Anda di halaman 1dari 49

Journal of Neurology and Neurocience

Editor in Chief Prof Jess Porta Etessam


Neurology Department. Hospital Universitario Clnico San Carlos, Madrid Faculdad de Medicina, Universidad Complutense de Madrid E-mail: jneuro@imedpub.com

http://www.jneuro.com/

v1
Where neurologists and neuroscientists publish together Published by IMedPub publishing house. ISSN: 2171-6625

2010

Content
Issue
1:2 1:3 1:4 1:5 2:1 2:2 2:3 2:4 3:1

http://www.jneuro.com/

Article
Migraine associated recurrent vertigo Epileptic seizures in neurodegenerative dementia syndromes Tc-MIBI muscle imaging and approach to assess functional anatomy of lower limb muscles
99m

Postural ocular pain due to orbital varix Pretectal syndrome caused by multiple sclerosis. Blood pressure changes in patients with migraine: Evidences, controversial views and potential mechanisms of comorbidity Acute Stroke in a 26 year old male Activity of serum Cathepsin D in Alzheimers disease Inheritance Of Alzheimers Disease Investigated By Complex Segregation Analysis

3:2

Clinical and functional description of a new form of autosomal recessive familial parkinsons disease with late onset

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/301

2010 Vol.1 No. 1:2

Migraine associated recurrent vertigo


Jess Porta-Etessam MD
Neurology Department. Hospital Clnico Universitario San Carlos. Madrid. Correspondence:Jess Porta-Etessam. C/ Andrs Torrejn, 15, 7. 28014 Madrid. Spain. E-mail jporta@yahoo.com, mporta@caminos.recol.es Phone: +34 667 062 4

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 literature. 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 becoming the most important reference document for the management 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 Cortazas short tale titled Cefalea (3). Although migraine patients mayn suffer different types of vertigo (table 1), MARV has its own specific clinical features. It is the third cause of consultation 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.

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

Delimiting MARV:
MARV differs from other vertigos present in migraine patients and from other types of recurrent vertigos. Most migraine patients 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 illusion 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
Under License of Creative Commons Attribution 3.0 License

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, typically 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
This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/301

2010 Vol.1 No. 1:2

gin of MARV. The duration of the episodes lasting even days without compensation, the lack of hypoacusia, fullness or tinnitus 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 effective 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 migraine with aura (11, 21). The vertigo attacks seem to respond to triptans (22). associated with migraine without aura (1). MARV not only differs 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, its well known the trigeminal innervations of the crista ampullaris, 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 subclinical vestibular alteration shown in migraine patients (11). Other explanation of vertigo in migraine patients is the cortical spreading 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 recurrent and chronic, the episodes last from hours to days, and both could be the result of peripheral or/and central neuronal mechanisms.

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, pathophysiology and treatment. Differential diagnosis should be make with benign positional vertigo, Meniere disease and basilar type migraine. 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 migraine. Brain 1984; 107: 11231142. 3) Cortazar J. Cefalea. En: Cortazar J. Cuentos completos. Madrid: Alfaguara. 1994; 134-143. 4) Porta-Etessam J, Martinez-Salio A, Berbel-Garca A, Ramos A, Milln 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. Vrtigo posicional paroxstico: Un sndrome para detectar, diagnosticar y solucionar. Neurologa 2004; 19: 495-496. 7) Olsson JE. Neurotologic findings in basilar migraine. Laryngoscope 1991; 101 (S52): 141. 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 Neurosurgery 2005; 108 :111-112.
This article is available from: http://www.jneuro.com

Neurons in lateral and medial vestibular nucleus respond to serotonin 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 participation 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 Under License of Creative Commons Attribution 3.0 License

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/301

2010 Vol.1 No. 1:2

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, Halmagyi GM (Eds) Disorders of the Vestibular System. Oxford 1996; 407-417. 12) Kluge M, Beyenburg S, Fernandez G, Elger CE. Epileptic vertigo: 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 serotonin 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 calcitonin 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 vertigo. 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, Lpez-de-Silanes C, Garca-Ramos R, Fernndez MJ. Neurology 2008:70, S1P05.036 19) Bisdorff AR. Treatment of migraine related vertigo with lamotrigine an observational study. Bull Soc Sci Med Grand Duche Luxemb. 2004; 2: 103-108. 20) Porta-Etessam J. Migraa y vertigo. In: Pascual J (Ed). Lectures 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. Zolmitriptan for treatment of migrainous vertigo: a pilot randomized placebo-controlled trial. Neurology. 2003; 60: 882-883. 23) Porta-Etessam J. Vrtigo asociado a la migraa. Rev Neurol 2007: 44; 490-493.

Publish with iMedPub Journals http://www.imedpub.com


Journal of Neurology and Neuroscience (JNeuro.com) is a hybrid, peer-reviewed journal that considers articles concerned with any aspect of clinical neurosciences such as neurology, psyciatry and neurosurgery, as well as basic research on neuroscience. Where neurologists and neuroscientists publish together.

Submit your manuscript here:

http://www.jneuro.com

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/302

2010 Vol.1 No. 1:3

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 Alzheimers disease compared to age-matched controls. Seizures also occur in prion disorders and some frontotemporal lobar degeneration syndromes, whereas parkinsonian dementia disorders seem relatively seizure free. Seizure pathogenesis in these conditions is uncertain, but may relate to neocortical and hippocampal hyperexcitability and synchronised activity, possibly as a consequence of dysfunctional protein metabolism, neuronal structural changes, and concurrent cerebrovascular disease. Alzheimers 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 dementia 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 characterised as an acquired impairment of cognitive functions, particularly memory, sufficient to interfere with social and occupational functioning (American Psychiatric Association, 2000). In addition to cognitive and functional decline, dementia syndromes 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 Alzheimers disease (AD) is the most common identified cause. Likewise, the differential diagnosis of cognitive deficits associated 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 seizures, 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 (Hgh 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 incidence 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 common dementia subtypes do not mention epileptic seizures, even as an exclusion criterion (Romn et al., 1993; McKeith et
Under License of Creative Commons Attribution 3.0 License

al., 1996, 1999; Neary et al., 1998; World Health Organisation, 1998; McKhann et al., 2001; Emre et al., 2007). This article briefly reviews seizure phenomena which have been reported in association with the common neurodegenerative dementia syndromes, specifically AD, frontotemporal lobar degeneration syndromes, Parkinsons disease dementia and dementia with Lewy bodies, prion diseases, and Huntingtons disease. Because of the pathological overlap between neurodegenerative disease and cerebrovascular changes, especially in AD, seizures in vascular dementia are also considered. Some brief comments on the management of seizures in neurodegenerative dementias are appended.

Seizures in Alzheimers disease


Epileptic seizures in AD have recently been extensively reviewed (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 1022% 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 incidence 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 seizures seem to predominate, presumably secondarily generalised from a partial seizure focus (Mendez & Lim, 2003). Complex partial seizures may also occur, although they may be underrecognised in the context of a progressive dementia (Rao et al., 2009).

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/302

2010 Vol.1 No. 1:3

The widely-accepted NINCDS-ADRDA clinical diagnostic criteria 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 uncertain 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 investigate 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 disease with a threshold of 65 years of age (McKhann et al., 1984), although there is scant evidence to suggest any biological difference in these entities. The relative risk of seizures is markedly 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 mutations 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). Downs syndrome (trisomy 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 seizures in AD (Palop & Mucke, 2009; Larner 2010). The amyloid hypothesis of AD pathogenesis suggests that altered metabolism 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 component 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 neuronal sprouting, may facilitate development of recurrent hypersynchronous discharges underpinning seizure activity. Tau deficient transgenic mice do not develop aberrant network activity despite excessive A_ (Roberson et al., 2007). Changes in neurotransmitter 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 variant frontotemporal dementia) and linguistic syndromes, the latter characterised by either non-fluent output with relatively preserved comprehension (progressive non-fluent aphasia) or
Under License of Creative Commons Attribution 3.0 License

fluent output with impaired comprehension (semantic dementia). Clinical or subclinical evidence of motor neurone disease may be found in some FTLD cases. Movement disorders associated with cognitive impairment such as progressive supranuclear 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 criteria (Neary et al., 1998), in contradistinction to AD in which EEG changes, particularly slowing of background rhythms, are common (Stam, 2006), particularly in the later stages of the disease. 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 exception 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 (CoreyBloom 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 proteinopathies (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 chromosome 17 (FTDP-17) may result from mutations in genes encoding 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 prominent 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, Parkinsons disease dementia, and other parkinsonian 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 associated with Parkinsons disease which has similar neuropsychological 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 (McKeith et al., 1996) these are not epileptic seizures, but are more likely to be related to the autonomic dysfunction which is common in this condition (Horimoto et al., 2003).
This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/302

2010 Vol.1 No. 1:3

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 literature 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 disorders.

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 recognised 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 increased 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 (Cordonnier 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 study 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 prion diseases


Prion diseases may be of sporadic, inherited or iatrogenic aetiology. Seizures have been reported in sporadic Creutzfeldt-Jakob disease (Cokgor et al., 1999), sometimes as the presenting feature, 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; Karatas et al., 2007) all reported. Localization-related seizures have been reported as the first presentation of variant CJD (Silverdale et al., 2000) but this would seem to be a rare or even exceptional event (Spencer et al., 2002). Since loss of the cellular prion protein has been reported to be associated with enhanced sensitivity to seizures, with neocortical and hippocampal hyperexcitability and synchronised activity (Walz et al., 2002), it is possible that prion disorders may resemble AD as neuronal network disorders clinically characterised by both cognitive decline and epileptic activity.

Seizures in Huntingtons disease


Chorea and a subcortical dementia are the classic features of Huntingtons disease (HD) associated with trinucleotide repeat expansions in the IT15 gene on chromosome 4. Epileptic seizures 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 phenotype should prompt consideration of the diagnosis of dentatorubral-pallidoluysian atrophy, in which condition seizures are much more common than in HD (Egawa et al., 2008).

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 patient. In AD, the neurodegenerative dementia most likely to be complicated with epileptic seizures, anti-epileptic drug (AED) therapy 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 demented individuals is often uncertain, although partial onset seizures with or without secondary generalisation are probably the most common (Mendez & Lim, 2003). Since AD prevalence 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 interactions. Use of AEDs with known cognitive and behavioural adverse effects (e.g. phenobarbitone, primidone, phenytoin, topiramate) may be considered undesirable in dementia syndromes.
This article is available from: http://www.jneuro.com

Seizures in vascular dementias and vascular cognitive 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 seizures, 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 Under License of Creative Commons Attribution 3.0 License

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/302

2010 Vol.1 No. 1:3

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 advanced 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 tolerability (Belcastro et al., 2007).

References
Amatniek JC, Hauser WA, DelCastillo-Castaneda C, Jacobs DM, Marder K, Bell K, Albert M, Brandt J, Stern Y. (2006) Incidence and predictors of seizures in patients with Alzheimers disease. Epilepsia 47:867-872. American Psychiatric Association. (2000) Diagnostic and statistical manual of mental disorders, 4th edition, text revison (DSM-IV-TR). Washington: American Psychiatric Association. Aronyk K, Petito F, Solomon GE. (1984) Partial elementary motor seizures as the first symptom of Creutzfeldt-Jakob disease. Ann Neurol 15: 210-211. Barker RA, Squitieri F. (2009) The clinical phenotype of juvenile Huntingtons disease. In: Quarrell OWJ, Brewer HM, Squitieri F, Barker RA, Nance MA, Landwehrmeyer GB (eds.). Juvenile Huntingtons disease and other trinucleotide repeat disorders. Oxford: Oxford University Press, pp 39-50 [esp. 45-46]. Belcastro V, Costa C, Galletti F, Pisani F, Calabresi P, Parnetti L. (2007) Levetiracetam monotherapy in Alzheimer patients with late-onset seizures: a prospective observational study. Eur. J. Neurol. 14:11761178. Blake RV, Wroe SJ, Breen EK, McCarthy RA. (2000) Accelerated forgetting in patients with epilepsy: evidence for an impairment in memory consolidation. Brain 123:472-483. Blass DM, Hatanpaa KJ, Brandt J, Rao V, Steinberg M, Troncoso JC, Rabins PV. (2004) Dementia in hippocampal sclerosis resembles frontotemporal dementia more than Alzheimer disease. Neurology 63:492-497. Cabrejo L, Guyant-Marchal L, Laquerrire A, Vercelletto M, De la Fournire F, Thomas-Anterion C, Verny C, Letournel F, Pasquier F, Vital A, Checler F, Frebourg T, Campion D, Hannequin D. (2006) Phenotype associated with APP duplication in five families. Brain 129:2966-2976. Cairns NJ, Bigio EH, Mackenzie IR, Neumann M, Lee VM, Hatanpaa KJ, White CL, Schneider JA, Grinberg LT, Halliday G, Duyckaerts C, Lowe JS, Holm IE, Tolnay M, Okamoto K, Yokoo H, Murayama S, Woulfe J, Munoz DG, Dickson DW, Ince PG, Trojanowski JQ, Mann DM, Consortium for Frontotemporal Lobar Degeneration. (2007) Neuropathologic diagnostic and nosologic criteria for frontotemporal lobar degeneration: consensus of the Consortium for Frontotemporal Lobar Degeneration. Acta Neuropathol. 114:5-22. Chan D, Walters RJ, Sampson EL, Schott JM, Smith SJ, Rossor MN. (2004) EEG abnormalities in frontotemporal lobar degeneration. Neurology 62:1628-1630. Cohen D, Kutluay E, Edwards J, Peltier A, Beydoun A. (2004) Sporadic Creutzfeldt-Jakob disease presenting with nonconvulsive status epilepticus. Epilepsy Behav. 5:792-796. Cokgor I, Rozear M, Morgenlander JC. (1999) Seizures and CreutzfeldtJakob disease. A case report and series review. N. C. Med. J. 60:108109. Cordonnier C, Hnon H, Derambure P, Pasquier F, Leys D. (2005) Influence of pre-existing dementia on the risk of post-stroke epileptic seizures. J. Neurol. Neurosurg. Psychiatry 76:1649-1653. Cordonnier C, Hnon H, Derambure P, Pasquier F, Leys D. (2007) Early epileptic seizures after stroke are associated with increased risk of new-onset dementia. J. Neurol. Neurosurg. Psychiatry 78:514-516. Corey-Bloom J, Sabbagh MN, Bondi MW, Hansen L, Alford MF, Masliah E, Thal LJ. (1997) Hippocampal sclerosis contributes to dementia in the elderly. Neurology 48:154-160. Egawa K, Takahashi Y, Kubota Y, Kubota H, Inoue Y, Fujiwara T, Onodera O. (2008) Electroclinical features of epilepsy in patients with juvenile type dentatorubral-pallidoluysian atrophy. Epilepsia 49:2041-2049. Emre M, Aarsland D, Brown R, Burn DJ, Duyckaerts C, Mizuno Y, Broe GA, Cummings J, Dickson DW, Gauthier S, Goldman J, Goetz C, Korczyn A, Lees A, Levy R, Litvan I, McKeith I, Olanow W, Poewe W, Quinn N, Sampaio C, Tolosa E, Dubois B. (2007) Clinical diagnostic criteria for dementia associated with Parkinsons disease. Mov. Disord. 22:16891707.
This article is available from: http://www.jneuro.com

Discussion
Although the clinical observation of seizures in dementia syndromes, particularly AD, is long established, there have been few systematic studies of seizures in these conditions. Mechanisms underlying seizure pathogenesis are unresolved, but recent studies raise the possibility, particularly in AD and possibly in prion disease, that seizures are related to the same pathogenetic 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 facilitate 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 valproate (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.

