J O U R N A L O F T H E

JN JNI • V O L U M E 4 I S S U E 2 • D E C E M B E R 2009

UNPARALLELED DEPTH. UNRIVALED E XCELLENCE.

New JerseyNeuroscience Inst i tute

J F K M E D I C A L C E N T E R

Cover Image: Image displaying all the human chromosomes with an ideogram of chromosome 14 containing the ataxin-3gene which maps to 14q24.3-q32.2. CAG trinucleotide repeat expansions in exon 10 of this gene cause Machado-Josephdisease/spinocerebellar ataxia type 3. Ideogram: Courtesy of National Library of Medicine.http://www.ncbi.nlm.nih.gov/mapview/maps.cgi?taxid=9606&chr=14 Chromosomes: Courtesy of National Human Genome Research Institute & National Institutes of Health. http://images.google.com/imgres?imgurl=http://www.genome.gov/Images/press_photos/highres/97-300.jpg&imgrefurl=http://www.genome.gov/13514624&usg=__yhiuqS2qgZDl3Bvn6Ux5lYreh50=&h=849&w=1732&sz=499&hl=en&start=1&um=1&tbnid=vuiW5n_hz92ZMM:&tbnh=74&tbnw=150&prev=/images%3Fq%3Dchromosomes%2Bpictures%26tbnid%3DvuiW5n_hz92ZMM%26imgtype%3Di_similar%26ndsp%3D18%26hl%3Den%26sa%3DX%26tbnh%3D0%26tbnw%3D0%26um%3D1 http://commons.wikimedia.org/wiki/File:Karyotype_color_chromosomes_white_background.pngDNA strand is an original by Leema Reddy Peddareddygari.

New Jersey Neuroscience Institute at JFK Medical Center . . . . . . . . . . . . . . . . . . . . 2

Aim and Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Editors’ Corner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Evolving treatment options for pain after spinal cord injury . . . . . . . . . . . . . . . . . . . 6

Poli Francois Kouya, D.MSci, PhD and Ratan Banik, MBBS, PhD

**A pediatrician’s approach to basic seizure principles . . . . . . . . . . . . . . . . . . . . 14

Gary N. McAbee, D.O., J.D. and Kavitha Velicheti, M.D.

Evaluation of risk factors for seizures in patients with subarachnoid hemorrhage . . . . . . . . . 22

Abuhuziefa Abubakr, MD, FRCP

A case of homozygous Machado Joseph Disease . . . . . . . . . . . . . . . . . . . . . . . 26

Liudmila Lysenko, MD; Leema Reddy Peddareddygari, MD; Wei Ma, MD; Raji P.Grewal, MD

Ocular myositis in Crohn’s disease with MRI imaging mimicking thyroid ophthalmopathy . . . . . 29

Shan Chen, MD, PhD; Mohammad Fouladvand, MD

**Cerebral ischemia due to venous air embolism during laparoscopic surgery . . . . . . . . . . 36

Aiesha Ahmed, MD; Max R. Lowden, MD; Gary Thomas, MD

What’s New in Neuroscience? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Sudhansu Chokroverty, MD, FRCP, FACP

Instructions to the Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Table of Contents

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** JNJNI CME ActivityReaders interested in earning CME credit are directed to the introductory pages preceding thearticles marked with the asterisks; these pages will provide all the necessary information to getstarted. For more information, please contact Kathleen DeCamp (kdecamp@solarishs.org).

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t w o

New Jersey Neuroscience Institute at JFK Medical Center

New Jersey Neuroscience Institute (NJNI) at JFK Medical Center is a

comprehensive facility designed exclusively for the diagnosis, treatment, and research

of complex neurological and neurosurgical disorders in adults and children. Services

offered at the Institute include programs in minimally invasive and reconstructive

spine surgery, peripheral nerve surgery, brain tumors, dizziness and balance

disorders, epilepsy, sleep, memory problems/dementia, cerebral palsy, stroke,

spasticity, movement disorders, and neuromuscular disorders. As a department of

Seton Hall University’s (SHU) School of Graduate Medical Education, NJNI serves

as the clinical setting for residency training in neurology and fellowship training in

clinical neurophysiology and sleep medicine. For more information on the New

Jersey Neuroscience Institute, call 732-321-7950 or visit the facility online at

www.njneuro.org.

The Journal of the New Jersey Neuroscience Institute (JNJNI) focuses on topics of

interest to clinical scientists covering all subspecialty disciplines of neuroscience as

practiced in the Institute and makes clinical information accessible to all

practitioners. The fundamental goal is to promote good health throughout the

community by educating practitioners and investigating the causes and cures of

neurological and neurosurgical ailments.

JNJNI publishes the following types of articles: editorials, reviews, original research

articles, controversies, case reports, what's new in neuroscience, images in

neuroscience, letters to the editors, and news and announcements.

AIM and SCOPE

EditorsSudhansu Chokroverty, MD, FRCP, FACP

Martin Gizzi, MD, PhD

Editorial Advisory BoardStephen Bloomfield, MD

Raji Grewal, MD

Gay Holstein, PhD

Thomas Steineke, MD, PhD

Michael Rosenberg, MD

Editorial Assistant: Annabella Drennan

Director of Public Relations and Marketing:Steven Weiss

Publishing Office: New Jersey Neuroscience Institute at JFK

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T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e f o u r

Welcome to the 2009 winter edition of Journal of the New Jersey Neuroscience Institute. We are introducing

a new feature offering selected articles for CME credit; please see Table of Contents. In this issue we

are publishing two review articles, one original article, three interesting case reports and three articles included in

our “What’s New in Neuroscience?”

The first article is a timely review article by Kouya and Banik summarizing current treatment options for pain after

spinal cord injury (SCI), which is a major problem in the USA with an estimated 400,000 patients, with 15000 new

injuries each year. A large proportion of such patients suffer from chronic neuropathic pain impacting morbidity and

satisfactory recovery of such patients. There is both pharmacologic and non-pharmacologic treatment available but

none is satisfactory because of a clear lack of understanding about the mechanism of SCI pain.

The second review article by McAbee and Velicheti outlines a pediatrician’s approach to basic principles of

seizure diagnosis and management. This is particularly important now because of a national shortage of child

neurologists. Approximately 0.5% of all children suffer from epilepsy which includes both relatively benign and

more complicated seizure types requiring a different approach to diagnostic procedures and management.

The third article by Abubakr evaluates risk factors for seizures through a retrospective review of records of 75

patients admitted between 1997 and 2000 with a diagnosis of subarachnoid hemorrhage. The only risk factor

identified by the author is the ruptured anterior communicating artery aneurysm. An important point is made that

prophylaxis with antiepileptic drug (AED) reduces the recurrence of seizure, although the author does not

mention the type of AED and the duration of prophylaxis. Despite the usual pitfalls of a retrospective report, this

article directs attention to a prospective study to verify these results.

The next article by Lysenko et al. describes the twelfth case in the literature of homozygous Machado Joseph

disease (MJD or spinocerebellar ataxia – SCA-3). Homozygous cases of any autosomal dominant disease are rare,

occurring with consanguineous marriages. This is a cytosine-adenosine-guanine (CAG) repeat expansion disease

(the cover of the journal shows such an abnormal repeat). The other unique features of this case include relatively

later age of onset of the disease and presentation with spastic paraparesis without extrapyramidal features or

significant ataxia, thus expanding the clinical heterogeneity of homozygous MJD patients.

Editors’ Corner

The fifth article by Chen and Fouladvand deals with a rare case of ocular myositis in Crohn’s disease mimicking

thyroid ophthalmopathy (TO). The characteristic ocular magnetic resonance imaging (MRI) finding in TO

generally associated with thyrotoxicosis is an enlargement of extraocular muscles sparing the tendons which is also

noted in this particular patient but without any evidence of thyroid dysfunction. Patients with ocular myositis

respond very well to corticosteroids as in the present case.

The sixth report by Ahmed et al. is a case of bihemispheric cerebral infarction due to paradoxical venous air

embolism (patient had an unknown patent foramen ovale) resulting from inferior vena cava laceration due to

trocar injury during laparoscopic gastric surgery. The authors describe the presenting signs of gas embolism and

the value of prophylactic transesophageal echocardiography prior to laparoscopic surgery.

The last section comprises our ongoing “What’s New in Neuroscience?” to keep abreast of some of the recent

developments in neuroscience.

