polymorphism rs17571 of the catD gene confers an increased risk for AD in men but not in women (13). These facts support the hypothesis of gender-specific dif- ferences in the pathogenesis of AD (27).

Further studies, assessing the interaction between gender, ApoE and catD genes polymorphisms and catD activity are needed to fully understand their relation.

Conclusion

In the light of our results, the activity of serum catD does not seem to be a useful biomarker to distinguish between AD and VD or to monitor the progression of the disease, but these re- sults confirm the possibility that the activity of serum catD in patients with AD is related to the ApoE genotype and gender and therefore might contribute to the pathogenesis of the dis- ease only in a concrete subpopulation of patients: men carriers of ApoE4.

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Inheritance Of Alzheimer´s Disease Investigated By Complex Segregation Analysis

Manzano S, MD, PhD 1 , Baron M, MD, PhD 2 , Gomez-Tortosa E, MD, PhD 3 , Barquero MS, MD, PhD 1 , Jimenez-Escrig A, MD, PhD 4 .

1 Hospital Clinico San Carlos, Madrid, Spain.

2 Fundación Jimenez Diaz, Madrid, Spain.

3 Fundación Hospital Alcorcon, Madrid, Spain.

4 Hospital Ramon y Cajal, Madrid, Spain.

Address correspondence to:

Dr. Jimenez-Escrig S. de Neurologia Hospital Ramon y Cajal 28034 Madrid, Spain Email: adriano.jimenez@hrc.es

Acknowledgement:

Genetics research in our laboratory is done thanks to a grant research of the Fundacion Areces

Abstract

Background: Complex segregation analysis (CSA) consists in the mathematical modeling of the hereditability of a transmissible condition. After generating a model, it can be known the most likely pattern of transmission, the frequency of the gene in that population and the penetrance of the condition. Objective: To assess the inheritance for Alzheimer’s disease in a Spanish population by CSA. Methods: We ascertained 21 families (297 individuals) through probands, with 76 individuals affected with Alzheimer’s disease fulfilling CERAD criteria. These families gave a total of 44 nuclear families to be included in the model. CSA was performed using the software POINTER examining the following models: non transmission, multifactorial (polygenic and environmental), Mendelian (dominant, recessive, codomi- nant), polygenic, mixed (Mendelian plus polygenic) and a general model (Mendelian plus multifactorial). Four liability classes where defined according to the age of onset of the disease (<60 year-old; 60-69; 70-79; >80). Hypothesis testing was performed by comparing the fit of the specific model to the general unrestricted model. Results: The model that best fitted the data in this population was the Mendelian dominant model with a gene frequency of 0.0164. This gene explains a 65.7% of the hereditability of this condition. Penetrance of the gene according to age followed an exponential pattern (2.47; 25.44; 27.88; 32.22). Conclusions: Alzheimer’s disease in these families is inherited due to a Mendelian dominant gene. The results support the importance of linkage efforts by suggesting that a Mendelian locus is segregating within a proportion of families with Alzheimer’s disease ascertained through probands.

Introduction

Alzheimer Disease (AD) is the most common neurodegenerative disease. This disease shares with other neurodegenerative dis- eases that following ageing, family history is the second risk fac- tor for the disease. The growing understanding of AD genetics is being the key to the knowledge of the pathogenic mechanism driving to the disease.

Familial aggregation was recognized as a prominent characte- ristic in many neurodegenerative disorders decades ago (Ber- tram and Tanzi, 2005b). After the molecular genetic (Martin,

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1999) and biochemical properties of these diseases have been unravelled, one of their characteristics which has emerged is the dichotomy between familial (rare) and seemingly non-familial (common) forms (sporadic or idiopathic) that is present in the genetic epidemiology of neurodegenerative diseases. Familial forms (Gail Pairitz J., 1998) have Mendelian patterns of trans- mission, while in seemingly sporadic forms a growing body of evidence suggests influence of multiple genetic traits that may associate an interaction with environmental factors. In AD, there are three rare fully penetrant autosomal dominant forms caused by mutations in APP (Goldgaber et al., 1987), PSEN1 (Barinaga, 1995) and PSEN2 (Levy-Lahad et al., 1995) genes, and a common

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incompletely penetrant susceptibility variant, namely, the ε4 al- lele in APOE gene (Chartier-Harlin et al., 1994), that significantly increases the risk by lowering the age of onset (AO) of the dis- ease (Bertram and Tanzi, 2005a).