Under License of Creative Commons Attribution 3.0 License

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/302

2010 Vol.1 No. 1:3

Fernandez-Torre JL, Solar DM, Astudillo A, Cereceda R, Acebes A, Calatayud MT. (2004) Creutzfeldt-Jakob disease and non-convulsive status epilepticus: a clinical and electroencephalographic follow-up study. Clin. Neurophysiol. 115:316-319. Forsgren L, Bucht G, Eriksson S, Bergmark L. (1996) Incidence and clinical characterization of unprovoked seizures in adults: a prospective population-based study. Epilepsia 37:224-229. Guerrini R, Aicardi J, Andermann F, Hallett M (eds.). (2002) Epilepsy and movement disorders. Cambridge: Cambridge University Press. Hatanpaa KJ, Blass DM, Pletnikova O, Crain BJ, Bigio EH, Hedreen JC, White CL, Troncoso JC. (2004) Most cases of dementia with hippocampal sclerosis may represent frontotemporal dementia. Neurology 63:538-542. Hgh P, Smith SJ, Scahill RI, Chan D, Harvey RJ, Fox NC, Rossor MN. (2002) Epilepsy presenting as AD: neuroimaging, electroclinical features, and response to treatment. Neurology 58:298-301. Horimoto Y, Matsumoto M, Akatsu H, Ikari H, Kojima K, Yamamoto T, Otsuka Y, Ojika K, Ueda R, Kosaka K. (2003) Autonomic dysfunction in dementia with Lewy bodies. J. Neurol. 250:530-533. Karatas H, Dericioglu N, Kursun O, Saygi S. (2007) Creutzfeldt-Jakob disease presenting as hyperparathyroidism and generalized tonic status epilepticus. Clin. EEG Neurosci. 38:203-206. Kertesz A, Munoz DG (eds.). (1998) Picks disease and Pick complex. Chichester: Wiley. Larner AJ. (2008) Neuropsychological neurology. The neurocognitive impairments of neurological disorders. Cambridge: Cambridge University Press. Larner AJ. (2010) Epileptic seizures in AD patients. NeuroMolecular Med. 12:in press.doi:10.1007/s12017-009-8076-z Larner AJ, Doran M. (2009a) Genotype-phenotype relationships of presenilin-1 mutations in Alzheimers disease: an update. J. Alzheimers Dis. 14:259-265. Larner AJ, Doran M. (2009b) Clinical heterogeneity associated with tau gene mutations. European Neurological Review 3(2):31-32. Leverenz JB, Agustin CM, Tsuang D, Peskind ER, Edland SD, Nochlin D, DiGiacomo L, Bowen JD, McCormick WC, Teri L, Raskind MA, Kukull WA, Larson EB. (2002) Clinical and neuropathological characteristics of hippocampal sclerosis. A community-based study. Arch. Neurol. 59:1099-1106. Loring DW, Marino S, Meador KJ. (2007) Neuropsychological and behavioural effects of antiepilepsy drugs. Neuropsychol. Rev. 17:413425. Lozsadi DA, Larner AJ. (2006) Prevalence and causes of seizures at the time of diagnosis of probable Alzheimers disease. Dement. Geriatr. Cogn. Disord. 22:121-124. Mackenzie IRA, Neumann M, Bigio EH, Cairns NJ, Alafuzoff I, Kril J, Kovacs GG, Ghetti B, Halliday G, Holm IE, Ince PG, Kamphorst W, Revesz T, Rozemuller AJM, Kumar-Singh S, Akiyama H, Baborie A, Spina S, Dickson DW, Trojanowski JQ, Mann DMA. (2009) Nomenclature for neuropathologic subtypes of frontotemporal lobar degeneration: consensus recommendations. Acta Neuropathol. 117:15-18. McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, Salmon DP, Lowe J, Mirra SS, Byrne EJ, Lennox G, Quinn NP, Edwardson JA, Ince PG, Bergeron C, Burns A, Miller BL, Lovestone S, Collerton D, Jansen EN, Ballard C, de Vos RA, Wilcock GK, Jellinger KA, Perry RH. (1996) Consensus guidelines for the clinical and pathologic diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 47:1113-1124. McKeith IG, Perry EK, Perry RH for the Consortium on Dementia with Lewy Bodies (1999) Report of the second dementia with Lewy body international workshop. Neurology 53:902-905. McKhann GM, Albert MS, Grossman M, Miller B, Dickson D, Trojanowski JQ. (2001) Clinical and pathological diagnosis of frontotemporal dementia. Report of the Work Group on Frontotemporal Dementia and Picks disease. Arch. Neurol. 58:1803-1809.
Under License of Creative Commons Attribution 3.0 License

McKhann G, Drachman D, Folstein M, Katzman R, Price D, Stadlan EM. (1984) Clinical diagnosis of Alzheimers disease. Report of the NINCDS-ADRDA work group under the auspices of the Department of Health and Human Service Task forces on Alzheimers disease. Neurology 34:939-944. Mendez MF, Catanzaro P, Doss RC, Arguello R, Frey WH. (1994) Seizures in Alzheimers disease: clinicopathologic study. J. Geriatr. Psychiatry Neurol. 7:230-233. Mendez MF, Cummings JL. (2003) Dementia. A clinical approach (3rd edition). Philadelphia: Butterworth Heinemann. Mendez MF, Lim GTH. (2003) Seizures in elderly patients with dementia: epidemiology and management. Drugs Aging 20:791-803. MRC CFAS. (2001) Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study. Lancet 357:169-175. Neary D, Snowden JS, Gustafson L, Passant U, Stuss D, Black S, Freedman M, Kertesz A, Robert PH, Albert M, Boone K, Miller BL, Cummings J, Benson DF. (1998) Frontotemporal lobar degeneration: a consensus on clinical diagnostic criteria. Neurology 51:1546-1554. Neufeld MY, Talianski-Aronov A, Soffer D, Korczyn AD. (2003) Generalized convulsive status epilepticus in Creutzfeldt-Jakob disease. Seizure 12:403-405. Nygaard TG, Duvoisin RC, Manocha M, Chokroverty S. (1989) Seizures in progressive supranuclear palsy. Neurology 39:138-140. Palop JJ, Chin J, Roberson ED, Wang J, Thwin MT, Bien-Ly N, Yoo J, Ho KO, Yu GQ, Kreitzer A, Finkbeiner S, Noebels JL, Mucke L. (2007) Aberrant excitatory neuronal activity and compensatory remodelling of inhibitory hippocampal circuits in mouse models of Alzheimers disease. Neuron 55:697-711. Palop JJ, Mucke L. (2009) Epilepsy and cognitive impairments in Alzheimer disease. Arch. Neurol. 66:435-440. Puri BK, Ho KW, Singh I. (2001) Age of seizure onset in adults with Downs syndrome. Int. J. Clin. Pract. 55:442-444. Qing H, He G, Ly PT,Fox CJ, Staufenbiel M, Cai F, Zhang Z, Wei S, Sun X, Chen CH, Zhou W, Wang K, Song W. (2008) Valproic acid inhibits Abeta production, neuritic plaque formation, and behavioral deficits in Alzheimers disease mouse models. J. Exp. Med. 205:2781-2789. Rao SC, Dove G, Cascino GD, Petersen RC. (2009) Recurrent seizures in patients with dementia: frequency, seizure types, and treatment outcome. Epilepsy Behav. 14:118-120. Rees JH, Smith SJ, Kullmann DM, Hirsch NP, Howard RS. (1999) Creutzfeldt-Jakob disease presenting as complex partial status epilepticus: a report of two cases. J. Neurol. Neurosurg. Psychiatry 66: 406-407. Roberson ED, Scearce-Levie K, Palop JJ, Yan F, Cheng IH, Wu T, Gerstein H, Yu GQ, Mucke L. (2007) Reducing endogenous tau ameliorates amyloid _-induced deficits in an Alzheimers disease mouse model. Science 316:750-754. Romn GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A. (1993) Vascular dementia: diagnostic criteria for research studies. Report of the NINDSAIREN international workshop. Neurology 43:250-260. Schon F, Martin RJ, Prevett M, Clough C, Enevoldson TP, Markus HS. (2003) CADASIL coma: an underdiagnosed acute encephalopathy. J. Neurol. Neurosurg. Psychiatry 74:249-252. Silverdale M, Leach JP, Chadwick DW. (2000) New variant CreutzfeldtJakob disease presenting as loclaization-related epilepsy. Neurology 54:2188. Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. (1997) Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277:813-817. Spencer MD, Knight RS, Will RG. (2002) First hundred cases of variant Creutzfeldt-Jakob disease: retrospective case note review or early psychiatric and neurological features. BMJ 324:1479-1482.
This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/302

2010 Vol.1 No. 1:3

Sperfeld AD, Collatz MB, Baier H, Palmbach M, Storch A, Schwarz J, Tatsch K, Reske S, Joosse M, Heutink P, Ludolph AC. (1999) FTDP-17: an early-onset phenotype with parkinsonism and epileptic seizures caused by a novel mutation. Ann. Neurol. 46:708-715. Stam CJ. (2006) Modern applications of electroencephalography in dementia diagnosis. In: Gauthier S, Scheltens P, Cummings JL (eds.). Alzheimers disease and related disorders annual 5. London: Taylor & Francis, 191-206 Vaz J, Sierazdan K, Kane N. (2005) Non convulsive status epilepticus in Creutzfeldt-Jakob disease a short report. J. Neurol. Neurosurg. Psychiatry 76:1318 (abstract 030). Wahlund L-O, Erkinjuntti T, Gauthier S (eds.). (2009) Vascular cognitive impairment in clinical practice. Cambridge: Cambridge University Press. Walz R, Castro RM, Velasco TR, Carlotti CG, Sakamoto AC, Brentani RR, Martins VR. (2002) Cellular prion protein: implications in seizures and epilepsy. Cell. Mol. Neurobiol. 22:249-257. World Health Organisation. (1998) Human transmissible spongiform encephalopathies. Wkly. Epidemiol. Rec. 73:361-372. Yamanouchi H, Budka H, Vass K. (1986) Unilateral Creutzfeldt-Jakob disease. Neurology 36:1517-1520. Zeman A. (2009) When a patient with epilepsy complains about poor memory. Practical Neurology 9: 85-89.

Publish with iMedPub Journals http://www.imedpub.com


Journal of Neurology and Neuroscience (JNeuro.com) is a hybrid, peer-reviewed journal that considers articles concerned with any aspect of clinical neurosciences such as neurology, psyciatry and neurosurgery, as well as basic research on neuroscience. Where neurologists and neuroscientists publish together.

Submit your manuscript here:

http://www.jneuro.com

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/303

2010 Vol.1 No. 1:4

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

Jos A. Ariasa,b, Susana Garcac, Mara L. Cuadradod, Carlos Pardoc, Gregoria Lapeac, Jos L. Carrerase
a Nuclear Medicine Department, Hospital Ramn y Cajal, Madrid, Spain. b School of Medicine, Universidad Alfonso X el Sabio, Villanueva de la Caada, Madrid, Spain. c Nuclear Medicine Department, Fundacin Jimnez Daz, Madrid, Spain. d Neurology Department, Hospital Clnico San Carlos, Universidad Complutense, Madrid, Spain. e Nuclear Medicine Department, Hospital Clnico San Carlos, Universidad Complutense, Madrid, Spain. Institution where the study was performed: Fundacin Jimnez Daz, Madrid, Spain. Correspondence to: Jose A. Arias, School of Medicine, Universidad Alfonso X el Sabio, Avda de la Universidad, 1 28691 Villanueva de la Caada (Madrid) Spain E-mail: josari@uax.es Tel.: +34 9181099975 Fax: +34 918105289

ABSTRACT: 99mTc hexakis-2-methoxyisobutyl-isonitrile (99mTc-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 99mTc-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. 99mTc-MIBI scintigraphic imaging might be a useful technique to assess the functional anatomy of lower limb muscles.