We hope you find these articles useful, and in our continuing efforts to meet your highest expectations, we

encourage you to send us your comments and suggestions. If you wish to submit an article for consideration please

send it to the editorial office by email (abdrennan@solarishs.org).

Sudhansu Chokroverty, MD, FRCP, FACP

Martin Gizzi, MD, PhD

Editors, JNJNI

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Spinal cord injury: Perspectives

Most spinal cord injuries (SCI) are caused by

mechanical trauma associated with accidents such as

crashing a motorbike, diving in shallow water, playing

violent sports, being a victim of criminal acts,

occupational injuries in the construction industry and

war injuries.14, 35 There are 400,000 SCI patients in the

USA alone, with nearly 15,000 new injuries each year.

Chronic pain is one of the complications in SCI

patients. The pain may limit recovery of function by

restricting the patient’s ability to participate in

rehabilitation programs. Several studies show that

60-90% of all SCI patients suffer from chronic pain

and one-third of them experience moderate to severe

pain. 4, 17, 48, 58, 25 Neuropathic pain is the most common

type of chronic pain associated with SCI. 48, 58 The pain

results from the abnormal processing of sensory input

due to damage to the nervous system. The pain may

begin at the time of injury or develop slowly over

months or years and it can be unbearable at its worst.

Symptoms and mechanisms of SCI pain

Patients suffering from spinal cord injury pain express

their pain as at-level, below-level or above-level of

the injury.47, 48

At-level SCI pain

Neuropathic pain at-level of injury is due to damage to

the actual nerve roots (“at-level radicular pain”) or to

the spinal cord itself (“at-level central pain”). This pain

may refer to segmental deafferentiation or girdle zone

pain, pain at the border of normal sensation and

anesthetic skin.12, 38, 49 The pain is usually bilateral and

follows a circumferential pattern, often from the

stomach around to the back.12, 66, 49 Like other types of

chronic pain, this can develop during the first few

weeks after initial injury. It may also develop more

slowly over time. Pain is often associated with allodynia

and hyperalgesia. Approximately 38-55% of all SCI

patients suffer from pain at-level of injury.10, 62

Below-level SCI pain

Pain below-level of injury is considered mostly as

central pain.16 The mechanism is not well known but it

may be seen as abnormal spinothalamic function and

central hyperexitability.16 It occurs caudal to the two

dermatome levels below the level of injury.42, 47 Its

distribution is generally regional, involving large areas

such as the anal region, the bladder, the genitals, the

legs, or the entire body below the level of injury. The

pain could also be associated with lesion in the anterior

cord.48 The character is often described as burning or

aching, although other descriptors such as pressure,

heaviness, cold, numbness, and pins and needles are

used.7, 11, 42, 47, 54, Approximately 34% of patients with SCI

suffer from pain below-level of spinal cord injury. The

pain is usually continuous and its intensity can fluctuate

in response to a number of factors including stress,

anxiety, fatigue, smoking, noxious stimuli and weather

changes.42

Above-level SCI pain

Pain Wegener’s granulomatosis of injury is not exclusive

to SCI. It includes similar patterns of neuropathic pain

that are commonly seen in the Complex Regional Pain

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Evolving treatment options for pain after spinal cord injuryPoli Francois Kouya, D.MSci, PhD and Ratan Banik, MBBS, PhD

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Syndromes, reflex sympathetic dystrophy and

compressive mononeuropathy.48 The mechanism and

etiology of this pain may come from the various soft

tissue and/or bony injuries sustained during a traumatic

event. One specific common subtype of above-level

pain is shoulder pain.5

Finding a way to manage pain is one of the

most important research concerns among individuals

with SCI.

Treatment options for SCI-pain: Current

understanding

Effective treatment of SCI pain is notoriously difficult.

Several pharmacological and non-pharmacological

approaches in SCI injury treatment have been used

with different degrees of success. Opioids and

derivates, tricyclic antidepressants, anticonvulsants,

local anesthetics and NMDA receptor antagonists are

used for the pharmacological aspect. Spinal cord

stimulation in neurosurgery is one of the non-

pharmacological management strategies. Analgesic

agents recommended for first and second-line

treatments include tricyclic antidepressants (TCA),

anticonvulsants, serotonin and noradrenalin reuptake

inhibitors and topical lidocaine. Tramadol and

controlled-release opioid analgesics are recommended

as third-line treatments for moderate to severe

pain.48 Recommended fourth-line treatments are

cannabinoids, methadone and anticonvulsants.

Anticonvulsants

Common anticonvulsants used in the treatment of

neuropathic pain from spinal cord injury are

lamotrigine, gabapentin and pregabalin.48, 15 These

drugs are thought to increase γ-amino butyric acid

(GABA)-mediated inhibition and decrease abnormal

neuronal excitability by modulating sodium and calcium

channels and inhibiting excitatory amino acids.15

Although gabapentin and pregabalin (a gabapentin

analogue) are the most frequently used drugs in

neuropathic pain, in some studies gabapentin was not

effective in producing satisfactory pain relief in SCI

patients. Gabapentin at a dose of 1800 mg failed to

relieve SCI pain but it reduced the unpleasant feeling.

In a study performed by Cardenas and Jensen8 only

17% of patients were compliant for use of gabapentin

throughout the course of the disease.

Side effects of gabapentin such as sedation, dizziness

and ataxia limit their use in the treatment of SCI pain.

In a randomized, double-blind, placebo-controlled trial

pregabalin was shown to be effective in reducing a few

types of chronic pain, but it was not significantly

effective in reducing pain symptoms associated with

brain and spinal injury patients.59

Lamotrigine, a well tolerated anticonvulsant was

effective only in relieving spontaneous pain and pain

below the injury level in patients with incomplete spinal

cord injury.15 In some clinical trials, however, dose

titration of lamotrigine up to 400 mg50 failed to produce

significant pain relief in SCI patients. Moreover, 400 mg

of lamotrigine combined with gabapentin, TCA or

NSAID as adjuvant spinal cord injury pain therapy did

not demonstrate efficacy.50

Antidepressants

Antidepressants generally inhibit the reuptake of

noradrenalin and serotonin; few drugs have some

NMDA receptor antagonist properties and opioid-like

effects. Some antidepressants also inhibit sodium

channels and that may contribute to their

antihyperalgesic effect.13 Common antidepressants used

in neuropathic pain SCI patients are tricyclic

antidepressants (TCA). These drugs exert a non-selective

effect on noradrenaline and serotonin reuptake.

Venlaflaxine and imipramin have shown equal potency in

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treating neuropatic pain in SCI.51 It has been proposed

that venlafaxine exerts some of its analgesic effect

through opioid-mediated and adrenergic mechanisms.

Mouse models of acute pain demonstrated that

venlafaxine-induced antinociception was significantly

inhibited by naloxone. Moreover, the antinociceptive

effect of venlafaxine was found to be influenced by the

kappa (κ) and delta (δ) opioid receptor subtypes and the

Alfa-2 (α2) adrenergic receptor.52 The strong side effects

of antidepressants result from their action on the

muscarinic-cholinergic, histaminic and α-1 adrenoceptor.

Sedation, confusion, blurred vision, postural hypotension

and anticholinergic actions (e.g., dry mouth,

constipation, and urinary retention) have been associated

with antidepressants in SCI pain treatment.16, 19

Excitatory amino acid receptor antagonists

The amino acid glutamate is the main excitatory

neurotransmitter in the peripheral and central nervous

system. The release of glutamate will activate the

metabotropic G-protein-coupled receptor and the

ionotropic NMDA and kainate AMPA receptors and

increase intracellular calcium. NMDA glutamate

receptor has been reported in the mechanisms of

central sensitization and hyperalgesia.65 The

contribution of the excitatory NMDA glutamate

receptors and other ionotropic glutamate receptors in

SCI pain was observed in animal studies.3

The NMDA glutamate receptor antagonist ketamine

has demonstrated analgesic efficacy in treating non-

responsive neuropathic pain.19, 60 In the treatment of

experimental neuropathic spinal cord injury pain, the

co-administration of NMDA receptor antagonists with

morphine increases morphine efficacy.31 The direct use

of NMDA receptor antagonists in spinal cord injury

pain is not reported. But methadone, which is an opioid

with NMDA receptor antagonist properties, and

ketamine24 are used in SCI pain treatment.