Familial aggregation in a disease does not necessarily imply a genetic etiology. When familial cases appear, genetic and/or en- vironmental factors may be influencing the observed pattern of disease transmission in families. The genetic factors may be Mendelian with any mode of inheritance, polygenic, or any mix- ture of these ones. Various methods have been proposed for the statistical inference of gene effects in familial data. When exam- ining a family with a certain disease present in several members, the issue is whether a genetic component or an environmental factor is the primary responsible for the trait. The simplest way to determine the genetic contribution to a trait is by examining the recurrence risk ratios. The most popular method is due to Risch (Risch, 1990) and is defined by

l R = k R /k

where R denotes the relationship with the proband, k R is the prevalence in relatives of type R, and k is the prevalence in the general population. In any genetic model

1 l 1 l s l M

The genotype relative risks for D at this locus are

g 1 = f Aa / f aa ; g 2 = f AA / f aa

The relationship between the sibling relative risk ratio and genotype relative risks depends on both allele frequency and mode of inheritance (Rybicki and Elston, 2000) Explicit formu- lae relating GRR and l s for a dominant, recessive, additive and multiplicative models may be found in Wittke-Thompson et al. (Wittke-Thompson et al., 2005).

When discussing the heritability of a trait is worth to consider that there are two different measures that may be both referred

to as heritability (Abney et al., 2001). Heritability in the broad sense (denoted H 2 ) is defined as the proportion of total vari- ance in a trait that is due to all genetic components (additive, dominance and epistatic), while narrow heritability (denoted h 2 )

is defined as the proportion of phenotypic variance that can

be attributed to additive genetic variance. The additive genetic variance at a locus measures the variance due to the mean ef- fects of single alleles. Dominance variance of a trait at a locus measures the variance due to the interaction of alleles that con- stitute a genotype. Epistatic variance is due to the interaction effect between loci. Total additive (respectively, dominance) variance is the additive (respectively, dominance) variance at each locus summed over the genome. Similarly, total epistatic variance is the total variance obtained by summing the contri-

where M, s and 1 are relationship subscripts that denote MZ twins, siblings and parents (or offspring) respectively. Typically, l R is calculated for siblings and l s is known as the sibling relative risk. Examples of l s for different diseases include Huntington’s

The power to detect genetic influence of a variant can also be

bution of epistatic variance of all pairs of loci over the genome. Typically, one assumes that the additive effects are the primary contributors to the trait. A heritability score near zero suggests that almost all variation is due to environmental causes, whereas

disease (where k s = 0.5, k = 0.0001, and so l s 5,000), recessive

a

heritability score near 1 implies that almost all variation is due

CMT (where k s = 0.25, k = 0.004, and so l s 500) and Parkin- son’s disease (where k s = 0.3, k = 0.1, and so l s = 3). In general,

to

genetic factors.

the greater the value of l s , the greater the genetic influence on the trait. However, in itself, l s is not necessarily a reliable pa- rameter for estimating the power of a proposed linkage study. For example, in some two locus models a l s as high as 10 does not guarantee that underlying genes will be easily mapped by linkage studies.