Introduction
Tc hexakis-2-methoxyisobutyl isonitrile (99mTc-MIBI) is a radiopharmaceutical which has been widely used for in vivo imaging of myocardial perfusion [1,2] and, less frequently, for evaluation of tumor processes[3,4]. 99mTc-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 skeletal muscles.
99m

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 photon emission computed tomographic (SPECT) study with 99mTcMIBI 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 metabolism, such as diabetes mellitus, were excluded. Subclinical or masked effects of cardiovascular disease in the lower extremities 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 elsewhere [22]. Briefly, conventional rest and post stress (treadmill exercise) SPECT studies were acquired after an intravenous administration of 740-925 MBq of 99mTc-MIBI (Cardiolite, Bristol-Myers Pharma, Brussels, Belgium) prepared according to the manufacturers instructions. Ten minutes after conventional myocardial tomographic studies, planar images were obtained from the lower extremities with a dual head whole-body gamma 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 obtained for 5 minutes in 256 x 256 pixel matrices, with the pixel
This article is available from: http://www.jneuro.com

A few studies have investigated the potential role of skeletal muscle imaging with 99mTc-MIBI in the assessment of peripheral 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 propionyl-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. Besides, technical limitations of former devices -i.e. insufficient spatial resolution- might have restricted the use of 99mTc-MIBI as a skeletal muscle tracer. In the present study, we test: 1) whether muscular morphological data can be obtained from 99mTc-MIBI scintigraphic images, and 2) the association between 99mc-MIBI muscular uptake and some physiological parameters obtained during exercise.

Under License of Creative Commons Attribution 3.0 License

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/301

2010 Vol.1 No. 1:2

width being 2.1 mm. Close to the surface of the patient, theoretical 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]

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), adductors, sartorius, quadriceps femoris, glutaeus maximus, semitendinosus, 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 recognizable. From a qualitative point of view, the muscles were more visibly depicted after exercise, specially in the calves. From a quantitative point of view, muscle exercise significantly increased 99mTc-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 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 99mTc-MIBI muscle scintigraphy with former devices, but current equipment has allowed us to get rather sharp images of skeletal muscles. Moreover, 99mTc-MIBI muscle imaging could be further improved by increasing the time of acquisition of planar images or by getting tomographic images with SPECT.
99m

RS =
and it equals 4.3 mm.

2 R C + R I2

Image analysis and interpretation Visual evaluation was performed comparing scintigraphic images 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 specialist in nuclear medicine (JAA), and a consensus on anatomical 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 difference 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.

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.

We have made use of 99mTc-MIBI muscle scintigraphy in a group of patients who were free of muscle disease. In this setting, 99mTc-MIBI has provided us with anatomical information, as major 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 quantitative change of 99mTc-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 99mTc-MIBI uptake 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 99mTc-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 99mTc-MIBI scintigraphy has not been thoroughly investigated for clinical purposes. Due to the pharmacokinetical properties of 99mTc-MIBI, this technique might be particularly suitable for the assessment of mitochondrial diseases. In fact, a cardiac decrease of 99mTc-MIBI-uptake has already been demonstrated when the heart is involved in some mitochondrial gene abnormalities [26-28]. It would be worth exploring any potential applications of rest and exercise 99mTc-MIBI imaging in the evaluation of different myopathies.

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 during exercise. Statistical analysis For each region of interest, values of uptake at rest and exercise were compared making use of the one-tailed paired Students t-test. Correlation between variables was analyzed by means of the Pearson coefficient.

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/301

2010 Vol.1 No. 1:2

Figure 2. 99mTc-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 gastrocnemius. (B) Posterior view of the calves: Gt, gastrocnemius (caput mediale and caput laterale); Sl, soleus.
99mTc-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 simple; 2) it has much lower cost, and 3) it provides different metabolic information, since 99mTc-MIBI is a mitochondrial tracer and does not follow the route of 18F-fluoro-deoxy-glucose, i.e. the usual tracer in PET.

Conclusion
99mTc-MIBI scintigraphic imaging is a simple procedure that provides both anatomical and functional information about skeletal muscles. Further research is needed to ascertain any potential clinical applications of 99mTc-MIBI for tracing muscular disorders.

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

References
1. Verani MS. Thallium-201 and technetium-99m perfusion agents: where we are in 1992. In: Zaret BL, Beller GA, editors. Nuclear cardiology: state of the art and future directions. St. Louis: Mosby; 1993. p. 216-224. 2. Kapur A, Latus KA, Davies G, Dhawan RT, Eastick S, Jarritt PH, Roussakis G, Young MC, Anagnostopoulos C, Bomanji J, Costa DC, Pennell DJ,
Under License of Creative Commons Attribution 3.0 License

Prvulovich EM, Ell PJ, Underwood SR. A comparison of three radionuclide myocardial perfusion tracers in clinical practice: the ROBUST study. Eur J Nucl Med 2002; 29:1608-1616. 3. Burak Z, Ersoy , Moretti JL, Erin R, zcan Z, Dirlik A, Sabah D, Basdemir G. The role of 99mTc-MIBI scintigraphy in the assessment of MDR1 overexpresion in patients with musculoskeletal sarcomas: comparison with therapy response. Eur J Nucl Med 2001; 28:1341-1350. 4. Schmaker K, Schicha H. Use of myocardial imaging agents for tumour diagnosis a success story? Eur J Nucl Med 2000; 27:1845-1863. 5. Arbab AS, Koizumi K, Toyama K, Arai T, Araki T. Effects of ion channel modulators in the influx and efflux of Tc-99m-MIBI. Ann Nucl Med 1999; 13:27-32. 6. Piwnica-Worms DP, Kronauge JF, LeFurgey A, Backus M, Hockett D, Ingram P, Lieberman M, Holman BL, Jones AG, Davison A. Mitochondrial localization and characterization of 99Tc-SESTAMIBI in heart cells by electron probe X-ray microanalysis and 99Tc-NMR spectroscopy. Magn Reson Imaging 1994; 12:641-652. 7. Piwnica-Worms DP, Kronauge JF, Chiu ML. Uptake and retention of hexakis (2-methoxyisobutylisonitrile) technetium (I) in cultured chick myocardial cells. Mitochondrial and plasma membrane potential dependence. Circulation 1990; 82:1826-1838. 8. Sayman HB, Urgancioglu I. Muscle perfusion with technetium-MIBI in lower extremity peripheral arterial diseases. J Nucl Med 1991; 32:1700-1703. 9. Wann LS, Hellman C, Dorros G. Evaluation of leg perfusion during exercise using technetium 99m sestamibi. A new test for peripheral vascular disease. Echocardiography 1992; 9:547-552. 10. Miles KA, Barber RW, Wraight EP, Cooper M, Appleton DS. Leg muscle scintigraphy with 99mTc-MIBI in the assessment of peripheral vascular (arterial) disease. Nucl Med Commun 1992; 13:593-603. 11. Bostrom PA, Diemer H, Leide S, Lilja B, Bergqvist D. 99mTc-sestamibi uptake in the leg muscles and in the myocardium in patients with intermittent claudication. Angiology 1993; 44:971-976. 12. Bajnok L, Kozlovsky B, Varga J, Antalffy J, Olvaszto S, Fulop T. Technetium-99m sestamibi scintigraphy for the assessment of lower extremity ischaemia in peripheral arterial disease. Eur J Nucl Med 1994; 21:1326-1332. 13. Celen YZ, Zincirkeser S, Akdemir I, Yilmaz M. Investigation of perfusion reserve using 99mTc-MIBI in the lower limbs of diabetic patients. Nucl Med Commun 2000; 21:817-822. 14. Edwards PD, Miles KA, Owens SJ, Kemp PM, Jenner JR. A new noninvasive test for the detection of compartment syndromes. Nucl Med Commun 1999; 20:215-218. 15. Sarikaya A, Sen S, ermik TF, Birtane M, Berkarda _. Evaluation of skeletal muscle metabolism and response to erythropoietin treatment in patients with chronic renal failure using 99mTc-sestamibi leg scintigraphy. Nucl Med Commun 2000; 21:83-87. 16. Lupatelli G, Palumbo B, Sinzinger H. Statin induced myopathy does not show up in MIBI scintigraphy. Nucl Med Commun 2001; 22:575578. 17. Banci M, Rinaldi E, Ierardi M, Tiberio NS, Boccabella GL, Barbieri C, Scopinaro F, Morelli S, DeSantis M. 99mTc SESTAMIBI scintigraphic evaluation of skeletal muscle disease in patients with systemic sclerosis: diagnostic reliability and comparison with cardiac function and perfusion. Angiology 1998; 49:641-648. 18. Scopinaro F, Manni C, Miccheli A, Massa R, De Vicentis G, Schillaci O, Ierardi M, Danieli R, Banci M, Iorio F. Muscular uptake of Tc-99m MIBI and Tl-201 in Duchenne muscular dystrophy. Clin Nucl Med 1996; 21:792-796. 19. Chang YY, Lan MY, Wu HS, Huang SH, Chen SS, Liu JS. Decreased muscular radionuclide uptake in Tc-99m MIBI scintigraphy during paralytic phase of thyrotoxic periodic paralysis. Clin Nucl Med 2008;33:297-298. 20. Cittanti C, Colamussi P, Giganti M, Orlandi C, Uccelli L, Manfrini S, Azzena G, Piffanelli A. Technetium-99m sestamibi leg scintigraphy for non-invasive assessment of propionyl-L-carnitine induced changes in
This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/301

2010 Vol.1 No. 1:2

skeletal muscle metabolism. Eur J Nucl Med 1997; 24:762-766. 21. Pekindil Y, Sarikaya A, Birtane M, Pekindil G, Salan A. 99mTc-sestamibi muscle scintigraphy to assess the response to neuromuscular electrical stimulation of normal quadriceps femoris muscle. Ann Nucl Med 2001; 15:397-401. 22. Muxi A, Magria J, Pavia J. Myocardial perfusion SPECT. Technical aspects. In: Martin-Comin J, Castell J, Muxi A, editors. Why should you ask for a myocardial perfusion SPECT? Barcelona: Masson, 2002. p. 6-14. 23. Chandra R. Introductory physics of nuclear medicine. Philadelphia: Lea & Febiger, 1992. 24. Netter FH. Atlas of human anatomy. Summit: Ciba, 1996. 25. Plas F, Viel E, Blanc Y. La marche humaine: kinsiologie dynamique, biomcanique et fatherland. Paris: Masson, 1989. 26. Ikawa M, Kawai Y, Arakawa K, Tsuchida T, Miyamori I, Kuriyama M, Tanaka M, Yoneda M. Evaluation of respiratory chain failure in mitochondrial cardiomyopathy by assessments of 99mTc-MIBI washout and 123I-BMIPP/99mTc-MIBI mismatch. Mitochondrion 2007; 7: 164-170. 27. Matsuo S, Nakajima K, Kinuya S, Sato Y, Matsumoto N, Horie M, Cardiac scintigraphic findings of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes: A case report. Exp Cli Cardiol 2008; 13: 93-95. 28. Yajima N, Yazaki Y, Yoshida K, Sano K, Takahashi W, Sasaki Y, Ikeda U. A case of mitochondrial cardiomyopathy with pericardial effusion evaluated by (99m)Tc-MIBI myocardial scintigraphy. J Nucl Cardiol 2009; 16: 989-994. 29. Iemitsu M, Itoh M, Fujimoto T, Tashiro M, Nagatomi R, Ohmori H, Ishii K. Whole-body energy mapping under physical exercise using positron emission tomography. Med Sci Sports Exerc 2000; 32:2067-2070. 30. Vanderthommen M, Depresseux JC, Dauchat L, Degueldre C, Croisier JL, Crielaard JM. Spatial distribution of blood flow in electrically stimulated human muscle: a positron emission tomography study. Muscle Nerve 2000; 23:482-489. 31. Pappas GP, Olcott EW, Dracle JE. Imaging of skeletal muscle function using 18FDG PET: force production, activation, and metabolism. J Appl Physiol 2001; 90:329-337. 32. Fujimoto T, Kemppainen J, Kalliokoski KK, Nuutila P, Ito M, Knuuti J. Skeletal muscle glucose uptake response to exercise in trained and untrained men. Med Sci Sports Exerc 2003; 35:777-783. 33. Oi N, Iwaya T, Itoh M, Yamaguchi K, Tobimatsu Y, Fujimoto T. FDGPET imaging of lower extremity muscular activity during level walking. J Orthop Sci 2003; 8:55-61.

Publish with iMedPub Journals http://www.imedpub.com


Journal of Neurology and Neuroscience (JNeuro.com) is a hybrid, peer-reviewed journal that considers articles concerned with any aspect of clinical neurosciences such as neurology, psyciatry and neurosurgery, as well as basic research on neuroscience. Where neurologists and neuroscientists publish together.

Submit your manuscript here:

http://www.jneuro.com

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/303

2010 Vol.1 No. 1:5

Postural ocular pain due to orbital varix


Casanova-Peo I, Gmez-Vicente L, Cuadrado ML, Porta-Etessam J Neurology Department. Hospital Clnico San Carlos. Madrid. Spain.
Correspondence to: Jess Porta-Etessam C/ Andrs Torrejn, 15, 7 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 venous 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 retrobulbar 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 abnormalities resulting from the pathological enlargement of one or more venous channels of the orbit (1, 2). The clinical syndrome is usually characterized by intermittent filling and emptying of the varix, resulting in variable proptosis. In infants, eye bulging during crying or orbital ecchymoses should raise this diagnostic possibility (3). We report a patient suffering ocular pain that appeared when the patient was bending over or lying.

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 hypotension 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 these 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 includes 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 suspect orbital varices even without positional exophthalmos.

Case reports
A 68 year-old woman consulted in our office because of a 3-month 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 association with dizziness, vertigo, visual or auditory disturbances. There was no proptosis and physical, neurological and neuroophthalmological 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 enhancing lesion in the left inferomedial retrobulbar area and an MR angiogram ruled out caroid-cavernous fistulas.