Spinal cord stimulation

The mechanisms of spinal cord stimulation based on

the gate control theory earlier described by Melzack

and Wall 35 are generally accepted, even though in

recent years accumulating evidence has shown that

gamma-aminobutyric acid (GABA) as well as

adenosine-related mechanisms are involved in epidural

spinal cord stimulation.36 Stimulation to the L1–L2

dorsal columns will produce vasodilation of peripheral

blood vessels. Moreover, the stimulation may activate

interneurons that may reduce the activity of

spinothalamic tract cells and also decrease the activity

of sympathetic preganglionic neurons.36 Spinal cord

stimulation may also reduce the release of

norepinephrine from sympathetic postganglionic

neurons. Spinal cord stimulation antidromically

activates the dorsal root afferent fibers and induces

release of calcitonin gene-related peptide (CGRP) and

nitric oxide.36 This technique has proved to be an

effective and safe means of controlling pain on a long-

term basis but only in selected groups of patients with

SCI pain.29, 37 Some studies showed that 40% of patients

with SCI pain were able to control their pain by

neurostimulation alone. Nevertheless, 12% needed

occasional analgesic supplements to achieve 50% or

more relief of the prestimulation pain.29 The effect and

side effects of spinal cord stimulation may depend on

the level of spinal cord. The risks involve leakage of

spinal fluid, persistent pain at the site of catheter

implantation, and the risks of the surgery itself, such as

bleeding, infection and paralysis (weakness, numbness

and clumsiness) below the level of the implant

electrodes.26 Undesirable changes in stimulation rate

have also been reported. These changes may be due to

changes in nerve cells or changes in the electrode

position.26

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Opioids

Opioids are historically good drugs for pain treatment

but their use is controversial for long term therapy

because of their addictive potential. Opioids produce

their analgesic effect by activating mu (μ), kappa (κ)

and delta (δ) receptors. These receptors are widely

distributed in the peripheral and central nervous

systems.41 Opioid receptors are a type of PTX-sensitive

G-protein-coupled receptor.61 Binding to these

receptors initiates a number of actions including

inhibition of the trans-membrane enzyme adenylate

cyclase, thereby reducing intracellular synthesis of

cyclic adenosine monophosphate (AMP). Opioids also

inactivate voltage-gated calcium channels, thus

inhibiting neurotransmitter release. Opioids stimulate

an inwardly rectifying potassium conductance21 to

reduce neuronal activities through membrane hyper-

polarization. Most of the analgesic effects of opioids

result from activation of the μ opioid receptor. In SCI

pain, the use of opioids will follow the usual stepwise

approach that starts from weak opioids such as codeine

and tramadol to strong opioids such as oxycodone,

morphine and methadone. In some studies, a moderate

dose of intravenous morphine significantly reduced the

intensity of brush-induced allodynia.1 SCI pain is

challenging due to complexities in the mechanisms as

previously described. Although opioids are not the first

choice in treating SCI pain, clinical data show that

opioids are efficacious on SCI pain resistant to other

treatments. Moreover, intrathecal morphine48 and a

mixture of morphine and clonidine49 provided relief in a

proportion of people with neuropathic SCI pain when

other treatment approaches failed. Morphine injected

intravenously significantly relieves SCI pain.1

Successful relief of SCI pain by intrathecal

hydromorphone is also reported.45 Side effects

associated with the use of opioids are respiratory

depression, dizziness, constipation and vomiting.

Problems with opioid pharmacology in SCI pain

A major problem encountered in the use of opioids is

the development of tolerance following long-term use.

Tolerance is defined as a reduction in the response to a

drug after prolonged use which creates the need to

increase the dose to reach therapeutic effect. SCI pain

is chronic and needs long term treatment. Progress has

been made in elucidating mechanisms underlying

opioid tolerance. It has been reported that an ongoing

painful stimulus activates the NMDA receptor, which

increases intracellular calcium ions in the neuron.40 The

increase of intracellular calcium facilitates the

activation of protein kinase C (PKC) and the increase of

nitrous oxide (NO) within the cells. These mechanisms

will reduce the responsiveness of the μ opioid receptor

to its ligand. In keeping with this, it has been shown that

opioid-induced hyperalgesia is prevented by NMDA

receptor antagonists.18 The analgesic effect of opioids is

also reduced by different neuropeptides released after

SCI; these include growth factors and mechanisms

involved in nerve regeneration.33 Cholecystokinin

(CCK) and nerve growth factor (NGF) play a key role

in inducing opioid tolerance.33 Finally, desensitization

and down regulation of opioid receptors after nerve

injury also contribute to reduced efficacy of opioids.

Interactions of CCK, NGF and opioids in SCI

neuropathic pain.

Cholecystokinin

Cholecystokinin (CCK) is a well characterized peptide

that was originally isolated from porcine intestine and

subsequently localized in the central nervous system.39

CCK plays a crucial role in the physiological actions of

opioid peptides.63 The CCK2 antagonists facilitate

opioid-induced analgesia,64 and co-administration of

CCK2 antagonists with morphine protects enkephalins

from degradation leading to strongly enhanced

analgesic responses. Use of CCK2 receptor knockout

mice30, 56 has identied the role of CCK in the

physiological and pathophysiological control of the

opioid system and the interaction of CCK with opioids.63

An antagonistic interaction between opioids and CCK

may exist in the rostro-ventral medulla (RVM) since the

on-cells are excited by CCK and inhibited by opioids.23

CCK is a critical component of descending facilitation of

nociception from the RVM.6

Nerve growth factor (NGF)

NGF was reported to be a pain-related neural

modulator that works by retrograde transport from the

periphery to the spinal cord and is expressed by dorsal

horn neurons.32 NGF produces its effects in the

responsive cells by interacting with either one or both of

two cell surface receptors: tyrosine kinase A (TrkA) and

neurotrophine (p75NTR) receptor.9 Nerve growth

factor (NGF) is involved in pain transduction

mechanisms and plays a key role in many persistent pain

states. Data also suggest a possible involvement of NGF

in the development of central sensitization after acute

peripheral nociceptive stimulation.

Nearly all nerve fibers that innervate the bone

express TrkA and p75NTR, the receptors through which

NGF sensitizes and/or activates nociceptors.20 Nerve

growth factor (NGF) involvement in reducing opioid

efficacy has been reported.

In addition, synergistic effect is observed when anti-

NGF (MNAC13) is administered in combination with

opioids at doses that are not efficacious per se,57

suggesting that inhibiting NGF could potentiate a low

dose of morphine. NGF-induced attenuation of opioid

action was observed and prevented by inhibition of TrkA

auto-phosphorylation.34

NGF interaction with cholecystokinin

The role of CCK and its interaction with NGF after

nerve injury has been reported in few publications. Some

experiments, however, have demonstrated that

cholecystokinin CCK-8 counteracts neuronal deficit

following chemical or surgical lesions in both the central

and peripheral nervous systems and that NGF is

involved in the CCK-induced recovery process.56

Moreover, evidence shows that intra-peritoneal injection

of CCK-8 has the ability to stimulate NGF synthesis in

brain and peripheral organs.56 Up-regulation of CCK in

neuronal regeneration processes has been observed

during nerve regeneration in culture.44 The up-

regulation of CCK-8 during neuronal growth might be

mediated through the stimulation of NGF synthesis.30

These observations suggest that effect of opioids in the

treatment of SCI neuropathic pain may be influenced by

CCK and/or NGF. The precise molecular interaction of

these compounds is open for future studies.

Evolving treatment options from interactions

between NGF, CCK and opioids

In our search for better control of SCI pain, so far, there

have been no investigations on the pharmacological

aspects of opioids in treating SCI pain and possible

involvement of NGF and/or CCK. These factors are

important in the regeneration of the nervous system

after injury. The “weakness” of opioids in treating SCI

pain may depend on their interaction with peptides such

as CCK and NGF involved in nerve recovery and acting

as anti-opioids. Although studies reported that down-

regulation of opioid receptors after nerve injury

decreases the analgesic efficacy of opioids in treating

neuropathic pain,2 some studies show that the reduction

of opioid receptors are followed by an up-regulation,55

which may re-establish opioid analgesia. Atypical

opioids such as buprenorphine, which do not necessarily

depend on opioids receptors,33 could be useful for

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treating SCI pain. Buprenorphine has been reported to

induce tolerance less than morphine,28 and tolerance to

its analgesic effects has not been detected in chronic

pain patients.22 Another problem with opioids is the

activation of the brain reward system following long-

term use. Opioids may activate the kappa opioid

receptor (KOR) dynorphine in the brain reward system,

leading to addiction behavior. Buprenorphine is an

antagonist to the kappa opioid receptor,43 and with its

dual pharmacological properties and therapeutic

efficacy in treating addiction, buprenorphine could

be an alternative therapy to morphine for spinal

injury pain.