defined in terms of genotype relative risks (GRR’s)( (Schaid and Sommer, 1993). Consider a biallelic locus with alleles of type A, a and relative frequencies f(A), f(a), where A is the disease suscepti- bility allele. The conditional probabilities that an individual with a particular genotype has a disease D are known as penetrance

is important to bear in mind that heritability is a ratio and as

such does not necessarily provide an accurate measure of how important genes are in determining the phenotype. Heritability reflects the proportion of total variation due to a gene variant, reflecting both the variant’s frequency in the population and the size of the effects that the gene variant causes and is pri- marily used for assessing the genetic contribution to a quantita- tive trait. Sibling relative risk, on the other hand, assesses the in- creased disease risk to siblings that share one-half of their genes with affected probands and is used in connection with qualita- tive traits. For a fixed value of l R the corresponding heritability decreases with decreasing population prevalence (Risch, 2001).

It

parameters and given by

A

major point when considering the hereditability of a tract is

f AA = P(D|AA), f Aa = P(D|Aa), f aa = P(D|aa)

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the evaluation of the segregation pattern. Simple segregation analysis considers the proportion of affected and not affected in the offspring and examines this proportion against the theoreti-

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cal proportion of autosomal dominant (50%) or recessive (25% of affected / 75% of non-affected, in the simplest case) and con- sidering the confidence intervals discloses whether a particular mode of transmission is possible or can be ruled out. A more general method for evaluating the transmission of a trait within pedigrees is complex segregation analysis (CSA), which test the fitting of the inheritance of the trait to different models, genetic and non genetic, allowing to select the model that obtains bet- ter fitting of the data. Whilst simple segregation analysis only evaluates whether the proportion of affected and unaffected offspring in families is consistent with Mendelian expectations, CSA can consider more complicated patterns of transmission and environmental perturbations. CSA can be applied to any pedigree structure and works with both qualitative and quan- titative traits.

The parameters estimated in CSA are: 1) an underlying discrete risk trait (that may be present in double dose (AA), one dose (Aa) or absent (aa)) that influences a given individual’s age-depend- ent risk for disease (in genetic models, this trait represents a high-risk allele, whereas in non-genetic models, the trait is inter- preted more generally as levels of exposure to an unmeasured major environmental risk factor); 2) the transmission parameters which represent the probability that a parent transmits the risk trait to an offspring; and 3) the penetrance of the risk trait. CSA can also be used to further define the genetic features of a trait, such as the high risk allele frequency in the population. In ad- dition, it can be used to evaluate etiologic heterogeneity in a trait, either by doing CSA in defined subsets or by contrasting the likelihoods under competing models for each family.

The mixed model, which is the one we have used here (another possibility for CSA is a regressive logistic model for disease (Bon- ney, 1986)) assumes that the liability to the disease (x) can be described by an underlying continuous liability scale in which a biallelic single major locus (g), a polygenic component (c), and environmental effects (e) operate independently. The liability (x) is then defined as x = g + c + e. The respective variances of these parameters are denoted as V = G + C + E. The relative contribu- tion of the polygenic component is defined by H, the heritability, which reflects genetic transmission not ascribed to a major gene or cultural transmission (H = C/V).

Model parameters in the mixed model are:

A major locus has two alleles (A,a), whose genotype frequen- cies have to follow the Hardy-Weinberg equilibrium. q, the frequency of the high risk allele A; t, the genetic distance or displacement at the single major locus measured in standard deviations on the liability scale between the two homozygous genotypes (AA and aa);

at the major locus obtained by

the equation

d,

0

degree of dominance

d =

Aa - µ aa )

/

AA - µ aa ), such that

d

=

corresponds to a recessive gene, d = 1 corresponds to a domi- nant gene, 0 < d < 1 corresponds to some degree of additivity and d = 0.5 is referred to as codominant;

H

the polygenic heritability in the children (k); H = C k /V

Z,

the ratio of adult to childhood heritability; Z = C a /C k

and t 1 , t 2 and t 3 , the respective probabilities that genotypes AA, Aa, and aa transmit the allele A.