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

doi: 10:3823/303

2010 Vol.1 No. 1:5

References:
1) Weill A, Cognard C, Castaings L, Robert G, Moret J. Embolization 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 management. 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 1:1160. 5) Garcia-Morales I, Porta-Etessam J, Galn L, Lagares A, Molina JA. Recurrent subdural haematomas in a patient with spontaneous intracranial hypotension. Cephalalgia 2001; 21: 703-705. 6) Mokri B, Aksamit AJ, Atkinson JLD. Paradoxical postural headaches 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.

Publish with iMedPub Journals http://www.imedpub.com


Journal of Neurology and Neuroscience (JNeuro.com) is a hybrid, peer-reviewed journal that considers articles concerned with any aspect of clinical neurosciences such as neurology, psyciatry and neurosurgery, as well as basic research on neuroscience. Where neurologists and neuroscientists publish together.

Submit your manuscript here:

http://www.jneuro.com

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:1


doi: 10:3823/305

Pretectal syndrome caused by multiple sclerosis.

Porta-Etessam J (1, 2), Garca-Ramos R (2), Ruiz-Gimnez J (3), Moreno T (3), Ruiz-Morales-J (3)
1) Headache and Neuroophthalmology Unit. 2) Neurology Department. Hospital Universitario Clnico San Carlos. 3) Neurology department. Hospital Universitario 12 de octubre. Madrid. Spain. Correspondence: Jess Porta-Etessam MD C/ Andrs Torrejn, 15, 7. 28014 Madrid Spain. E-mail: jporta@yahoo.com

Pretectal syndrome refers to a complex clnical elements and symptoms secundary to damage of the pretectum structures. The two most important pretectal areas are the rostral intersticial nucleus of the medial longitudinal fasciculus (riRLF) and interstitial nucleus of Cajal. This syndrome is highlighted by supranuclear vertical upgaze paresis, pupillary, eyelid and convergegence retraction nystagmus1,2. 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. General examination was normal and on neurological examination, she showed supranuclear gaze restriction affecting both vertical 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 convergence insufficience.

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 gadoliniumenhanced ,another small lesion in the temporal white matter on the left and T2-hyperintense lesion traversing the corpus callosum on 1.5-mm thick, T2-weighted imaging. The most common causes of pretectal syndrome are hydrocephalus, tumours and cerebrovascular disorders; however multiple sclerosis is really rare 3 Problems associated with the similar terminologies including Parinauds syndrome, sylvian aqueduct syndrome or dorsal midbrain syndrome were discussed. The eponym is attributed to Henri Parinaud, an ophthalmologist who worked under Charcot at the Salpetriere in Paris in the late 19th century and wrote two landmarks articles describing various types of conjugate gaze palsies and paralyses of convergence4. Nowadays, the syndrome includes pupillary and eyelid abnormalities, as well as convergence retraction nystagmus, for this reason the term pretectal syndrome are more popular4,5. The supranuclear vertical gaze restriction in this syndrome results 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 involment of upgaze while those located more ventrally are associated with greater downgaze paresis 5. Fibers mediating the upward gaze originate in the rostral interstitial MLF (riMLF) project
This article is available from: http://www.jneuro.com

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

Figure 2. Slight limitation in superior smooth movement


Under License of Creative Commons Attribution 3.0 License

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:1


doi: 10:3823/305

ipsilateraly to ipsilateral oculomotor complex, cross through the posterior commissure, and terminate in the contralateral oculomotor 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 differential 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, 584626. 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.

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

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 hypertension 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 prevalent 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 establishing 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 encountered in Neurology and Internal Medicine clinics. A series of population-based studies based on the new operational International 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 prevalence was 2.65% 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
Copyright iMedPub

is 16.6% (female to male ratio: 1.33) (5). Overall, migraine prevalence varies by age, gender, race, and income. Before puberty, migraine prevalence is approximately 4%. As adolescence approaches, 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 general 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 textThis article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

books, the relationship between migraine and hypertension is poorly characterized. Epidemiologic and population-based studies found no (12,13) or even negative (14) correlation between 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 association i.e. one disorder causes the other, 5) a shared environmental 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 association of two conditions in the same individual (16). The present article serves as an overview of the blood pressure changes encountered in patients with migraine. Studies in migraine literatures present in pubmed which highlighted migraine and blood pressure, migraine and hypertension, headache 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 evidences 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 uncertainties 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 illness, both hypertension and migraine have to be carefully treated to avoid the development of cardio- and cerebrovascular complications.

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 authors found that the prevalence of hypertension was 35,9% among all patients (migrainous and non-migrainous headache), 28,5% among migraine patients and 44,8% among patients with tension headache. The prevalence of resistance to treatment was 39,8%, 34,3% and 41,3%, respectively. Of the patients 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. Hypertension was present in 28% of the patients, and was particularly common in medication-overuse headache (60.6%), chronic tension 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 tension headache than migraine with aura (p<0.024). Information about the comorbidity of migraine and hypertension 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 pressure (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 diastolic 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
This article is available from: http://www.jneuro.com

Evidences of blood pressure changes in migraine:


A) Evidences that hypertension is positively associated with migraine:
Since several decades, the comorbidity of migraine with hypertension is a widely accepted issue despite the absence of confirmation by well-designed studies. In general, headache, particularly 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 subjects with arterial hypertension and since then the relation
Copyright iMedPub

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

and pulse pressure significantly decreased the probability of migraine 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 relevant 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 angiotensin 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 activity, inhibit free radical activity, increase prostacyclin synthesis and block the degradation of bradykinin, encephalin and substance 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 populations 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 hypertension in 508 young women with migraine and 3902 without migraine. In a cross sectional study of Wiehe et al. (12), the authors studied 1174 individuals older than 17 years, representative of inhabitants 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), investigated 1763 subjects for the association between hypertension classified at moderate to severe stages and headache. The authors found that headache and hypertension was not associated. 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
Copyright iMedPub

in 1984-6, and responded to a headache questionnaire at follow 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 nonmigrainous 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 pressure. 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 determine 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 population 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 difference 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 hypertension of mild to moderate degree does not cause headache but this may not be the case in patients with hypertension classified 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 (coincidental or chance association). Hypertension is also a common and consistent health problem in both developed and developing 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 populaThis article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

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 Berksons 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 hypertension (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. Tzourios et al. (55) found lower blood pressure and reduced carotid-intima media thickness (evidence of hypertension) in migraine patients. Recently, 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-Trndelag Health Survey 1984-1986) and HUNT2 (Nord-Trndelag Health Survey 1995-1997). The main topics of HUNT-1 included blood pressure, 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 headache (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.

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 animals and humans and in groups deemed to be at an increased risk for the development of hypertension (61-63), and c) previous studies confirmed that increasing blood pressure was linked to decreasing amounts of chronic musculoskeletal pain in different 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 normal 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 musculoskeletal pains. The mechanism for hypertension-associated hypalgesia is not clear. but data from humans and rats suggest an interaction between 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 homeostatic process that helps to maintain blood pressure) in response to increased blood pressure is assumed to inhibit pain transmission at both spinal and supraspinal levels, possibly because of an interaction of the centers modulating nociception and cardiovascular 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 antinociception and cardiovascular regulation rather than a specific effect of hypertension itself. Sanya et al. (66) assessed the baroreflex 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 stimulating 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 oscillatory 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 pathophysiology of migraine related blood pressure changes.

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
Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

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 catecholamines, 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 metabolism of catecholamines, may influence the response to pain (67) and may also be important also for blood pressure regulation (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. However, 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, Seil et al. (69), recorded blood pressure at 3 times in 62 normotensive 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 migraine attack (5.1%). The authors hypothesized that pathophysiological 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 reported in many functional neuroimaging studies (fMRI and PET) with migraine (49). It has been found that during migraine attacks, some substances are released especially calcitonin generelated 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).

vessels (72), decreased brachial artery flow-mediated dilatation and increased nitrate-mediated response (73), increased brachial artery intima-media thickness (72), presence of microvascular retinal abnormalities (74) and reduced number and function 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 significant 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 correlated with systolic and diastolic blood pressure and carotid artery 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 pressure (35), disturbed lipid profile (79), elevated body mass index (BMI) (80), insulin resistance (81), metabolic syndrome (82), hyperhomocysteinemia (83), ischemic cerebrovascular stroke (84) and coronary heart disease (85), all indicate the possibility of migraine being a local manifestation of a systemic vascular abnormality 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 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 cerebrovascular risk (86,87). 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 (42,87,88). Some evidence suggests that poor control of blood pressure may exacerbate the frequency and severity of migraine and other headaches (17).
This article is available from: http://www.jneuro.com

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, including: generalized peripheral vasoconstriction (71), increased diameter and/or decreased distensibility of peripheral blood
Copyright iMedPub

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

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-inflammatory 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. Recently, angiotensin converting enzyme inhibitors and blockers of angiotensin II provide beneficial results in migraine prophylaxis (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 profile 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).

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

References
1. Stewart WF, Lipton RB, Celentano DD, Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA 1992;267(1):64-69. 2. Sakai F, Igarashi H. Prevalence of migraine in Japan: a nationwide survey. Cephalalgia 1997;17(1):1522. 3. Marcellin AL, Yves RJ, Prisca AO. Prevalence de la migraine a madagascar: resultats dune enquete menee dans une population generale migraine prevalence in malagasy: results of a general population survey. AJNS 2005;24 (1). 4. Benamer HTS, Deleu D, Grosset D. Epidemiology of headache in Arab countries. The Journal of Headache and Pain. 2010;11(1):1-3. 5. Ahmed HN, Farweez H, Farghaly WA, Kamed NF, Bakhet A. Prevalence of migraine among schoolchildren (primary and preparatory) in Assuit city, Egypt. Eastern Mediterranean health journal 1999;5:402 423. 6. Rasmussen BK. Epidemiology of headache in Europe. In: Olesen J, ed. Headache classification and Epidemiology. New York: Raven Press; 1994, pp. 231-237. 7. Weiss NS. Relation of high blood pressure to headache, epistaxis, and selected other symptoms. N Engl J Med 1972;287(13):631633. 8. Cooper WD, Glover DR, Hormbrey JM, Kimber GR. Headache and blood pressure: evidence of a close relationship. J Hum Hypertens 1989;3(1):41-44. 9. Couch JR, Hassanein RS. Headache as a risk factor in atherosclerosisrelated diseases. Headache 1989;29(1):4954. 10. Mathew NT. Migraine and hypertension. Cephalalgia 1999;19 Suppl 25:17-19. 11. Hamed SA, Hamed EA, Mahmoud AA, Mahmoud NM. Vascular risk factors, endothelial function and carotid thickness in patients with migraine: relationship to atherosclerosis. J of stroke and cerebrovascular diseases 2010;19(2):92-103. 12. Wiehe M, Fuchs SC, Moreira LB, Moraes RS, Fuchs FD. Migraine is more frequent in individuals with optimal and normal blood pressure: a population-based study. Hypertens 2002;20(7):1303-1306. 13. Muiesan ML, Padovani A, Salvetti M, Monteduro C, Poisa P, Bonzi B, Paini A, Cottini E, Agosti C, Castellano M, Rizzoni D, Vignolo A, AgabitiRosei E. Headache: Prevalence and relationship with office or ambulatory blood pressure in a general population sample (the Vobarno Study). Blood Press 2006;15(1):14-19. 14. Tronvik E, Stovner LJ, Hagen K, Holmen J, Zwart J-A. High pulse pressure protects against headache: Prospective and cross-sectional data (HUNT study). Neurology 2008;70(16):1329-1336. 15. Hamed SA. The vascular risk associations with migraine: Relation to migraine susceptibility and progression. Atherosclerosis 2009;205(1): 15-22. 16. Feinstein AR. The pretherapeutic classification of comorbidity in chronic disease. J Chron Dis 1970; 23:455-468. 17. Pietrini U, De Luca M, De Santis G. Hypertension in headache patients? A clinical study. Acta Neurol Scand 2005;112(4):259-264. 18. Janeway TC. A clinical study of hypertensive cardiovascular disease. Arch Intern Med 1913;12:755798. 19. Waters WE. Headache and blood pressure in the community. BMJ 1971;1(5741):142143. 20. Weiss NS. Relation of high blood pressure to headache, epistaxis, and selected other symptoms. N Engl J Med 1972;287(13):631633.