Conclusion

While NGF and CCK are involved in the recovery of

the nervous system after injury, they also play a key role

in the analgesic efficacy of opioids as described in this

review. These regeneration factors may not only

interact with opioids, but their probable “effect” on

other drugs used in treating neuropathic pain SCI

should also be considered.

It is evident that the analgesic effect of TCA in treating

SCI is not exclusively explained by their antidepressant

mechanisms. Behavioral and electrophysiological

studies have shown that serotonergic effects of

antidepressants on supraspinal analgesia are mediated

by the periaqueductal gray matter (PAG) and nucleus

raphae magnus,27 indicating the involvement of the

opioidergic systems.

For SCI pain patients, standard drugs should have

few side effects and good efficacy. Thus a new

treatment strategy is necessary. One option is use of

lower doses of analgesic drugs to prevent side effects by

modulating endogenous mediators NGF and CCK or

NGF-CCK. The point where NGF and CCK actions

negatively affect drugs for SCI pain treatments and the

function of these substances in nerve recovery should

be investigated. Better understanding of SCI pain

mechanisms and the effect of opioids, their

mechanisms of action and their interaction with

neuropeptides such as NGF and CCK could benefit the

treatment of spinal injury pain. Determining the effect

of analgesic drugs and the influence of NGF and CCK

at different stages of injury could benefit both

regeneration and pain treatment.

References 1. Attal N, Guirimand F, Brasseur L, Gaude V, Chauvin M,

Bouhassira D. Effects of IV morphine in central pain: A

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554-563

2. Ballantyne JC, Mao J. Opioid therapy for chronic pain. N Engl J

Med. 2003; 349(20):1943-53

3. Bennett AD, Everhart AW, Hulsebosch CE. Intrathecal

administration of an NMDA or a non-NMDA receptor antagonist

reduces mechanical but not thermal allodynia in a rodent model of

chronic central pain after spinal cord injury. Brain Res. 2000;

859(1):72-82

4. Bonica J. Introduction: semantic, epidemiologic, and educational

issues. In: Casey KL, ed. Pain and Central Nervous System

Disease. Raven Press 1991, New York, p. 13–30

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Faculty/Authors: Gary N. McAbee, DO, JD, Director of Pediatric Neurology, NJ Neuroscience Institute, JFK Medical Center,Edison, NJ & Assistant Professor of Neuroscience, Seton Hall University, South Orange, NJ. Kavitha Velicheti, MD, Attending Pediatric Neurologist, NJ Neuroscience Institute, JFK Medical Center,Edison, NJ & Assistant Professor of Neuroscience, Seton Hall University, South Orange, NJ.

Editorial Committee for this CME Activity:Sudhansu Chokroverty, MD, FRCP, FACP, Co-Chair of Neurology (Clinical Neurophysiology and SleepMedicine), New Jersey Neuroscience Institute, JFK Medical Center, Edison, NJ; Professor of Neuroscience,Seton Hall University School of Graduate Medical Education, South Orange, NJ; and Co-Editor, Journal of theNew Jersey Neuroscience Institute.Annabella Drennan, Editorial Assistant, Journal of the New Jersey Neuroscience Institute, NJ NeuroscienceInstitute at JFK Medical Center, Edison, NJ.Martin Gizzi, MD, PhD, Chairperson, New Jersey Neuroscience Institute, JFK Medical Center, Edison, NJ;Professor and Chairperson, Neuroscience, Seton Hall University School of Graduate Medical Education, SouthOrange, NJ; and Co-Editor, Journal of the New Jersey Neuroscience Institute.Carole Kolber, PhD, Administrative Director, Professional Development/CME, JFK Medical Center & ClinicalAssistant Professor, Health Sciences, Seton Hall University School of Health & Medical Sciences, S. Orange, NJ.

Activity Description/Need/Practice Gap: Studies have shown that some generalists feel uncomfortable treating complicated pediatric patients withseizures.1, 2 Although practice parameters regarding pediatric seizures do exist, many generalists are unaware ofthem or do not follow them. General Pediatricians and other primary care physicians need this informationbecause seizures are frequent among child neurology diagnoses and often these patients are referred back to the general pediatrician for routine follow-up. This article discusses some basic general principles about pediatricseizures for the generalist including common pediatric seizure types, the value of EEG and neuroimaging, and principles of antiepileptic drugs (AEDs) and anticonvulsant levels. The goal is to close the gap betweencurrent practice in diagnosing and managing pediatric seizures and what is potentially achievable based on thestate of the science.

Objective: At the conclusion of this CME activity, participants should be able to:1. Discuss and apply basic principles related to seizures and epilepsy in children. 2. Discuss common pediatric epilepsy syndromes, the value of EEG and neuroimaging, and concepts of

antiepileptic drugs.

Audience:General Pediatricians and other Primary Care Physicians, Pediatric Neurologists, Epidemiologists, and Internists

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e f o u r t e e n

CME Activity: A Pediatrician’s Approach To Basic Seizure PrinciplesIntroductory Required Reading

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Accreditation Information:JFK Medical Center is accredited by the Accreditation Council for Continuing Medical Education to providecontinuing medical education for physicians. Credit: JFK Medical Center designates this educational activity for a maximum of .50 AMA PRA Category 1Credit(s).TM Physicians should only claim credit commensurate with the extent of their participation in theactivity.

Conflict of Interest/Content Validation: The Office of CME of JFK Medical Center utilizes the followingmechanisms to identify and resolve conflicts of interest and validate content: 1) Disclosures by faculty andplanning committee of any relationships that might create a potential, apparent or real conflict of interest; 2)Disclosures of off-label drug uses to audience; 3) Participant evaluation of CME activity’s freedom fromcommercial bias; and 4) Faculty Attestation of best available evidence.

Disclosure: The authors for this Journal CME activity, Gary N. McAbee, DO, JD, and Kavitha Velicheti, MD,did not indicate any financial interest/arrangement or affiliation with any corporate organization relevant to thisjournal article. The members of the Editorial Committee, Sudhansu Chokroverty, MD, Annabella Drennan,Martin Gizzi, MD, PhD, and Carole Kolber, PhD did not indicate any financial interest/arrangement oraffiliation with any corporate organization relevant to this journal article. The content does not includeinformation on experimental or off-label uses of pharmaceutical products.

Educational Media: This self-study CME activity entails reading a selected article from the Journal of the New Jersey NeuroscienceInstitute and completing a post-test and evaluation form which demonstrate reflection on the article content,including changes in knowledge, and intended changes in practice patterns. It has been developed as a JournalCME activity through the Office of CME of JFK Medical Center in collaboration with the authors.

Learner Responsibility: The learner is responsible for the following:1. Reading the activity description, learning objectives, target audience, disclosure information,

and printed article.2. Completing a 5 question post-test with a minimum score of 80% and completing an evaluation form.3. Completion of the post-test and evaluation form serves as validation of participation in this activity.

Participants will be issued certificates of completion/entered into the JFK/ MSL physician participation database.

Instructions for Receiving Post-Test and Evaluation FormPlease email your request for the post-test and evaluation form to kdecamp@solarishs.org. Upon receipt, linksto access the post-test and evaluation form will be forwarded to your email address. After successful completion,you will receive an electronic certificate.

Estimated Time To Complete: 30 minutes (This includes required reading of introductory information,journal article and completion of post-test and participant evaluation form).

Release Date: December 1, 2009

Termination Date: November 30, 2012

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T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E R

Abstract

The national shortage of child neurologists is likely to

continue to place additional burden on general

pediatricians to handle non-complicated neurological

problems in children, either alone or in consultation with

available regional child and adult neurologists. Seizures

are frequent among child neurology diagnoses. Often

these patients are referred back to the general

pediatrician for routine follow-up. Studies have shown

that some generalists feel uncomfortable treating

complicated patients.1 Although practice parameters

regarding pediatric seizures do exist, many generalists

are unaware of them or do not follow them.2, 3 This

review discusses some basic general principles about

pediatric seizures for the generalist including common

pediatric seizure types, the value of EEG and

neuroimaging, and principles of antiepileptic drugs

(AEDs) and anticonvulsant levels.

Overview

Uncomplicated seizures and epilepsy (i.e., seizures that

are not overly difficult to control with antiepileptic

medication) are common disorders in the U.S.