The general model contains the most parameters. This model is then compared with a Mendelian transmission model, an envi- ronmental transmission model, and a polygenic model. Under

a Mendelian model, the transmission probabilities, namely, the

probabilities that the AA, Aa, and aa genotypes will pass on an A allele, do not significantly differ from the Mendelian expecta- tions of 1, 0.5, and 0, respectively, whereas in the general model these transmission probabilities can take any value. Under the environmental model, these probabilities are all equal because the phenotypic mode that a child is in is unrelated to the mode that the parent is in. Whilst the Mendelian and environmental models can contain multiple small genetic and environmental effects, a polygenic model considers only the multiple small ge- netic effects so it has no large deviation in the trait caused by either a major locus or the environment. Having a Mendelian model favoured in a data set, dominant and recessive Mende- lian submodels can be evaluated.

There are several software packages that can perform CSA: PAP (Pedigree Analysis Package, Department of Medical Biophysics and Computing, University of Utah, Salt Lake City), SAGE (Case Western Reserve University Statistical Analysis for Genetic Epi- demiology at http://darwin.cwru.edu/sage/), GAP (Genetic Analysis Package from Epicenter Software, at http://icarus2.hsc. usc.edu/epicenter/gap.html) and POINTER (ftp://cedar.genetics. soton.ac.uk/pub/PROGRAMS/pointer/). These variety of soft- ware aimed to do CSA perform a maximum likelihood analysis to find the combination of the parameter listed above values which gives the largest overall likelihood for the observed data. Within the variety of models considered, it proceeds usually by testing a general non-restricted model, which contain the maxi- mum parameters that is fitted to the data and will give the best fit models of varying degrees of generality, both to determine whether a Mendelian locus is likely to exert a large effect on the phenotype of interest and to estimate the magnitude of genetic

sources of variation in the trait (Gail Pairitz J., 1998). This model

is then compared with restricted models such as the Mendelian

transmission models (Mendelian dominant, Mendelian recessive and Mendelian co-dominant), the environmental transmission model, and the polygenic or ‘no major gene model’. These mod- els are built by testing the genetic hypotheses by keeping the relevant parameters from d, t, q, and H constant, whereas the remaining parameters are estimated by maximizing the likeli-

hood of the phenotypes in the families.

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Mendelian models assume a major locus with two alleles that act either in a dominant, co-dominant or recessive fashion. The ‘no major gene’ model assumes that the baseline risk is not influenced by the risk trait (i.e. all persons have the same spe- cific risk of disease). The environmental model assumes that an individual’s phenotype depends on his or her environmental exposures and is independent of the phenotype of the parents. There are two parameters to test multifactorial heritability. The parameter H represents polygenic heritability in the offspring,

where H = C k /V, in which C k is the multifactorial component and

V is the overall variance. The second parameter is Z for which

H Z represents the multifactorial heritability in parents, where Z = C a /C k , the ratio of the multifactorial component in adults and children. Significant deviation of Z from 1 suggests a genera- tional difference in multifactorial heritability.

In segregation analysis, it is incorrect to assume that the gene

frequency is constant at all ages because any gene causing specific mortality must decrease with age. Risks (R) can then be determined using mortality figures that allow to calculate cu-

mulative mortalities and risk, so that the R j , the risk attributed

to the j th liability class, is

R j = (I j –M j - 1 )/(1–M j - 1 )

where I j is the cumulative incidence to the mid-point and M j - 1

is the cumulative specific mortality to the end of the preceding

class.

As we pointed above, models are compared by a likelihood ratio test. The difference between the minus twice the log likelihood plus a constant (-2lnL + k) calculated under a general model (with m parameters) and under a reduced model (with n pa-

rameters) is asymptotically distributed as χ 2 with m - n degrees of freedom. Another way to compare hypotheses is by using the Akaike information criterion (AIC) (Akaike HA, 1974). AIC is calculated as -2lnL + k plus twice the number of free parameters

in the model. The model with the lowest AIC is taken to give

the best fit to the data. Comparison by means of AIC values has the advantage that one model does not have to be a subset of the other so it can be used for examining non-nested models.