21. Schle R, Ahlborg B, Ekbom K. Physical characteristics and allergic history in young men with migraine and other headaches. Headache 1978;18(2):8086. 22. Kottke TE, Tuomilehto J, Puska P, Salonen JT. The relationship of symptoms and blood pressure in a population sample. Int J Epidemiol 1979;8(4):355359. 23. Abramson JH, Hopp C, Epstein LM. Migraine and non-migrainous headaches: a community survey in Jerusalem. J Epidemiol Community Health 1980;34(3):188193. 24. Featherstone HJ. Medical diagnosis and problems in individuals with recurrent idiopathic headaches. Headache 1985;25(4):136140. 25. Paulin JM, Waal-Manning J, Simpson FO, Knight RG. The prevalence of headache in a small New Zealand town. Headache 1985;25(3):147 151. 26. DAlessandro R, Benassi G, Lenzi PL, Gamberini G, Sacquegna T, De Carolis, P, Lugaresi E. Epidemiology of headache in the republic of San Marino. J Neurol Neurosurg Psychiatry 1988;51(1):2127. 27. Gardner JW, Mountain GE, Hines EA. The relationship of migraine to hypertension and to hypertension headaches. Am J Med Sci 1940;200:5053. 28. Badran RH, Weir RJ, McGuiness JB. Hypertension and headache. Scott Med J 1970;15(2):4851. 29. Bulpitt CJ, Dollery CT, Carne S. Change in symptoms of hypertensive patients after referral to a hospital clinic. Br Heart J 1976;38(2):121128. 30. Jaillard AS, Mazetti P, Kala E. Prevalence of migraine and headache in a high-altitude town of Peru: a population-based study. Headache 1997;37(2):95101. 31. Markush RE, Herbert RK, Heyman A., OFallon, W.M. Epidemiologic study of migraine symptoms in young women. Neurology 1975;25(5):430435. 32. Marcoux S, Berube S, Brisson J, Fabia J. History of migraine and risk of pregnancyinduced hypertension. Epidemiology 1992;3(1):5356. 33. Ziegler DK, Hassanein RS, Couch, JR. Characteristics of life headache histories in a non-clinic population. Neurology 1977;27(3):265269. 34. Baldrati A, Bini L, DAlessandro R, Cortelli P, de Capoa D, De Carolis P, Sacquegna T. Analysis of outcome predictors of migraine towards chronicity. Cephalgia 1985;5(S2):195-199. 35. Cirillo M, Stellanto D, Lombardi C, De Santo NG, Covelli V. Headache and cardiovascular risk factors: positive association with hypertension. Headache 1999;39(6):409-416. 36. Atkins JB. Migraine as a sequel to infection by L icterohaemorrhagiae. BMJ 1955;1(4920):10111012. 37. Merikangas KR, Fenton BT. Comorbity of migraine with somatic disorders in a large-scale epidemiological study in the United States. In: Olesen J, eds. Headache classification and epidemiology. New York: Raven Press, 1994, pp. 301314. 38. Franceschi M, Colombo B, Rossi P, Canal N. Headache in a population-based elderly cohort. An ancillary study to the Italian longitudinal study of aging (ILSA). Headache 1997;37(2):7982. 39. Grebe HP, Nunes da Silva MJ, Diogo-Sousa L. Role of arterial hypertension in comorbidity of chronic headaches. Rev Neurol 2001;33(2):119122. 40. Prudenzano MP, Monetti C, Merico L, Cardinali V, Genco S, Lamberti P, Livrea P. The comorbidity of migraine and hypertension. A study in a tertiary care headache centre. J Headache Pain 2005;6(4):220-222.

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

41. Scher AI, Terwindt GM, Picavet HS, Verschuren WM, Ferrari MD, Launer LJ. Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 2005;64(4):614620. 42. Gudmundsson LS, Thorgeirsson G, Sigfusson N, Sigvaldason H, Johannsson M. Migraine patients have lower systolic but higher diastolic blood pressure compared with controls in a population-based study of 21,537 subjects. The Reykjavik Study. Cephalalgia 2006; 26(4):436-44. 43. Paterna S, Di Pasquale P, DAngelo A, Seidita G, Tuttolomondo A, Cardinale A, Maniscalchi T, Follone G, Giubilato A, Tarantello M, Licata G. Angiotensin-converting enzyme gene deletion polymorphism determines an increase in frequency of migraine attacks in patients suffering from migraine without aura. Eur Neurol 2000;43(3):133136. 44. Schrader H, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with angiotensin converting enzyme inhibitor (lisinopril): randomised, placebo controlled, crossover study. BMJ 2001;322(7277):19-22. 45. Sliwka U, Harscher S, Diehl RR, van Schayck R, Niesen WD, Weiller C. Spontaneous oscillations in cerebral blood flow velocity give evidence of different autonomic dysfunctions in various types of headache. Headache 2001;41(2):157-163. 46. Chen TC, Leviton A, Edelstein S, Ellenberg JH. Migraine and other diseases in women of reproductive age. The influence of smoking on observed associations. Arch Neurol 1987;44(10):10241028. 47. Fuchs FD, Gus M, Moreira LB, Moreira WD, Gonalves SC, Nunes G. Headache is not more frequent among patients with moderate to severe hypertension. J Hum Hypertens 2003;17(11):787-790. 48. Hagen K, Stovner LJ, Vatten L, Holmen J, Zwart JA, Bovim G. Blood pressure and risk of headache: a prospective study of 22 685 adults in Norway. J Neurol Neurosurg Psychiat 2002;72(4):463-466. 49. Breslau N, Rasmussen BK. The impact of migraine: Epidemiology, risk factors, and co-morbidities. Neurology 2001;56 Suppl 1:S4-S12. 50. Headache Classification Committee of the international Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias, and facial pain. Cephalalgia 1988;(suppl 7):196. 51. World Health Report 2002: Reducing risks, promoting health life. Geneva, Switzerland: World Health Organization, 2002. http://www. who.int/whr/2002/ 52. Hajjar I, Kotchen TA. Trends in prevalence, awareness, treatment, and control of hypertension in the United States, 1988-2000. JAMA 2003;290(2):199-206. 53. Kearney PM, Whelton M, Reynolds K. Whelton PK, He J. Worldwide prevalence of hypertension: a systematic review. J Hypertens 2004;22(1):1119. 54. Ibrahim MM, Rizk H, Appel LJ, El Aroussy W, Helmy S, Sharaf Y, Ashour Z, Kandil H, Roccella E, Whelton PK, for the NHP Investigative Team. Hypertension Prevalence, Awareness, Treatment, and Control in Egypt. Results From the Egyptian National Hypertension Project (NHP). Hypertension 1995;26 (6 Pt 1):886-890. 55. Tzourio C, Gagniere B, El Amrani M, Alprovitch A, Bousser MG. Relationship between migraine, blood pressure and carotid thickness. A population-based study in the elderly. Cephalalgia 2003;23(9):914920. 56. Charles JA, Jotkowitz S, Byrd LH. Prevention of migraine with olmesartan in patients with hypertension/prehypertension. Headache 2006;46(3):503507 57. Tronvik E, Stovner LJ, Helde G, Sand T, Bovim G. Prophylactic treatment of migraine with an angiotensin II receptor blocker. JAMA 2003;289(1):6569.

58. Hagen K, Zwart JA, Vatten L, Stovner LJ, Bovim G. Head-HUNT: validity and reliability of a headache questionnaire in a large populationbased study in Norway. Cephalalgia 2000;20(4):244251. 59. Aamodt AH, Stovner LJ, Midthjell K, Hagen K, Zwart JA. Headache prevalence related to diabetes mellitus. The Head-HUNT study. Eur J Neurol 2007;14(7):738-744. 60. Bruehl S, Chung OY, Ward P, Johnson B, McCubbin JA. The relationship between resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain sufferers: the effect of opioid blockade. Pain 2002;100(1-2):191-201. 61. Ghione S. Hypertension-associated hypalgesia. Evidence in experimental animals and humans, pathophysiological mechanisms, and potential clinical consequences. Hypertension 1996;28(3):494504. 62. Schobel HP, Ringkamp M, Behrmann A, Forster C, Schmieder RE, Handwerker HO. Hemodynamic and sympathetic nerve responses to painful stimuli in normotensive and borderline hypertensive subjects. Pain. 1996;66(2-3):117-124. 63. alAbsi M, Petersen KL, Wittmers LE. Blood pressure but not parental history for hypertension predicts pain perception in women. Pain 2000;88(1):61-68 64. Hagen K, Zwart JA, Holmen J, Svebak S, Bovim G, Stovner LJ, NordTrndelag Health Study. Does hypertension protect against chronic musculoskeletal complaints? The Nord-Trndelag Health Study. Arch Intern Med 2005 25;165(8):916-922. 65. DAntono B, Ditto B, Sita A, Miller SB. Cardiopulmonary baroreflex stimulation and blood pressurerelated hypoalgesia. Biol Psychol 2000;53(2-3):217-231. 66. Sanya EO, Brown CM, von Wilmowsky C, Neundrfer B, Hilz MJ. Impairment of parasympathetic baroreflex responses in migraine patients. Acta Neurol Scand 2005;111(2):102-107. 67. Zubieta JK, Heitzeg MM, Smith YR, Bueller JA, Xu K, Xu Y, Koeppe RA, Stohler CS, Goldman D. COMT val158 met genotype affects -opioid neurotransmitter responses to a pain stressor. Science 2003;299(5610):1240-1243. 68. Helkamaa T, Mnnist PT, Rauhala P, Cheng ZJ, Finckenberg P, Huotari M, Gogos JA, Karayiorgou M, Mervaala EM. Resistance to salt-induced hypertension in catechol-O-methyltransferase-gene-disrupted mice. J Hypertens 2003;21(12):2365-2374. 69. Seil Y, Unde C, Beckmann YY, Bozkaya YT, Ozerkan F, Baolu M. Blood Pressure Changes in Migraine Patients before, during and after Migraine Attacks. Pain Pract 2010;10(3):222-227 70. Juhasz G, Zsombok T, Modos EA, Olajos S, Jakab B, Nemeth J, Szolcsanyi J, Vitrai J, Bagdy G. NO-induced migraine attack:strong increase in plasma calcitonin gene-related peptide (CGRP) concentration and negative correlation with platelet serotonin release. Pain 2003;106(3):461470. 71. Iversen HK, Nielsen TH, Olesen J, Tfelt-Hansen P. Arterial responses during migraine headache. Lancet 1990;336(8719):837839. 72. de Hoon JN, Willigers JM, Troost J, Struijker-Boudier HA, van Bortel LM. Cranial and peripheral interictal vascular changes in migraine patients. Cephalalgia 2003;23(2):96104. 73. Yetkin E, Ozisik H, Ozcan C, Aksoy Y, Turhan H. Increased dilator response to nitrate and decreased flow-mediated dilatation in migraineurs. Headache 2007;47(1):104-110. 74. Rose KM, Wong TY, Carson AP, Couper DJ, Klein R, Sharrett AR. Migraine and retinal microvascular abnormalities: the Atherosclerosis Risk in Communities Study. Neurology 2007;68(20):1694-700.

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:2


doi: 10:3823/306

75. Lee ST, Chu K, Jung KH, Kim DH, Kim EH, Choe VN, Kim JH, Im WS, Kang L, Park JE, Park HJ, Park HK, Song EC, Lee SK, Kim M, Roh JK. Decreased number and function of endothelial progenitor cells in patients with migraine. Neurology 2008;70(17):1510-1517. 76. Nagai T, Tabara Y, Igase M, Nakura J, Miki T, Kohara K. Migraine is associated with enhanced arterial stiffness. Hypertens res 2007;30():577 583. 77. Nichols, W.W. Clinical measurement of arterial stiffness obtained from noninvasive pressure waveforms. Am J Hypertens 2005;18(1 Pt 2):3S10S. 78. Armentano, R., Megnien, J.L., Simon, A., Bellenfant, F., Barra, J., Levenson, J. Effects of Hypertension on Viscoelasticity of Carotid and Femoral Arteries in Humans. Hypertension 1995;26(1):48-54. 79. Bic Z, Blix GG, Hopp HP, Leslie FM, Schell MJ. The influence of a low fat-diet on incidence and severity of migraine headaches. J Womens Heath Gender-based Med 1999;8:623-630. 80. Bigal ME, Gironda M, Tepper SJ, Feleppa M, Rapoport AM, Sheftell FD, Lipton RB. Headache prevention outcome and body mass index. Cephalgia 2006;26(4):445-450. 81. Rainero I, Limone P, Ferrero M, Valfr W, Pelissetto C, Rubino E, Gentile S, Lo Giudice R, Pinessi L. Insulin sensitivity is impaired in patients with migraine. Cephalgia 2005;25(8):593-597. 82. Watson KE, Peters Harmel AL, Matson G. Atherosclerosis in type 2 diabetes mellitus: the role of insulin resistance. J Cardiovasc Pharmacol Ther 2003;8(4);253-260.

83. Lea RA, Ovcaric M, Sundholm J, MacMillan J, Griffiths LR. The methylenetetrahydrofolate reductase gene variant C677T influences susceptibility to migraine with aura. BMD Medicine 2004;2(9):3-10. 84. Schwaag S, Nabavi DG, Frese A, Husstedt IW, Evers S. The association between migraine and juvenile stroke: A case-control study. Headache 2003;43(2):90-93. 85. Vanmolkot FH, Van Bortel LM, de Hoon JN. Altered arterial function in migraine of recent onset. Neurology 2007;68(19):1563-1570. 86. Guasti L, Zanotta D, Diolisi A, Garganico D, Simoni C, Gaudio G, Grandi AM, Venco A. Changes in pain perception during treatment with angiotensin converting enzyme-inhibitors and angiotensin II type 1 receptor blockade. J Hypertens 2002;20(3):485-491. 87. Agostoni E, Aliprandi A. Migraine and hypertension. Neurol Sci 2008;29 Suppl 1:S37-39. 88. Rasmussen BK, Olesen J. Symptomatic and non-symptomatic headaches in a general population. Neurology 1992;42(6):1225-1231. 89. Farinelli I, Missori S, Martelletti P. Proinflammatory mediators and migraine pathogenesis: moving towards CGRP as a target for a novel therapeutic class. Expert Rev Neurother 2008;8(9):1347-1354.

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:3


doi: 10:3823/307

Acute Stroke in a 26 year old male


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 neurosarcoidosis. 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 patients 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 problem 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.

While hospitalized, the team suspected meningitis and proceeded with the proper work-up. The patient experienced one episode of hallucinations and complained of pain in his posterior 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 untreated positive PPD, and while cultures were growing, the patient began anti-tuberculosis RIPE regimen (Rifampin, Isoniazid, Pyrazinamide, Ethambutol, and Pyridex) and oral steroids. Although all cultures remained negative (blood, fungal, AFB), the patients 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 identified slurred speech, right facial droop, brisk lower extremity reflexes, 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 cervical spinal cord extending from C3 to C4-5 level, containing a
This article is available from: http://www.jneuro.com

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 motor 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 105F, occipital headache, neck pain and stiffness, dizziness, nausea and vomiting, and anorexia. When that admitting team pried further, they discovered 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.
Under License of Creative Commons Attribution 3.0 License

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:3


doi: 10:3823/307

Discussion
The exact etiology of sarcoidosis is unknown, but proposed causes include infectious agents, occupational and environmental 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 Neurosarcoidosis presents in less than five percent of individuals with sarcoidosis, and it usually occurs only after other systemic symptoms 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, pituitaryhypothalamic axis, the spinal cord, and peripheral nerves.1 Typical presentation include affects of the cranial nerves including 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 stenosis, and embolism.3,4 As in this case, when systemic manifestations are absent, imaging 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, immunosuppressants, and possible surgical excision of lesions.1 Corticosteroids like prednisone are the main therapeutic agent in the management of neurosarcoidosis.2 Small studies have found resistant cases to respond to immunosuppressants, including methotrexate, 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

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 cervical 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, demyelinated lesions, or infection. The pathology from the spinal biopsy 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.
Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:3


doi: 10:3823/307

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 neurosarcoidosis. 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 sarcoidosis 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.