Approximately one out of ten persons in this country will

have a seizure in their lifetime. There is a bimodal

distribution with the most common incidences of

seizures occurring in childhood and the elderly.

Epilepsy, defined as two or more seizures without acute

provocation, occurs in approximately 0.5% of all

children.4 Not all pediatric seizures require extensive

diagnostic workup or treatment. Many seizures in

childhood are benign, especially if they are idiopathic.

Common pediatric epilepsy syndromes include febrile

seizures, benign childhood epilepsy with centrotemporal

spikes (i.e., rolandic seizures), complex partial seizures

and juvenile myoclonic epilepsy.

Seizure type vs. epilepsy syndrome

Pediatricians should be aware that diagnosing the type of

seizure is not simply an academic endeavor for

neurologists, but has relevance for workup, treatment

and prognosis. The diagnosis of seizures is a two step

process. First, one determines the type of the seizure,

e.g., tonic-clonic, absence, complex partial, myoclonic

(Table 1). Then one determines whether the seizure fits

A pediatrician’s approach to basic seizure principles

Gary N. McAbee, D.O., J.D. and Kavitha Velicheti, M.D.

Table 1. Classification of seizures*

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Table 2. Genetic & Developmental Epilepsy Syndromes by Age of Onset*

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into a specific “epilepsy syndrome,” e.g., febrile,

rolandic, juvenile myoclonic, infantile spasms (Table 2).

Epilepsy syndromes are typically defined by their

clinical and electroencephalographic (EEG) features,

may or may not require additional diagnostic testing,

may require a specific AED treatment, and may have a

predictable prognosis. For example, a teenager

presenting with a new onset generalized tonic-clonic

seizure will require further history about early morning

myoclonic jerks and/or absence episodes. If either

myoclonus or absence episodes are present, the teenager

may not have experienced an idiopathic tonic-clonic

seizure (which does not require treatment) but instead

has juvenile myoclonic epilepsy (JME). Distinguishing

this is important because JME may require prolonged

treatment with specific AEDs due to the high risk of

lifelong recurrence of seizures.

Febrile Seizures

Febrile seizures (FS) occur in 2-5% of infants and

children between the ages of 6 and 60 months (peak 18-

24 months). There can be no evidence of central nervous

system infection, metabolic disorder or prior afebrile

seizure before classifying a seizure as a FS. Most are

“simple,” i.e., generalized, single event and brief (lasting

less than 15 minutes in duration). Approximately one-

third are “complex,” i.e., focal, multiple, or prolonged

(lasting longer than 15 minutes duration). Neuroimaging

is typically not required and EEGs are not helpful in

predicting the risk of either recurrent FS or future

epilepsy. An American Academy of Pediatrics practice

parameter states that lumbar puncture should be

considered in those less than 18 months because clinical

meningeal signs may be lacking,5 but more recent data

question the usefulness of this.6 The recurrence rate of

FS is 30% but higher (50%) if first FS onset is before 12

months of age. If FS occur a second time, the risk of a

third occurrence is 50%. Simple FS do not cause death,

brain damage or cognitive difficulties. The major

morbidity associated with FS is association with future

development of epilepsy. Risk of future epilepsy is

approximately 1-4% depending on risk factors present.

The highest risk is in children with a complex feature

(especially if prolonged), immediate family history

of afebrile seizures, and a prior abnormal

neurodevelopmental status. Treatment (phenobarbital,

primidone or valproic acid prophylactically, or else oral

valium during the time of fever) may reduce recurrences,

but most children do not require treatment unless there

are multiple events because the benefit of treatment

may not outweigh its risks.7 Rectal diazepam can be used

to stop an acute seizure. Parents must be counseled and

reassured about the benign nature of febrile seizures.

Treatment of fever with antipyretics is reasonable but

may not necessarily prevent the seizure from recurring.

Benign Childhood Epilepsy with Centrotemporal

Spikes (BCECTS; Rolandic)

This epilepsy syndrome is the most common focal

epilepsy in childhood. It is genetically inherited as an

autosomal dominant trait with variable penetrance.

Onset is typically between ages 3 and 13 years. The

typical focal seizure involves anarthria (sudden inability

to speak). Drooling or facial twitching may also occur.

The child must be asked about focal episodes as they

might be ignored since they are brief in duration, are

unassociated with loss or alteration of consciousness, and

have no post-ictal phase. More obvious are early

morning or nocturnal generalized tonic-clonic seizures

which occur in about half of children; children who

present with these types of generalized seizures should

be asked about the focal episodes. EEGs may be helpful

for diagnosis as they demonstrate a typical pattern of

unilateral or bilateral centrotemporal spike and wave.

Neuroimaging is not routinely required if the

presentation is typical. This epilepsy syndrome is

important to identify because it is “age-dependant,” i.e.,

seizures generally stop by ages 14-16.

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Complex Partial Seizures (formally, partial

seizures with complex symptomatology)

Complex partial seizures (previously called psychomotor

seizures) can occur at any age and have a variable

frequency of both seizures and prognosis. Alteration of

consciousness is typical. Symptoms are variable and

many tend to localize around the eyes (dazed look, glassy

eyed, “drugged”), mouth (lip smacking, gurgling,

drooling) and abdomen (nausea, vomiting, funny

abdominal sensation). Most last for minutes and have a

post-ictal phase of confusion, headache, lethargy and/or

sleep. Secondary generalization to a tonic-clonic seizure

can occur; thus, a witness to a generalized seizure should

be asked about behavior prior to the generalized event.

Magnetic resonance imaging (MRI) should be

considered to detect abnormalities such as mesial

temporal sclerosis which may be a predictor that the

seizures may become refractory to AEDs. This seizure

type usually requires treatment as recurrence rate can

be high.

Juvenile Myoclonic Epilepsy (JME)

This epilepsy syndrome is a “triad” of seizure types:

myoclonic, generalized tonic-clonic and absence; only

two out of three may be present. The absence episodes

mimic “petit mal” seizures. The generalized episodes

often occur upon awakening. Onset is usually between

the ages of 12 and 18 years. The myoclonus also typically

occurs in the early morning, unassociated with alteration

of consciousness, and consists of rapid repetitive neck

and shoulder flexion or extensor spasms. Patients may

complain that “things fly out of [their] hands.” Sleep

deprivation can provoke a seizure. EEG may be helpful

for diagnosis by demonstrating patterns such as

generalized 4-6 Hz polyspike and wave and/or a

photoconvulsive effect. It is important to identify this

epilepsy syndrome since many patients will have lifelong

seizures and lifelong treatment may be necessary. This

epilepsy syndrome may have specific antiepileptic

medications that are effective such as valproic acid,

levetiracetam, lamictal and zonisamide.

Value of EEG

The diagnosis of a seizure is based on clinical history and

not necessarily on EEG. This is because many children

with definite seizures will have normal or near normal

interictal EEGs. In one large study of children with

new onset seizures, 60% of remote symptomatic

seizures (etiology known) and 38% of idiopathic seizures

had abnormalities on EEG.8 Only epilepsy syndromes

such as absence (“petit mal”) epilepsy and infantile

spasms will invariably have an abnormal EEG. The

EEG helps establish the diagnosis of epilepsy by

assisting in differentiating seizure events from non-

seizure events and by defining the epileptic syndrome.

In addition, abnormalities on the EEG can be a useful

predictor of recurrence after a first unprovoked seizure.