Finally, CSA not only allows to determine whether a major gene

is involved in a familial trait but also to predict the pattern of

inheritance of the hypothesized gene, the penetrance and the disease allele frequency. Taking the age-specific mortality into account, (Iselius et al., 1991) defined the penetrance in gene car- riers (G’) as the approximate cumulative incidence for gene car- riers in the j th liability class, given by the following:

P j = P (aff | G’, j) + [ l - P (aff | G’,j)] M’ j - 1

where the genotype-specific mortality is,

M’ j - 1 = ΣP(G’ | aff, i )(M i – M i - 1 ) / ΣP(P’| aff, i ) (I i – I i - 1 )

The aim of our study was to assess the contribution of genetic factors in AD in an unselected large number of Spanish families, and to investigate a possible Mendelian inheritance as explana- tion for the reported familial aggregation of AD.

Patients and methods

In a prospective study, we ascertained through probands 21 multigenerational extended pedigrees (297 individuals), with 76 individuals affected with Alzheimer´s disease fulfilling CERAD criteria. These families gave a total of 44 nuclear families to be included in the model. Information was gathered on the pro- bands themselves, as well as about the family history of two previous generations. Since probands were unable to give ac- curate answer to most questions, we interviewed the caregiver, usually a family member to ensure the accuracy of the informa- tion. Questions included the proband date of birth, sex, date of diagnosis, birthplace and birthplace of grandparents. The family history included any incidence of cognitive deterioration in the proband relatives, including cause and date of death for de- ceased relatives, cognitive status, type of cognitive status, date of diagnosis, and records of diagnosis.

CSA was carried out using the unified version of the mixed mod-

el of Morton and Mac-Lean (1974), implemented in the computer

program POINTER (Morton et al., 1971). We analyzed the fol-

lowing models: non transmission (cohort effect), multifactorial (polygenic and environmental), Mendelian (dominant, recessive, codominant), polygenic, mixed (Mendelian plus polygenic) and

a general model.

Liability classes

The POINTER program permits the construction of four male and

four female liability classes, which describe age specific risks. To take into account age-specific mortality, all individuals whose age was known at the time of ascertainment were assigned to one of four liability classes according to its age at ascertainment, diagnosis, or death (Table 2). The liability indicator was calcu-

lated as previously described

four classes were formed according to the age ranges given in Table 2. Cumulative incidence figures, to the mid-point of each class, were calculated given the rates per 100.000 as described in Bermejo (1987) and individuals were assigned to one of the four liability classes (<60 year-old; 60-69; 70-79; >80) (Table 2)

R j = (I j - M j - 1 )/(1 - M j - 1 ). Therefore,

according to their prior probability of affection based on the age

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specific prevalence rates for AD in Spain (Bermejo, 1987). Since the phenotypes were defined as dichotomies of affection status:

normal versus affected, the liability to affection represented by x can be defined by a threshold on the liability scale, such that affection occurs when x is greater than a given threshold.

Table 1. Age and sex-specific prevalences of AD in Spain based on data by Bermejo 1987.

Liability class

Age of onset (years)

Mortality rates per 100,00 population

I

<60

0.3

II

60-69

30

III

70-79

230

IV

>80

1,300

Ascertainment probability

The ascertainment probability (π), as used in POINTER, is ~0 if the probability of ascertaining a family increases in proportion to the number of affected offspring (single selection) and close

to 1 if the probability of ascertaining a family is independent of the number of affected offspring (complete selection). Since POINTER only accepts nuclear families as an input, extended pedigrees have to be analyzed by dividing them into their com- ponent nuclear families. Those nuclear families not containing affected probands though containing affected relatives of the “POINTER” (nominal probands) were codified in each sibling considering that the ascertainment probability value (π) is 1. Only nuclear families ascertained through pointers with at least one affected individual were included. This last approach was chosen because simulations and empirical results have shown similar results either including or not families with no affected members (Marazita et al., 1992). In this case, first-degree relatives of the proband were partitioned into nuclear families containing the proband as a parent (complete selection) or as a child (in- complete selection). There was only one proband in each family, and therefore an ascertainment probability (π) of 0.001 was used in the analysis, corresponding to single selection. Nevertheless, when all models are examined while varying the ascertainment probability over the range 0.001–0.2, the results found to be highly robust to changes in the specified ascertainment model (Figure 1).