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:4


doi: 10:3823/308

Activity of serum Cathepsin D in Alzheimers disease


Manuel Menndez-Gonzlez1,2, Ana Surez3, Patricia Lpez3, Mara Teresa Calatayud4, Marta Martnez-Rivera1, Rene Ribacoba4, Alfonso Lpez-Muiz2
1 Neurologa, Hospital lvarez-Buylla, Mieres 2 Departamento de Morfologa y Biologa Celular, Universidad de Oviedo 3 Departamento de Biologa Funcional, Universidad de Oviedo 4 Neurologa, 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 Alzheimers disease (AD) is a complex disease 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 cathepsin 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 Alzheimers 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.
Under License of Creative Commons Attribution 3.0 License

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 January 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 according to Petersens criteria (14), AD according to the NINDS-ADRA criteria (15), and VD according to the NINDS-AIREN criteria (16).

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:4


doi: 10:3823/308

Exclusion criteria

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

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 being carrier of the E4 allele. Finally, the MannWhitney U test was used for assessing differences related both to gender and ApoE genotype.

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

Results
Sample description
We studied 40 controls and 149 patients. Sixteen patients suffered 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 carrier of the ApoE4 allele.

Clinical Assessment
All patients were studied with neuroimaging and full neuropsychological assessment following the AAN recommendations (17). Neuropsychological assessment included the Test Barcelona Abreviado (18) in all patients as well as other tests depending on each patients 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 described (21). The staging of the disease was performed following the GDSFAST criteria (22): mild AD: GDS4, moderate AD: GDS5 and severe AD: GDS6.

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 significant 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 groups Control mild AD moderate AD severe AD MCI VD Total Mean 659,84 648,92 674,44 587,36 676,14 706,99 660,48 N 40 52 38 18 16 25 189 Std. Dev. 401,35 435,04 358,31 107,40 277,59 379,45 369,45

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 (amino4-trifluoromethyl coumarin) released after cleavage of the preferred cathepsin-D substrate sequence RGFFP labelled with AFC. To this end serum samples were added to the synthetic substrate in fluorescence validate black 96-wells microtiter plates (BD FalconTM, Becton Dickinson) and incubated at 37C for 2 hours. Fluorescence was quantified in a Cary Eclipse Fluorescence Spectrophotometer (Varian Ibrica 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.

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:4


doi: 10:3823/308

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 mild AD moderate AD severe AD 704 730 582 E4 585 652 547

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 implicated 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 diagnosis 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 studies (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 A (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 differences 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.

On the other hand being carrier of two E4 allele did not associate 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).

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 results 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 disease only in a concrete subpopulation of patients: men carriers of ApoE4.
This article is available from: http://www.jneuro.com

Figure 1. Comparison of catD activity (units/ml) in men and women in carriers and not carriers of ApoE4.
Under License of Creative Commons Attribution 3.0 License

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:4


doi: 10:3823/308

References
1. Cataldo AM, Hamilton DJ, Barnett JL, Paskevich PA, Nixon RA. Properties of the endosomal-lysosomal system in the human central nervous system: disturbances mark most neurons in populations at risk to degenerate in Alzheimers disease.J Neurosci. 1996 Jan;16(1):186-99 2. Kohnken RE, Ladror US, Wang GT, Holzman TF, Miller BE, Krafft GA. Cathepsin D from Alzheimers-diseased and normal brains. Exp Neurol. 1995 Jun;133(2):105-1 3. Ladror US, Snyder SW, Wang GT, Holzman TF, Krafft GA.Cleavage at the amino and carboxyl termini of Alzheimers amyloid-beta by cathepsin D. J Biol Chem. 1994 Jul 15;269(28):18422-8 4. Diedrich JF, Minnigan H, Carp RI, Whitaker JN, Race R, Frey W 2nd, Haase AT. Neuropathological changes in scrapie and Alzheimers disease are associated with increased expression of apolipoprotein E and cathepsin D in astrocytes. J Virol. 1991;65(9):4759-68 5. Papassotiropoulos A, Bagli M, Kurz A, Kornhuber J, Frstl H, Maier W, Pauls J, Lautenschlager N, Heun R.A genetic variation of cathepsin D is a major risk factor for Alzheimers disease. Ann Neurol. 2000 Mar;47(3):399-403 6. Mariani E, Seripa D, Ingegni T, Nocentini G, Mangialasche F, Ercolani S, Cherubini A, Metastasio A, Pilotto A, Senin U, Mecocci P. Interaction of CTSD and A2M polymorphisms in the risk for Alzheimers disease. J Neurol Sci. 2006 Sep 25;247(2):187-91 7. Mateo I, Snchez-Guerra M, Combarros O, Llorca J, Infante J, Gonzlez-Garca J, del Molino JP, Berciano J. Lack of association between cathepsin D genetic polymorphism and Alzheimer disease in a Spanish sample. Am J Med Genet. 2002 Jan 8;114(1):31-3 8. Schuur M, Ikram MA, van Swieten JC, Isaacs A, Vergeer-Drop JM, Hofman A, Oostra BA, Breteler MM, van Duijn CM. Cathepsin D gene and the risk of Alzheimers disease: A population-based study and metaanalysis. Neurobiol Aging. 2009 Nov 18. [Epub ahead of print] 9. Sun Y, Shi JJ, Zhang SZ, Tang MN, Han HY, Guo YB, Ma C, Liu XH, Li T. The C224T polymorphism in the cathepsin D gene is not associated with sporadic Alzheimers disease in Chinese. Yi Chuan. 2005 Mar;27(2):190-4 10. Ingegni T, Nocentini G, Mariani E, Spazzafumo L, Polidori MC, Cherubini A, Catani M, Cadini D, Senin U, Mecocci P. Cathepsin D polymorphism in Italian elderly subjects with sporadic late-onset Alzheimers disease. Dement Geriatr Cogn Disord. 2003;16(3):151-511.

11. Li XQ, Chen D, Zhang ZX, Qu QM, Zhang JW. Association between cathepsin D polymorphism and Alzheimers disease in a Chinese Han population. Dement Geriatr Cogn Disord. 2004;18(2):115-9 12. Davidson Y, Gibbons L, Pritchard A, Hardicre J, Wren J, Tian J, Shi J, Stopford C, Julien C, Thompson J, Payton A, Thaker U, Hayes AJ, Iwatsubo T, Pickering-Brown SM, Pendleton N, Horan MA, Burns A, Purandare N, Lendon CL, Neary D, Snowden JS, Mann DM. Genetic associations between cathepsin D exon 2 C-->T polymorphism and Alzheimers disease, and pathological correlations with genotype. J Neurol Neurosurg Psychiatry. 2006 Apr;77(4):515-7 characterization and outcome. Arch Neurol. 1999;56(3):303-8 13. Albayrak O, Tirniceriu A, Riemenschneider M, Kurz A, Scherag A, Egensperger R. The cathepsin D (224C/T) polymorphism confers an increased risk to develop Alzheimers disease in men. J Gerontol A Biol Sci Med Sci. 2010;65(3):219-24. 14. Petersen RC, Smith GE, Waring SC, Ivnik RJ, Tangalos EG, Kokmen E. Mild cognitive impairment: clinical characterization and outcome. Arch Neurol. 1999 Mar;56(3):303-8. 15. Tierney MC, Fisher RH, Lewis AJ, Zorzitto ML, Snow WG, Reid DW, Nieuwstraten P. The NINCDS-ADRDA Work Group criteria for the clinical diagnosis of probable Alzheimers disease: a clinicopathologic study of 57 cases. Neurology. 19;38(3):359-64. 16. Roman GC, Tatemichi TK, Erkinjuntti T, Cummings JL, Masdeu JC, Garcia JH, Amaducci L, Orgogozo JM, Brun A, Hofman A, et al. Vascular dementia: diagnostic criteria for research studies. Report of the NINDSAIREN International Workshop. Neurology. 1993;43(2):250-60 17. Knopman DS, DeKosky ST, Cummings JL, Chui H, Corey-Bloom J, Relkin N, Small GW, Miller B, Stevens JC. Practice parameter: diagnosis of dementia (an evidence-based review): report of the quality standards subcommittee of the American Academy of Neurology. Neurology 2001;56(9):1143-53 18. Pea-Casanova J, Guardia J, Bertran-Serra I, Manero RM, JArne A. Versin abreviada del Test Barcelona (I): subtest y perfiles normales. Neurologia 1997;12:99-111 19. Mahoney FI, Barthel DW. Functional evaluation: The Barthel index, Maryland State Med J 1965; 14: 61-5 20. Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNAfrom human nucleated cells. Nucleic Acids Res 16 (1988), 1215

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 2:4


doi: 10:3823/308

21. J.E. Hixson and D.T. Vernier, Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI, J Lipid Res 31 (1990), 545548 22. S. Auer and B. Reisberg, The GDS/FAST staging system, IntPsychogeriatr 9 (1997), 167171. 23. Haque A, Banik NL, Ray SK. New insights into the roles of endolysosomal cathepsins in the pathogenesis of Alzheimers disease: cathepsin inhibitors as potential therapeutics. CNS Neurol Disord Drug Targets. 2008 Jun;7(3):270-7 24. Zhou W, Scott SA, Shelton SB, Crutcher KA. Cathepsin D-mediated proteolysis of apolipoprotein E: possible role in Alzheimers disease. Neuroscience. 2006;143(3):689-701 25. Hook V, Schechter I, Demuth HU, Hook G. Alternative pathways for production of beta-amyloid peptides of Alzheimers disease. Biol Chem. 2008 Aug;389(8):993-1006. 26. Hamazaki H. Cathepsin D is involved in the clearance of Alzheimers -amyloid protein (1996) FEBS Letters, 396 (2-3), pp. 139-142. 27. Ghebremedhin E, Schultz C, Thal DR, Rb U, Ohm TG, Braak E, Braak H. Gender and age modify the association between APOE and AD-related neuropathology. Neurology. 2001 Jun 26;56(12):1696-701.

Under License of Creative Commons Attribution 3.0 License

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

Inheritance Of Alzheimers Disease Investigated By Complex Segregation Analysis


Manzano S, MD, PhD1, Baron M, MD, PhD2, Gomez-Tortosa E, MD, PhD3, Barquero MS, MD, PhD1, Jimenez-Escrig A, MD, PhD4.
1 Hospital Clinico San Carlos, Madrid, Spain. 2 Fundacin Jimenez Diaz, Madrid, Spain. 3 Fundacin 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 Alzheimers disease in a Spanish population by CSA. Methods: We ascertained 21 families (297 individuals) through probands, with 76 individuals affected with Alzheimers 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, codominant), 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: Alzheimers 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 Alzheimers disease ascertained through probands.

Introduction
Alzheimer Disease (AD) is the most common neurodegenerative disease. This disease shares with other neurodegenerative diseases that following ageing, family history is the second risk factor 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 characteristic in many neurodegenerative disorders decades ago (Bertram and Tanzi, 2005b). After the molecular genetic (Martin,
Copyright iMedPub

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 transmission, 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
This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

incompletely penetrant susceptibility variant, namely, the 4 allele in APOE gene (Chartier-Harlin et al., 1994), that significantly increases the risk by lowering the age of onset (AO) of the disease (Bertram and Tanzi, 2005a). Familial aggregation in a disease does not necessarily imply a genetic etiology. When familial cases appear, genetic and/or environmental 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 mixture of these ones. Various methods have been proposed for the statistical inference of gene effects in familial data. When examining 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 lR = kR/k where R denotes the relationship with the proband, kR is the prevalence in relatives of type R, and k is the prevalence in the general population. In any genetic model 1 l1 ls lM where M, s and 1 are relationship subscripts that denote MZ twins, siblings and parents (or offspring) respectively. Typically, lR is calculated for siblings and ls is known as the sibling relative risk. Examples of ls for different diseases include Huntingtons disease (where ks = 0.5, k = 0.0001, and so ls 5,000), recessive CMT (where ks = 0.25, k = 0.004, and so ls 500) and Parkinsons disease (where ks = 0.3, k = 0.1, and so ls = 3). In general, the greater the value of ls, the greater the genetic influence on the trait. However, in itself, ls is not necessarily a reliable parameter for estimating the power of a proposed linkage study. For example, in some two locus models a ls as high as 10 does not guarantee that underlying genes will be easily mapped by linkage studies. The power to detect genetic influence of a variant can also be defined in terms of genotype relative risks (GRRs)( (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 susceptibility allele. The conditional probabilities that an individual with a particular genotype has a disease D are known as penetrance parameters and given by fAA = P(D|AA), fAa = P(D|Aa), faa = P(D|aa)

The genotype relative risks for D at this locus are g1 = fAa / faa ; g2 = fAA/ faa 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 formulae relating GRR and ls 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 H2) is defined as the proportion of total variance in a trait that is due to all genetic components (additive, dominance and epistatic), while narrow heritability (denoted h2) 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 effects of single alleles. Dominance variance of a trait at a locus measures the variance due to the interaction of alleles that constitute 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 contribution 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 a heritability score near 1 implies that almost all variation is due to genetic factors. It 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 variants frequency in the population and the size of the effects that the gene variant causes and is primarily used for assessing the genetic contribution to a quantitative trait. Sibling relative risk, on the other hand, assesses the increased disease risk to siblings that share one-half of their genes with affected probands and is used in connection with qualitative traits. For a fixed value of lR the corresponding heritability decreases with decreasing population prevalence (Risch, 2001). A major point when considering the hereditability of a tract is 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-

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

cal proportion of autosomal dominant (50%) or recessive (25% of affected / 75% of non-affected, in the simplest case) and considering 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 better 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 quantitative 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 individuals age-dependent risk for disease (in genetic models, this trait represents a high-risk allele, whereas in non-genetic models, the trait is interpreted 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 addition, 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 (Bonney, 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 contribution 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 frequencies 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); d, degree of dominance at the major locus obtained by the equation d = (Aa - aa) / (AA - aa), such that d = 0
Copyright iMedPub

corresponds to a recessive gene, d = 1 corresponds to a dominant 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 = Ck/V Z, the ratio of adult to childhood heritability; Z = Ca/Ck and t1, t2 and t3, 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 environmental 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 expectations 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 genetic 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 Mendelian 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 Epidemiology 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 software 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 maximum 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 models 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 likelihood of the phenotypes in the families.