The typical EEG abnormality that correlates with

seizures is a spike or sharp wave, possibly followed by a

slow wave. Spikes and sharp waves in the occipital or

central region may not necessarily be epileptiform in

nature and may be seen in other conditions (e.g.,

migraine).9 Slow wave activity is common in the period

following the seizure. Early EEGs (within 48 hours of

seizure) may be valuable when the clinical history is

vague since a higher percentage of EEG abnormalities

occur in this time frame.10 Serial EEGs and sleep

deprived EEGs can also be valuable and increase the

yield of finding an abnormality. The severity of the

EEG abnormality does not necessarily correlate with

the severity of the seizures. Several neurological

conditions, such as autism and Fragile X syndrome, can

have severely abnormal EEGs in the absence of clinical

seizures. Routine follow-up EEGs are generally not

valuable in management. Up to 3% of children without

seizures have abnormal EEGs, especially if they have

other evidence of brain injury.11

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T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E R

Value of Neuroimaging

A review of studies that assessed neuroimaging in

children with a first seizure noted that up to 20% will

have abnormal CT studies.12 For children with epilepsy,

abnormalities exist in up to a third.12 MRI studies, which

are fewer, have noted up to a third of children with new

onset seizures will have an abnormality.12 Nevertheless,

an average of only 2% (maximum 11%) of children will

have an abnormality considered to be therapeutically

significant (e.g., tumor, cyst, hydrocephalus).12 CT scans

are valuable in detecting blood (trauma) and calcium

(TORCH, neurocysticercosis), and MRIs are valuable in

detecting developmental brain defects. The practice

parameter of the American Academy of Neurology/

Child Neurology Society/ American Epilepsy Society has

no definite recommendation for neuroimaging after a

new onset seizure.12 Neuroimaging is not usually needed

for epilepsy syndromes such as childhood or juvenile

absence epilepsy, juvenile myoclonic epilepsy or benign

childhood epilepsy with centrotemporal spikes

(Rolandic epilepsy).13 But neuroimaging should be

strongly considered for children with other types of

epilepsy. The practice parameter recommends that

MRI is the preferred modality when imaging is obtained

and that nonurgent MRI be seriously considered in a

child who also has cognitive or motor impairment of

unknown etiology, unexplained abnormalities on

neurological exam, a seizure of focal onset, an EEG that

does not represent a benign partial or primary

generalized epilepsy, or in children under one year of

age.12 Thus, consideration of neuroimaging is contingent

on clinical circumstances as well as whether an imaging

test needs to be done urgently (usually with CT) or not

(preferably with MRI). In addition, if CT is being

considered, the benefits of the information gained

should be assessed in the context of the radiation

exposure from the CT.

Comorbid conditions

Any practitioner treating children and adolescents with

epilepsy should screen for comorbid conditions. Anxiety

and depression are common in children and adolescents

with seizures, even after their initial episode.14, 15

Antiepileptic Drugs

Most children’s seizures will be controlled by the first

AED selected. Doses should be titrated slowly, if

possible, to minimize side effects and maximize

compliance. The typical approach is to increase a dosage

until seizures are controlled or side effects occur.

Monotherapy is the goal, as multiple medications

increase the risk of drug-drug interaction with resulting

side effects. Treatment of some epilepsy syndromes

requires specific AEDs (e.g., valproic acid or

levetiracetam as a choice for JME). Parents should be

informed that treatment will likely lower the risk of

recurrence but will not guarantee that the child will

remain seizure free. Also, anticonvulsant medication

may be effective to prevent recurrences, but may do

little in altering the prognosis for long term remission

(thus, the term antiepileptic drug or AED is a

misnomer).16

Substitution with generic AEDs continues to be

controversial. Breakthrough seizures have been

reported when a trade name product has been replaced

with a generic.17 Practitioners should be aware that

multiple manufacturers make multiple generic versions

of the same AED and that each generic may not be

therapeutically equivalent to each other or to the trade

name product.17, 18

Discontinuing AED TreatmentThe majority of children whose seizures are in remission

while taking AEDs will remain seizure free when the AED

is withdrawn.19 In general, maintenance treatment with an

AED is recommended for a two-year seizure-free period.

p a g e t w e n t y - o n e

Uncontrolled seizures and progressive neurological illness

are two examples of indicators for continuing treatment.

Factors that increase the risk of recurrence include remote

symptomatic etiology, abnormal EEG and seizure onset at

less than 2 years of age.19 If an initial discontinuation trial

is unsuccessful, AEDs are usually restarted.

Approximately 50% of children will then become seizure

free for a sufficient amount of time that a second trial of

discontinuation is possible.19

“Therapeutic” Drug Levels

This concept is often misunderstood by non-neurology

physicians. These levels are established via animal and

human studies, the latter typically involving patients

with refractory seizures who may require higher serum

levels to be effective. There is no “magic” serum level

that is “therapeutic.” Increasing a dose to reach a

certain serum level in a child who is seizure free might

only result in side effects. The therapeutic dose for an

individual child is the dose in which the child is seizure

free and without side effects. For example, the typical

“therapeutic” level for phenytoin in most laboratories is

reported as 10-20 mg/dl. Yet experienced epileptologists

will report patients who are seizure free with serum

levels between 5 to 25 mg/dl.20 Indications for obtaining

serum levels are poor seizure control, evaluation of drug

toxicity and documentation of compliance.

Dodson summarized this concept well: changing the

dosage of an anticonvulsant drug based solely on the

basis of a serum drug level is like “driving a car looking

at the speedometer and not out the window. Wrecks are

going to be frequent and inevitable”.20

References1. Smith K, Siddarth P, Zima B, Sankar R. Unmet mental health

needs in pediatric epilepsy: insights from providers. EpilepsyBehav 2007;11(3):401-408.

2. Bale JF, Caplan DA, Bruse JD et al. Practice parameters in childneurology: do pediatricians use them. J Child Neurol 2009 March18, epub ahead of print PMID 19295180

3. Shaked O, Pena BM, Linares MY et al. Simple febrile seizures:

are the AAP guidelines regarding lumbar puncture beingfollowed? Pediatr Emerg Care 2009;25(1):8-11

4. Hauser WA. The prevalence and incidence of convulsive disordersin children. Epilepsia 1994;35(suppl 2):S1-6.

5. Practice Parameter: the neurodiagnostic evaluation of the childwith a first simple febrile seizure. American Academy ofPediatrics. Provisional Committee on Quality Improvement,Subcommittee on Febrile Seizures. Pediatrics 1996;97:769-75.

6. Kimla AA, Capraro AJ, Hummel D. et al. Utility of lumbarpuncture for first simple febrile seizure among children 6 to 18months of age. Pediatrics 2009;123:6-12.

7. Steering Committee on Quality Improvement and Management,Subcommittee on Febrile Seizures. Febrile seizures: clinicalpractice guideline for the long-term management of the child withsimple febrile seizures. Pediatrics 2008;121:1281-1286.

8. Shinnar S, Kang H, Berg AT, Goldensohn ES, Hauser WA, MosheSL. EEG abnormalities in children with a first unprovokedseizure. Epilepsia 1994;35(3):471-476.

9. Mizrahi EM. Avoiding the pitfalls of EEG interpretation inchildhood epilepsy. Epilepsia 1996;37(suppl 1): S41-51.

10. King MA, Newton MR, Jackson GD, et al. Epileptology of thefirst seizure presentation: a clinical, electroencephalographic, andmagnetic resonance imaging study of 300 consecutive patients.Lancet 1998;352:1007-11.

11. Cavazzuti GB, Capella L, Nalin A. Longitudinal study ofepileptiform EEG patterns in normal children. Epilepsia1980;21:43-55.

12. Quality Standards Subcommittee of the American Academy ofNeurology, the Child Neurology Society, and the AmericanEpilepsy Society. Practice parameter: evaluating a first nonfebrileseizure in children. Neurology 2000;55:616-623.

13. Gaillard WD, Chiron C, Helen Cross J, Simon Harvey A, et al.ILAE Committee for Neuroimaging, Subcommittee for PediatricNeuroimaging. Guidelines for imaging infants and children withrecent-onset epilepsy. Epilepsia 2009;50(9): 2147-2153.

14. Ekinci O, Titus JB, Rodopman AA, Berkem M, et al. Depressionand anxiety in children and adolescents with epilepsy: prevalence,risk factors, and treatment. Epilepsy Behav 2009 Jan;14(1):8-18.Epub 2008 Oct 18.

15. Loney JC, Wirrell EC, Sherman EM, Hamiwka LD. Anxiety anddepressive symptoms in children presenting with a first seizure.Pediatr Neurol 2008;39(4):236-240.

16. Camfield P, Camfield C. Special considerations for a first seizurein childhood and adolescence. Epilepsia 2008;49 (Suppl 1):40-44.

17. Gidal BE, Tomson T. Debate: substitution of generic drugs inepilepsy: is there cause for concern. Epilepsia 2008;49 (suppl 9):56-62.

18. Duh MS, Paradis PE, Latremouille-Viau D, Greenberg PE, Lee,SP, Durkin MB, Wan GJ, Rupnow MFT, LeLorier J. The risks andcosts of multiple-generic substitution of topirimate. Neurology2009;72:2122-2129.

19. Shinnar S, Berg AT, Moshe SL, Kang H, Alemany M, GoldensohnES, Hauser WA. Discontinuing antiepileptic drugs in childrenwith epilepsy: a prospective study. Ann Neurol 1994;35(5):534-545.