to changes in the specified ascertainment model (Figure 1). Figure 1. Example of multigenerational extended family

Figure 1. Example of multigenerational extended family divided into nuclear families.

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Test of genetic heterogeneity

The data set consisting of all nuclear families was analyzed first in order to determine whether polygenic or major locus models would explain the occurrence of AD entirely. In a second step of the study, we analyzed those individuals whose DNA was avail- able to examine the APOE genotype. DNA was extracted from a blood sample using a phenol-chlorophorm extraction and etha- nol precipitation method (Beránek M., 2006). APOE genotype was determined by amplification of the exon 4 of APOE gene by polymerase chain reaction, followed by restriction fragment length polymorphism analysis using the restriction enzyme Hha I (Hixon JE, 1990). To determine whether the genetic background to AD was different depending on APOE genotype, overall data were subsequently analyzed in two subsets of families, those which have a proband APOE ε4 carrier versus those families whose proband was not an APOE ε4 carrier. Parameters for the polygenic, dominant, and recessive models were estimated separately in these two groups. Since the difference between the summed likelihoods in the partitioned analysis and the likeli- hood of the total data set is asymptotically distributed as χ 2 with p(g - 1) degrees of freedom, where p is the number of iterated parameters and g is the number of subgroups, heterogeneity χ 2 test (Khoury et al., 1993;Williams and Anderson, 1984) compared the sum of -2lnL of a particular model, computed on the subsets, with the -2lnL computed on the total 21 (44 nuclear families) families. This statistic was computed as follows: χ 2 = -2 [ΣlnL (best-fitted model/subgroup i) -lnL (bestfitted model/all family data)], where Σ is the sum overall i subgroups.

Results

The total number of individuals included in the study was 76 (23% males and 77% females) with an average age of onset of 70 years-old. The results from the CSA for all families are given in the Table 2. The familial aggregation of AD was not due to chance, since the sporadic model was rejected (χ 2 = 143 df = 1, P<0.001). All models incorporating a major gene for genetic transmission gave a better fit to these data than the multifac- torial model (χ 2 = 6 df = 1, p<0.025). The best fit among the Mendelian models was for the dominant model with a gene frequency of 0.0164 and a penetrance that increases with age (about 32.29% >80 years old, see Figure 2). When we examined the general model, we found that a gene explains the 66.7% of the heritability with t 2 = 0.18, that is below 0.5 what means that there are epistatic interactions. Penetrance of a hypothe- sized gene in homozygous or heterozygous carriers are 32.29% (>80 year-old); 27.88% (70-79 year-old); 25.44% (60-69 year-old); 2.37% (<60 year-old) (Figure 2).

Table 2. Results of CSA of the overall data. Parameter estimates corresponding to maximum likelihood models under each set of constraints are shown for each examined model.

Models

-2ln(L)

d

t

q

H

t1

t2

t3

Z

df

(1) no

transmisibility

321.97

(0)

(0)

(0)

(0)

-

-

-

-

8

(cohort effect)

(2) multi-factorial

179.02

(0)

(0)

(0)

0.105

-

-

-

(1)

7

(3) dominant

163.61

(1)

3.06

0.0164

(0)

(1.0)

(0.5)

(0.0)

(1)

6

(4) codominant

163.82

(0.5)

6.14

0.016

(0)

(1.0)

(0.5)

(0.0)

(1)

6

(5) recessive

176.48

(0)

3.0

0.176

(0)