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

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 specific risk of disease). The environmental model assumes that an individuals 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 = Ck/V, in which Ck is the multifactorial component and V is the overall variance. The second parameter is Z for which HZ represents the multifactorial heritability in parents, where Z = Ca/Ck, the ratio of the multifactorial component in adults and children. Significant deviation of Z from 1 suggests a generational 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 cumulative mortalities and risk, so that the Rj, the risk attributed to the jth liability class, is Rj = (IjMj - 1)/(1Mj - 1) where Ij is the cumulative incidence to the mid-point and Mj - 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 parameters) is asymptotically distributed as 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 carriers (G) as the approximate cumulative incidence for gene carriers in the jth liability class, given by the following: Pj = P (aff | G, j) + [ l - P (aff | G,j)] Mj - 1

where the genotype-specific mortality is, Mj - 1 = P(G | aff,i)(Mi Mi - 1) / P(P| aff,i) (Ii Ii - 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 explanation 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 Alzheimers disease fulfilling CERAD criteria. These families gave a total of 44 nuclear families to be included in the model. Information was gathered on the probands themselves, as well as about the family history of two previous generations. Since probands were unable to give accurate answer to most questions, we interviewed the caregiver, usually a family member to ensure the accuracy of the information. 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 deceased 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 model of Morton and Mac-Lean (1974), implemented in the computer program POINTER (Morton et al., 1971). We analyzed the following 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 calculated as previously described Rj = (Ij - Mj - 1)/(1 - Mj - 1). Therefore, 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) according to their prior probability of affection based on the age

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

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 I II III IV Age of onset (years) <60 60-69 70-79 >80 Mortality rates per 100,00 population 0.3 30 230 1,300

Ascertainment probability
The ascertainment probability (), 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 component 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 () 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 (incomplete selection). There was only one proband in each family, and therefore an ascertainment probability () 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 0.0010.2, the results found to be highly robust to changes in the specified ascertainment model (Figure 1).

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


Copyright iMedPub This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

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 available to examine the APOE genotype. DNA was extracted from a blood sample using a phenol-chlorophorm extraction and ethanol precipitation method (Bernek 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 4 carrier versus those families whose proband was not an APOE 4 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 likelihood of the total data set is asymptotically distributed as 2 with p(g - 1) degrees of freedom, where p is the number of iterated parameters and g is the number of subgroups, heterogeneity 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: 2 = -2 [lnL (best-fitted model/subgroup i) -lnL (bestfitted model/all family data)], where is the sum overall i subgroups.

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 (1) no transmisibility (cohort effect) -2ln(L) d t q H t1 t2 t3 Z df

321.97

(0)

(0)

(0)

(0)

(2) multi-factorial 179.02 (3) dominant (4) codominant (5) recessive 163.61

(0) (1)

(0)

(0)

0.105 (0) (0) (0)

(1) (1) (1) (1)

7 6 6 6

3.06 0.0164 6.14 3.0 0.016 0.176

(1.0) (0.5) (0.0) (1.0) (0.5) (0.0) (1.0) (0.5) (0.0)

163.82 (0.5) 176.48 (0)

(6) t1=t2=t3 (polygenic-no 288.49 transmission of major effect) (7) mixed (d non restricted) (8) general(non restricted) 179.41

1.0

3.2

0.03

0.30 (0.97) (0.97) (0.97) (1)

1.0

1.72

0.507

0.44

(1.0) (0.5) (0.0)

(1)

172.95

1.0

1.64

0.354 0.343

1.2

0.18 0.01 0.348

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 (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 multifactorial model (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 t2 = 0.18, that is below 0.5 what means that there are epistatic interactions. Penetrance of a hypothesized 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).

In the second part of the study, we compared two subsets, those carrying an APOE 4 allele and not carrier ones and the bestfitting model was evaluated separately in these two subgroups. The total number of families analyzed by APOE genotyping were 4 APOE3/3 and 13 APOE 3/4 or 4/4. CSA of the two separated groups (APOE 4 carriers, APOE 4 non carriers) concluded that the best model of inheritance was the dominant one for APOE 4 carriers, and the codominant one for 4 non carriers families, but we could not reject the other inheritance models. The penetrance for APOE 4 carriers was 22.95% (>80 years old) and 20.37% (>80 years old) for APOE 4 non carriers. A gene can explain the 48% and 34% of the heritability for APOE 4 carriers and 4 non carriers respectively, with epistatic interactions (t2 = 0.35;<0.5). The difference between the 2lnL of the overall set and the sum of the 2lnL for the two groups yielded an 2 = 54 with df = 7; p< 0.01. This indicated evidence for etiologic heterogeneity between families ascertained.

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

Figure 2. Penetrance of the candidate gene by age.

Table 3. Results of CSA of the families with APOE 4/4 or 3/4 carriers.
Models (1) no transmisibility (2) multi-factorial (3) dominant (4) Codominant (5) Recessive (6) t1=t2=t3 (7) Mixed (8) general(non restricted) -2ln(L) d t q H t1 t2 t3 Z df

Table 4. Results of CSA of the families with APOE 3/3 carriers.

Models (1) no transmisibility (2) multi-factorial (3) dominant (4) Codominant (5) Recessive (6) t1=t2=t3 (7) Mixed (8) general (non restricted)

-2ln(L)

t1

t2

t3

df

181.61

(0)

(0)

(0)

(0)

57.84

(0)

(0)

(0)

(0)

88.61 83.06

(0) (1)

(0) 3.1 6.3 3.45 3.2 1.42 1.48

(0) 0.0137 0.013 0.149 0.03 0.56 0.50

0.105 (0) (0) (0) 0.30

(1) (1) (0) (1) (1)

7 6 6 6 1 3 0

28.46 25.86 25.83 28.17 51.96 29.09 28.66

(0) (1) (0.5) (0) 1.0 1.0 1.0

(0) 3.41 6.8 5.22 3.2 1.76 1.27

(0) 0.016 0.015 0.161 0.03

0.999 (0) (0) (0) 0.30

(1) (1) (0) (1) (1) 0.4

7 6 6 6 1 3 0

(1.0) (0.5) (0.0) (1.0) (0.5) (0.0) (1.0) (0.5) (0.0) 0.97 0.97 0.97

(1.0) (0.5) (0.0) (1.0) (0.5) (0.0) (1.0) (0.5) (0.0) 0.97 0.97 0.97

83.31 (0.5) 84.77 (0)

159.68 1.0 88.31 87.49 1.0 1.0

0.687 (1.0) (0.5) (0.0) 0.49 0.588 1.0 0.35 0.1 0.58

0.544 0.484 (1.0) (0.5) (0.0) 0.461 0.667 1.0 0.35

0.1 0.409

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

Discussion
Complex diseases such as AD are difficult to study from a genetic point of view. Nevertheless, a genetic approach to this disease through methodology as CSA that have demonstrated its practical usefulness in diverse genetic conditions can be very useful. In breast cancer, several different reports using CSA supported an autosomal dominant inheritance with a variable penetrance between 70 and 90 percent in gene carriers, at least in a subset of breast cancer cases (Williams and Anderson, 1984). These results provided the logical platform for additional linkage studies resulting in the discovery of the two breast cancer genes BRCA1 and BRCA2 (Hall et al., 1990;Wooster et al., 1994). These studies support that epidemiological approaches such as CSA allow to obtain preliminary data and make a good selection of the familial aggregates in order to obtain much more accuracy in further genetic studies, because if Mendelian segregation is not supported, analyses of candidate loci or random markers for linkage to the trait of interest would likely be unproductive, at least in the same data set. We must assume that CSA has limitations in order to consider the results showed above. First of all, the major limitation of CSA is that a large amount of a very specific type of data is generally needed. Ascertainment of an appropriate sample is also necessary. Moreover, there is no reliable method to determine the sample size required for a desired level of power to detect a Mendelian locus by CSA (Gail Pairitz J., 1998). Another practical limitation is the inability to distinguish the effect of a single locus that underlies a trait and the effects of two or more independently acting loci with similar transmission pattern (Gail Pairitz J., 1998). Since CSA cannot detect whether one phenotype is caused by different genotypes, i.e. genetic heterogeneity, a high impact of a small proportion of the families in which there was a strong genetic effect cannot be completely ruled out in our results. Third, the POINTER software assumes that any major gene inheritance occurs through a single twoallele autosomal locus, but actually, the inheritance pattern may be more complex, making the identification of a specific model more difficult.

A known limitation of CSA is that of a lack of assessment of statistical power. The effect of a rare major gene may remain masked, under the overwhelming number of sporadic AD cases. Although 21 families were included in this study, lack of power may be an explanation for the findings, since none of the models examined could be rejected. The involvement of a genetic factor in AD seems obvious considering the striking reports of extensive families but the influence of this genetic factor cannot easily be unravelled by CSA. The inclusion of more individuals, especially larger-sized families (i.e. inclusion of second-degree relatives) may improve power to detect genetic mechanisms underlying transmission of AD in this cohort. Although data on age at the onset of disease were available, the data are incomplete and possibly subject to error because of the difficulty in defining onset. Further CSA studies might usefully distinguish early and late onset as a route to discriminating between genetic and environmental etiology. To date, apart from our study there is only one other CSA of AD (Farrer et al., 1991). The shortage of CSA studies in AD and other neurodegenerative diseases is caused by the theoretical difficulties of these studies and the troubles in collecting the data for doing it. Nevertheless, there is a need for more studies using this sort of analysis that will allow to know the real situation of the genetics of these diseases. In conclusion, the results strongly support a Mendelian dominant or codominant susceptibility gene for AD, acting in a proportion of families. Nevertheless, Mendelian factors alone are not sufficient to fully explain the familial aggregation of this phenotype, and residual familial effects are necessary to adequately fit the data. This suggests that polygenic factors may also contribute to the etiology of AD. Parameters derived from this study may facilitate future linkage studies and have uncourageous to start searching of new genes for AD in this population.

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:1


doi: 10:3823/310

Bibliography
1. Abney M, McPeek MS, Ober C (2001) Broad and narrow heritabilities of quantitative traits in a founder population. Am J Hum Genet 68:13021307 2. Akaike HA (1974) New look at the statistical model identification IEEE. Transmission Automation Control 19:716-723 3. Barinaga M (1995) New Alzheimers gene found. Science 268:18451846 4. Bernek M. (2006) Comparison of various methods used for extraction of cell-free genomic DNA from human plasma., 14 edn pp 21-24 5. Bertram L, Tanzi RE (2005b) The genetic epidemiology of neurodegenerative disease. J Clin Invest 115:1449-1457 6. Bertram L, Tanzi RE (2005a) The genetic epidemiology of neurodegenerative disease. J Clin Invest 115:1449-1457 7. Bonney GE (1986) Regressive logistic models for familial disease and other binary traits. Biometrics 42:611-625 8. Chartier-Harlin MC, Parfitt M, Legrain S, Perez-Tur J, Brousseau T, Evans A, Berr C, Vidal O, Roques P, Gourlet V,. (1994) Apolipoprotein E, epsilon 4 allele as a major risk factor for sporadic early and late-onset forms of Alzheimers disease: analysis of the 19q13.2 chromosomal region. Hum Mol Genet 3:569-574 9. Farrer LA, Myers RH, Connor L, Cupples LA, Growdon JH (1991) Segregation analysis reveals evidence of a major gene for Alzheimer disease. Am J Hum Genet 48:1026-1033 10. Gail Pairitz J. (1998) Statistical genetics 98. Complex segregation analysis: Uses and limitations. Am J Hum Genet 63, 942-946. 1998. 11. Goldgaber D, Lerman MI, McBride OW, Saffiotti U, Gajdusek DC (1987) Characterization and chromosomal localization of a cDNA encoding brain amyloid of Alzheimers disease. Science %20;235:877-880 12. Hall JM, Lee MK, Newman B, Morrow JE, Anderson LA, Huey B, King MC (1990) Linkage of early-onset familial breast cancer to chromosome 17q21. Science 250:1684-1689 13. Hixon JE VD (1990) Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with Hhal. J Lipid Res 31:545-548 Iselius L, Slack J, Littler M, Morton NE (1991) Genetic epidemiology of breast cancer in Britain. Ann Hum Genet 55:151-159