20. Dodson WE. Level off (editorial). Neurology 1998;51:S8-14.

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t w e n t y - t w o

O r i g i n a l R e s e a r c h

Abstract

Objective: To evaluate risk factors for seizures in

patients with subarachnoid hemorrhage (SAH) and to

evaluate if prophylactic antiepileptic drug (AED) use

decreases seizure occurrence.

Background: SAH is associated with significant

morbidity and mortality. In patients with SAH, 22%

develop early seizures (within 2 weeks) and 8% have late

onset seizures. CT evidence of infarct and a Hunt and

Hess score > 3 are among the reported risk factors

associated with seizures.

Methods: Records of 75 patients admitted between 1997

and 2000 with the diagnosis of subarachnoid

hemorrhage were reviewed. The cohort was divided into

two groups: 1) patients with seizures and 2) patients

without seizures. Comparisons were made based on the

following variables: patient demographics (age and

gender), Hunt and Hess score, infarct on CT scan,

intracerebral hemorrhage (ICH), intraventricular

hemorrhage (IVH), acute hydrocephalus, aneurysm

location and use of prophylactic AED. Fisher’s exact test

and Student’s t-test were utilized for the analysis of the

categorical and continuous variables.

Results: The study included 29 males and 46 females,

with a mean age of 55 years and an average Hunt and

Hess grade of 2.8. Seventeen out of 75 patients had

seizures. Early seizures occurred in 76.4% of these

patients. Anterior communicating artery aneurysm

(ACOM) was significantly associated with seizures

(p=0.04). No other clinical or radiological predictors of

seizures were identified. Use of AED prophylaxis was

significantly associated with reduced seizure occurrence

(p= 0.00012).

Conclusions: In these SAH patients treatment with

AED prophylaxis reduced seizure occurrence. Only

ruptured anterior communicating artery aneurysm was

associated with an increased risk of seizures.

Introduction

Complications following subarachnoid hemorrhage

(SAH) may result in significant morbidity and mortality.

These complications include among others vasospasm,

hydrocephalus, rebleeding and seizures. In patients with

SAH, 22% develop acute seizures (within 2 weeks) and

8% have late onset seizures. Several clinical variables

have been reported to be associated with the risk of

developing seizures after SAH.1, 2, 4, 5 Among these are

CT evidence of infarct and Hunt and Hess scores higher

than 3.

Indications for seizure prophylaxis have remained

poorly defined. Some physicians consider AED

prophylaxis a standard of care; others may choose to

treat seizures once they occur.

Evaluation of risk factors for seizures in patients with subarachnoid hemorrhage

Abuhuziefa Abubakr, MD, FRCP.

p a g e t w e n t y - t h r e e

The primary purpose of our study was to identify risk

factors associated with developing seizures after SAH.

Secondarily, we sought to evaluate if prophylactic AED

use decreases seizures in SAH.

Methods

Patients included in this retrospective study were more

than 18 years of age and admitted to JFK Medical

Center (between 1997 and 2000) with primary diagnosis

of SAH. New Jersey Neuroscience Institute is a tertiary

care, neurological and neurosurgical facility and part of

JFK Medical Center. Also part of JFK Medical Center is

the Johnson Rehabilitation Institute, a referral center

for New Jersey and New York. Patients were identified

from the hospital database. Medical records of 83

patients with a mean follow-up duration of 8 weeks were

reviewed. Eight were eliminated because of pre-morbid

seizures or length of stay less than 24 hours. Seventy-

five patients were enrolled in the study. Diagnosis of

SAH was documented by CT scan and aneurysm by

cerebral angiography. Age and gender were included as

demographic data. Clinical data consisted of Hunt and

Hess score and seizures. Radiological data were

obtained regarding associated infarct, acute

hydrocephalus, intraventricular hemorrhage (IVH),

intracerebral hemorrhage (ICH) and location of the

aneurysm.

The occurrence of a seizure was identified upon a

convincing description by a non-medical witness or a

note by nursing staff or physician. Loss of consciousness

without jerking movements or urinary incontinence was

not considered to be a seizure. Seizures occurring

within 2 weeks following the SAH were defined as acute

seizures and more than 2 weeks were considered late

seizures.

Statistical analysis was done using Fisher’s exact

test (categorical variables) and Student’s t-test

(continuous variables). See tables.

Results

Etiology of SAH: aneurysm in 54 patients, arterio-

venous malformation in 5, hypertension in 6, trauma in

one, spinal anesthesia in one, anticoagulant in one and

unknown in 7 patients.

Twenty-nine males and 46 females were included in

the study, with a mean age of 55 years. Seventeen

patients out of 75 with a mean age of 54 years developed

seizures (22.6%). Thirteen out of 17 patients had early

onset seizures (76.4%) and 4 patients had late onset

seizures. Hunt and Hess score for the seizure group was

3.0 and for the seizure-free group 2.76. Cerebral

infarction occurred in 6 out of

the 17 patients with seizures,

compared to 12 of the seizure-

free patients. Intracerebral

hemorrhage occurred in 5

patients with seizures and 19

patients without seizures.

Intraventricular bleeding was

observed in 9 patients with

Table 1. Complications of SAH and seizures

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t w e n t y - f o u r

O r i g i n a l R e s e a r c h

seizures and in 21 patients without seizures.

Hydrocephalus was present in 9 patients with seizures

and 25 patients without seizures (Table 1).

The association between anterior communicating

aneurysm (ACOM) and seizure occurrence was

significant (p= 0.04). A trend towards statistical

significance was observed for the association between

cerebral infarct, Hunt and Hess scores higher than 3 and

seizures. In concordance with previous studies, no other

clinical or radiological predictors of seizures were

observed (Table 2).1, 3

A reduced incidence of seizures was observed upon

administration of AED prophylaxis (p=0.0015; Table 3).

Discussion

The incidence of epileptic seizures in the study sample

is 22.6%, which coincides with the incidence reported in

previous studies (ranging between 9-21%). It is

important to note that our cohort included patients with

non-aneurysmal SAH.

The main reasons for the utilization of AED

prophylaxis in patients with SAH are 1) seizures

precipitating re-rupture of the aneurysm or AVM

secondary to increase in blood pressure and 2) seizures

causing metabolic stress, in turn leading to pathological

increase in metabolic demand in a baseline state of

decreased cerebral flow due to swelling or vasospasm.1

Both reasons can increase neurological morbidity and

mortality. The goal is to identify patients with increased

risk of seizures associated with SAH and to place them

on AED.

In concordance with previous studies1, 3 we did not

find any significant risk factors for the development of

seizures apart from location of the aneurysm in the

anterior communication artery. The trend towards

significance for cerebral infarct and a higher Hunt and

Hess score was also reported previously.2, 4, 5

In our study an ACOM location of the aneurysm was

found to increase the risk of seizures. To our knowledge,

only one recent study1 found ACOM to be the most

common location of the ruptures aneurysm (31%) in

SAH. In the same study a higher representation of

ACOM aneurysm was found in patients with seizures

than in patients without seizures, but no statistical

significance was obtained.1

The efficacy of AED prophylaxis is unclear from the

literature [1]. Our results suggest that the incidence of

seizures in patients on AED prophylaxis is significantly

reduced (p=. 0.0015). The risk of epilepsy after SAH was

Table 3. Antiepileptic drugs and seizures

Table 2. Location of aneurysm and seizures occurrence

p a g e t w e n t y - f i v e

not evaluated in the current study. Most of our patients

had acute seizures (76.4%), confirming data from

previous literature.1,2,7,8 Acute seizures are caused by

metabolic imbalance at the focus, as opposed to late

seizures, which are related to the scarring process of

epilptogensis. Various studies have examined the risk of

the development of epilepsy in patients with acute

seizures. In a study by Olafsson et al.3 25% of the

patients developed epilepsy within 4 years of the insult.

Seven out of 10 patients with acute seizures (70%)

developed epilepsy. On the other hand, Hasan et al.2

did not find an increased risk of developing epilepsy in

SAH patients with epileptic seizures in the first 12

hours following the initial bleed.

Based on our results we recommend the use of AED

prophylaxis in all patients with SAH and especially in

those with ACOM aneurysm rupture as the cause for

cerebral hemorrhage. Further larger prospective

studies are necessary to confirm our data and to look at

the duration of using AED prophylaxis.

Acknowledgements

I thank Dr I. Wambacq for assistance with the

statistical analysis.

References

1. Rhoney DH, Tipps LB, Murry KR, Basham MC, Michael DB,Coplin WM. Anticonvulsant prophylaxis and timing of seizuresafter aneurysmal subarachnoid hemorrhage. Neurology 2000;55:258-265.