14. Khoury MJ, Beaty TH, Cohen BH (1993) Scope and strategies of genetic epidemiology: analysis of articles published in Genetic Epidemiology, 1984-1991. Genet Epidemiol 10:321-329 15. Levy-Lahad E, Wasco W, Poorkaj P, Romano DM, Oshima J, Pettingell WH, Yu CE, Jondro PD, Schmidt SD, Wang K,. (1995) Candidate gene for the chromosome 1 familial Alzheimers disease locus. Science 269:973977 16. Marazita ML, Hu DN, Spence MA, Liu YE, Melnick M (1992) Cleft lip with or without cleft palate in Shanghai, China: evidence for an autosomal major locus. Am J Hum Genet 51:648-653 17. Martin JB (1999) Molecular basis of the neurodegenerative disorders. N Engl J Med 340:1970-1980 18. Morton NE, Yee S, Lew R (1971) Complex segregation analysis. Am J Hum Genet 23:602-611 19. Risch N (1990) Linkage strategies for genetically complex traits. I. Multilocus models. Am J Hum Genet 46:222-228 20. Risch N (2001) The genetic epidemiology of cancer: interpreting family and twin studies and their implications for molecular genetic approaches. Cancer Epidemiol Biomarkers Prev 10:733-741 21. Rybicki BA, Elston RC (2000) The relationship between the sibling recurrence-risk ratio and genotype relative risk. Am J Hum Genet 66:593-604 22. Schaid DJ, Sommer SS (1993) Genotype relative risks: methods for design and analysis of candidate-gene association studies. Am J Hum Genet 53:1114-1126 23. Williams WR, Anderson DE (1984) Genetic epidemiology of breast cancer: segregation analysis of 200 Danish pedigrees. Genet Epidemiol 1:7-20 24. Wittke-Thompson JK, Pluzhnikov A, Cox NJ (2005) Rational inferences about departures from Hardy-Weinberg equilibrium. Am J Hum Genet 76:967-986 25. Wooster R, Neuhausen SL, Mangion J, Quirk Y, Ford D, Collins N, Nguyen K, Seal S, Tran T, Averill D,. (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12-13. Science 265:2088-2090

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:2


doi: 10:3823/311

Clinical and functional description of a new form of autosomal recessive familial parkinsons disease with late onset
Manzano Palomo S1, Rioja M2, J. Kulisevsky3, Jimnez-Escrig A4.
1 Servicio de Neurologia, Hospital Clnico San Carlos, Madrid, Spain. 2 Servicio de Medicina Nuclear, Hospital Ramon y Cajal, Madrid, Spain. 3 Servicio de Neurologia, Hospital Santa Cruz y San Pablo, Barcelona, Spain. 4 Servicio de Neurologa, Hospital Ramon y Cajal, Madrid, Spain. Corresponding author: Dr. Jimnez-Escrig, Servicio de Neurologa Hospital Ramon y Cajal 28034 Madrid. Email: adriano.jimenez@hrc.es. Fax: 34 1 3369016 Running title: New autosomal recessive PD Word count: 1124 words

Abstract

We report the clinical and dopaminergic functional study of two families with autosomal recessive Parkinson disease coming from a genetic isolate region, in which known causative genes for recessive Parkinson disease (PARKIN, DJ1, PINK 1) were ruled out by homozygosity search. LRRK2 frequent mutation G2019S and -synuclein were also examined and discarged as well, as the cause of a pseudorecessive pattern of transmission. Functional study with iodine-123-betaIoflupane SPECT (DaTSCAN, GE) of affected cases showed a bilateral although asymmetrical uptake in putamen and caudate nucleus, demonstrative that a presynaptic lesion was responsible for the clinical picture. 123IBZM SPECT was normal, ruling out a postsynaptic lesion. These families present a late onset benign Parkinson disease that represents a new form of recessive familial Parkinson disease. Key words: Parkinsons disease, PINK1, DJ1, PARKIN, LRRK2, -synuclein.

Introduction
The majority of PD cases are sporadic although genetic forms are increasingly recognized. In familial PD of Mendelian inheritance there are twelve forms reported so far. Focussing on those with recessive transmission, three forms have been reported to date. PARK2, secondary to Parkin mutations was the first described, occurring worldwide.1 These patients have clinical manifestations very early, at about 20-30 years of age. PARKIN mutations are responsible of 49% of familial early onset cases and some sporadic cases with early onset.2 The other two recessive forms, PARK6 and PARK7, were reported in two European families previously mapped to chromosome 1p36. In PARK6, the responsible gene was identified as the PTEN-induced putative kinase 1, or PINK1 kinase (1p35-36),3 and PARK7 as DJ-1.4 Mutations in PARKIN are usually rearrangements, deletions or insertions, although point mutations have been also reported. Mutations in DJ-1 are an exon deletion, point deletions and a

substitution Leu166Pro in exon 54 while so far in PINK1 only point mutations have been reported. However, according to simulation and epidemiological studies the genetic cause of at least 50% of familial cases of PD is still unknown,5 and possibly the number of causative genes in PD may be up to twenty. The finding of these genes and the study of the function of the codified protein and its role in the degenerative pathways of PD is a major method to unravel the cause of this disease. To achieve this objective, the study of families with this disorder has been a major tool. In these cases, the study begins with the clinical description of these families and their genetic investigation to rule out the involvement of genes known to date. We report the clinical and genetic data on a Spanish family with a late onset autosomal recessive Parkinsons disease and the molecular genetic exclusion of the previously reported genes causative of the recessive forms of PD (Parkin, DJ1 and PINK1), of mutations in the coding region of -synuclein gene and of the common mutation G2019S in LRRK2 gene.
This article is available from: http://www.jneuro.com

Copyright iMedPub

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:2


doi: 10:3823/311

Patients and methods


The kin group as presently collected is shown in Figure 1. They were originally from a village in a mountain range that is geographically isolated. Affected cases were directly evaluated by at least one of the authors. Evaluation consisted of a physical and neurological examination, and genealogical history to ascertain additional affected family members. In identified cases, we tested serum glucose and creatinine, hepatic function, erythrocyte sedimentation rate, and serum caeruloplasmin and copper levels without finding abnormalities. The diagnosis of PD was based on the presence of two of two or more of the three cardinal clinical symptoms (tremor, ridigity or akinesia) during the period of the study, as well as the absence of signs or symptoms of atypical parkinsonism or secondary causes, plus the presence of clinical response to levodopa therapy. Age at onset was defined as the age when the individual first complained of neurological symptoms, for example rest tremor. Retrospective data on neurological disease in deceased family members was obtained from their living relatives. Affected subjects were videotaped according to a standard protocol and blood samples

were drawn under informed consent for DNA extraction. Total genomic DNA was isolated from blood by Quiagen Maxiprep DNA extraction kit. For homozygosity exclusion, we selected two markers flanking each gene (Parkin: D6S1035F, D6S980F; DJ-1: D1S548F, D1S1612; PINK1: D1S1571F, D1S478F) using the Taiwan Polymorphic Database. These markers where amplified by polymerase chain reaction (PCR) and run in an ABI342 to determine their size. Homozygosity for a mutation in a candidate gene was excluded if both flanking markers of the gene where heterozygous. LRRK2 G2019S mutation was ruled out by PCR amplification and sequencing of exon 41 of the LRRK2 gene. Mutations in the coding region of alpha synuclein were ruled out as well by sequencing of -synuclein exons 1-6. In order to confirm the presynaptic involvement of the disease striatal uptake of iodine-123-betaIoflupane SPECT (Datscan, GE) was assessed in two cases. Patients received a single intravenous injection of 123I-Ioflupane (111185 MBq DaTSCAN, Amersham Health, Buckinghamshire, UK) and underwent a SPECT scan four hours later. sequences. In addition, the postsynaptic D2-receptor density was determined by 123I-iodobenzamide (IBZM) SPECT.

Figure 1. Pedigree of the families.

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:2


doi: 10:3823/311

Results
The pedigree diagram in figure 1 depicts ages, age of onset and Hohen and Yahr stage of disease. Their inheritance pattern is autosomal recessive with a common founder because the three affected members are only from the last generation and it is a highly inbred pedigree considering that two of them are the child of first cousins, that they were born in the same region, a genetic isolate in a mountain range and that they share the family name. These three patients have a slowly progressive Parkinson disease with good levodopa response. Age at onset ranged 66-68 years, and duration of disease ranged 1-7 years. Dementia, pyramidal, cerebellar or autonomic disturbances were not present. Since there are not deceased cases we lack data about neuropathology. The iodine-123-betaIoflupane SPECT (Datscan, GE) of cases Family 1 III-1 (Figure 2A) and family 2 III-3 (Figure 2B) showed a reduced uptake in putamen and caudate nucleus bilateral although asymmetrical, demonstrative that a presynaptic lesion was responsible for the clinical picture. The striatal IBZM uptake was normal in Family 2 case III-3 (Figure 2D), whilst case Family 1 III-1 of had a reduced basal ganglia/frontal cortex ratio (Figure 2C).

Discussion
These patients represent a new form of autosomal recessive familial Parkinson disease that contrariwise to the previous reported forms is characterized by a late clinical onset. This is an interesting finding in the genetics of PD considering that all recessive forms reported so far have early onset,6-9 although there are a few families described with an atypical late onset PD as the cases reported herein.7 The molecular study ruled out the recessive genes described so far. In addition, the common mutation in LRRK2 G2019S was also ruled out considering that this mutation is very frequent is South Europe populations and that mutations in this gene have an incomplete penetrance that can resemble a recessive inheritance. We also ruled out mutations in the coding region of -synuclein, despite mutations so far reported in this gene have an autosomal dominant transmission, because of the key role of this gene in PD. The presynaptic origin of the lesion was confirmed by iodine-123betaIoflupane SPECT DaTSCAN demostrating a degeneration of the nigrostriatal pathway,10 likewise to idiopatic late onset PD, with the anteroposterior gradient typically seen in idiopathic PD11 that conveys the preferential involvement of the posterior striatum because of the preferential cell loss in the ventrolateral tier of the pars compacta of substantia nigra which projects to posterior putamen rather than to caudate.12 The presence of a reduced density of postsynaptic receptors in one case (family 1, case III-1) is not irreconcilable with idiopathic PD since previous studies using 11C-raclopride PET in patients with PARK2 showed reduced binding showed reduced binding in the striatum13. Besides, this patient was on dopamine agonists therapy that was discontinued only 48 hours prior to scanning, a washout phase too short to reverse all the possible down-regulation of postsynaptic D2 receptors known to occur during long-term dopaminergic therapy.14 Late onset disease genetically determined is not simple to detect for reasons such as mortality by unrelated diseases or accident before reaching the age of penetrance, comorbidity and geographical separation of affected relatives. In addition, if the disease is recessive the probability of two or more siblings affected is lower, increasing difficulties to detect these familial forms. The presence of late onset together with a recessive pattern of transmission may justify the complex genetics attributed to neurodegerative diseases, PD among others.15 However, naming it complex genetics points only to our lack of understanding of the genetics of a disease, and this term is abandoned and replaced by another the very moment the mechanism of the disease is unravelled.

Figure 2. Iodine-123-betaIoflupane (Datscan) (upper side) and IBZM SPECT (lower side). A,C, patient Family 1, IV-1; B,D patient Family 1, IV-3

Copyright iMedPub

This article is available from: http://www.jneuro.com

iMedPub Journals

JOURNAL OF NEUROLOGY AND NEUROSCIENCE

2010 Vol.1 No. 3:2


doi: 10:3823/311

References
1. Ishikawa A, Tsuji S. Clinical analysis of 17 patients in 12 Japanese families with autosomal-recessive type juvenile parkinsonism. Neurology. 1996; 47:160-166 2. Lucking CB, Abbas N, Durr A et al. Homozygous deletions in parkin gene in European and North African families with autosomal recessive juvenile parkinsonism. The European Consortium on Genetic Susceptibility in Parkinsons Disease and the French Parkinsons Disease Genetics Study Group. Lancet. 1998; 352:1355-1356 3. Valente EM, Bentivoglio AR, Dixon PH et al. Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36. Am J Hum Genet. 2001; 68:895-900 4. Bonifati V, Oostra BA, Heutink P. Linking DJ-1 to neurodegeneration offers novel insights for understanding the pathogenesis of Parkinsons disease. J Mol Med. 2004; 82:163-174 5. Lking CB, Drr A, Bonifati V, and et al. Association between earlyonset Parkinsons disease and mutations in the parkin gene. N.Engl.J Med. 342, 1560-1567. 2000. 6. Klein C, Hedrich K, Wellenbrock C et al. Frequency of parkin mutations in late-onset Parkinsons disease. Ann Neurol. 2003; 54:415-416 7. Valente EM, bou-Sleiman PM, Caputo V et al. Hereditary early-onset Parkinsons disease caused by mutations in PINK1. Science. 2004; 304:1158-1160 8. Bonifati V, Rohe CF, Breedveld GJ et al. Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes. Neurology. 2005; 65:87-95 9. Kitada T, Asakawa S, Hattori N, and et al. Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism. Nature 392, 605-608. 1998.

10. Catafau AM, Tolosa E. Impact of dopamine transporter SPECT using 123I-Ioflupane on diagnosis and management of patients with clinically uncertain Parkinsonian syndromes. Mov Disord. 2004; 19:11751182 11. Khan NL, Valente EM, Bentivoglio AR et al. Clinical and subclinical dopaminergic dysfunction in PARK6-linked parkinsonism: an 18F-dopa PET study. Ann Neurol. 2002; 52:849-853 12. Bernheimer H, Birkmayer W, Hornykiewicz O et al. Brain dopamine and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. J Neurol Sci. 1973; 20:415-455 13. Hilker R, Klein C, Ghaemi M et al. Positron emission tomographic analysis of the nigrostriatal dopaminergic system in familial parkinsonism associated with mutations in the parkin gene. Ann Neurol. 2001; 49:367-376 14. Antonini A, Schwarz J, Oertel WH et al. Long-term changes of striatal dopamine D2 receptors in patients with Parkinsons disease: a study with positron emission tomography and [11C]raclopride. Mov Disord. 1997; 12:33-38 15. Mayeux R. Mapping the new complex genetic disorders. J Clin Invest 115, 1404-1407. 2005.

Copyright iMedPub

This article is available from: http://www.jneuro.com