2. Hasan D, Schonck RS, Avezaat CJ, Tanghe HL, van Gijn J, van derLugt PJ . Epileptic seizures after subarachnoid hemorrhage. AnnNeurol 1993;33:286-291.

3. Olafsson E, Gudmundsson G, Hauser WA. Risk of epilepsy in longterm survivors of surgery for aneurysmal SAH : a population basedstudy in Iceland. Epilepsia, 2000; 41(9):1201-1205.

4. Ohman J. Hypertension as a risk factor for epilepsy afteraneurysmal subarachnoid hemorrhage and surgery. Neurosurgery1990; 27:578-581.

5. Pinto AN, Canhao P, Ferro JM. Seizures at the onset ofsubarachnoid haemorrhage. J Neurol 1996; 243:161-164.

6. Rose FC, Sarner M. Epilepsy after ruptured intracranial aneurysm.Br Med J 1965; 1:18-21.

7. Sundaram MB, Chow F. Seizures associated with spontaneoussubarachnoid hemorrhage. Can J Neurol Sci 1986; 13:229-231.

8. Hart RG, Byer JA, Slaughter JR, Hewett JE, Easton JD.Occurrence and implications of seizures in subarachnoidhemorrhage due to ruptured intracranial aneurysm. Neurosurgery1981;8:417-421.

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t w e n t y - s i x

C a s e R e p o r t

Introduction

The spinocerebellar ataxias (SCAs) are a clinically and

genetically heterogeneous group of neurodegenerative

disorders caused by cytosine-adenosine-guanine (CAG)

trinucleotide repeat expansions. Machado-Joseph

Disease (MJD) or SCA-3 was originally described in

Portuguese Azores islands,

and currently it is the

most common autosomal

dominant SCA worldwide.

It is caused by CAG repeat

expansion in the exon

10 of MJD gene which

codes for the ataxin-3

protein and maps to

chromosome14q24.3-q31.

The number of CAG

repeats in normal individual

ranges from 12 to 40 while

affected individuals carry 51

to 86 CAG repeats (Fig. 1)

in the disease producing allele.1

MJD is an autosomal dominant disorder resulting

from presence of a disease causing CAG repeat

expansion in only one allele. Homozygous cases of any

autosomal dominant disease are rare, however, they can

occur in regions where consanguineous marriages are

common. There have been eleven cases of genetically

confirmed homozygous MJD described in the literature,

2 cases of Azorean origin, 3 cases of Japanese origin and

6 patients of Jewish descent from a small isolated region

in Yemen.2, 3, 4, 5, 6 In addition, two siblings of Azorean

origin with early onset and rapid progression of MJD

were reported. They were not genetically confirmed but

presumed to be homozygous; one of the children died

eight years after the onset of

symptoms.7 In homozygous

MJD cases, the disease

course had a wide range of

age at onset (4-43 years old)

with more pronounced extra

pyramidal signs and

pyramidal changes. The

disease appears to be

especially severe in the

pediatric population. After

normal development, these

children had regression

in motor skills, bulbar

symptoms (difficulty swallowing,

dysarthria), extrapyramidal changes (dystonia,

bradykinesia and tremor), upper motor neuron signs and

ataxia. Five years after onset the affected individuals

became nonambulatory and were bedridden. Two

patients with disease onset at the age of 16 years and 28

years presented with the development of spasticity,

dysphagia, dysarthria, nystagmus and severe generalized

dystonia and became nonambulatory within four years.3,4

A case of homozygous Machado Joseph Disease

Liudmila Lysenko, MD; Leema Reddy Peddareddygari, MD; Wei Ma, MD; Raji P.Grewal, MD.

Figure 1. Image displaying all the human chromosomeswith an ideogram of chromosome 14 containing theataxin-3 gene which maps to 14q24.3-q32.2. CAGtrinucleotide repeat expansions in exon 10 of this genecause Machado-Joseph disease/spinocerebellar ataxiatype 3. (See inside front cover for full description.)

p a g e t w e n t y - s e v e n

The latest onset of homozygous MJD described was 43

years old and he presented with REM behavior disorder

followed by ataxia, bulbar changes, mild spasticity and

psychiatric symptoms.6 None of these cases described

exhibited sensory changes.

We report a patient with homozygous MJD

presenting with spastic paraperesis.

Case Report

Our patient, a 33-year-old male of Portuguese/Brazilian

descent, presented with onset of muscle cramps,

twitching in his calves and spastic gait disturbance about

4 years prior to evaluation. These symptoms had been

slowly progressive since onset. There were no ocular or

bulbar complaints, weakness or sensory symptoms.

His past medical history was unremarkable. Family

history disclosed that his parents were first cousins and

that both his father and mother became symptomatic at

the age of 40 years. In addition, his paternal grandfather

and a cousin on his father’s side also had similar

symptoms with onset around 40 years of age (Fig. 2).

The patient’s neurological examination revealed a

normal mental status, normal cranial nerve and sensory

examinations. The extraocular movements were intact

and there was no nystagmus. His speech and swallowing

were preserved. He showed full strength with spastic

muscle tone in both upper and lower extremities;

fasciculations were observed in the tongue and muscles of

both upper and lower limbs. The muscle stretch reflexes

were increased and plantars were extensor bilaterally. He

had mild difficulty with tandem gait. He had no limb

ataxia. No extrapyramidal findings were noted.

The patient’s metabolic panel including B12, folate,

thyroid-stimulating hormone, rapid plasma reagin and

aldolase were normal. His creatine kinase levels were

elevated (978 units/L, normal range in males is 38 - 174

units/L). Magnetic resonance imaging of the brain did

not reveal any evidence of cerebellar atrophy. An

electrophysiological study showed no evidence of

generalized sensory-motor or sensory neuropathy.

Needle electromyography revealed fasciculations in

many muscles sampled from upper and lower

extremities. Motor unit potential morphology and

duration were normal; except for the presence of

fasciculations, no abnormal spontaneous activity was

observed. Taking into account his Portuguese/Brazilian

ancestry and a family history suggestive of an autosomal

dominant progressive neurodegenerative disorder, MJD

(SCA-3) was suspected and genetic testing was

performed by a commercial laboratory. This analysis

confirmed that this patient had homozygous MJD with

expansions of 63 and 60 repeats.

Figure 2. Pedigree of the patient’s family. The squares indicatemales, circle female, dark fill indicates affected individuals andgray is probably affected.

C a s e R e p o r t

Discussion

The “CAG” codon codes for the amino acid glutamine

and the presence of expanded CAG repeats results in a

polyglutamine expansion in the resulting protein. The

polyglutamine rich ataxin-3 protein is neurotoxic for

susceptible areas of the brain including cerebellum

(mostly dentate nucleus and cerebellar peduncles),

brainstem (mostly oculomotor nuclei and vestibular

nuclei), basal ganglia (mostly subthalamic nucleus,

globus pallidus and striatum) and spinal cord (mostly

spino-cerebellar tracts, Clarke’s column nucleus, dorsal

columns and anterior horn cells), and it may also affect

the peripheral nerves.

MJD/SCA-3 represents 21% of familial ataxia in the

USA and is most prevalent in families of Portuguese and

Brazilian descent. The number of CAG repeats is

inversely correlated with the age of onset and severity of

disease and has been clinically characterized into 5

types. Long CAG repeats are associated with early onset

(5 to 30 years), a rapidly progressive course and clinical

features of dystonia, spasticity, facial and lingual

fasciculations and exopthalmos (type I). Patients with

intermediate CAG expansions repeats disease manifest

the disease at approximately age 36 and present with

moderately progressive ataxia (type II). The later onset

of disease (40 years) is associated with cerebellar signs,

peripheral neuropathy and ophthalmoplegia (type III).

The fewest CAG repeats result in late onset (38-47

years), slow progression and features of Parkinsonism,

fasciculations, peripheral neuropathy and distal atrophy

(type IV). In a new subtype reported in Japanese

families, SCA-3/MJD, patients show marked spastic

paraparesis with or without cerebellar ataxia (subtype V).

(http://neuromuscular.wustl.edu/ataxia/domatax.html#mjd)

This is the twelfth case of genetically confirmed

homozygous MJD reported. In homozygous individuals,

compared with the heterozygous patients, the age of onset

is typically earlier, more severe and the degree of disease

progression is more rapid. Our patient had relatively

earlier age at onset of symptoms compared to the other

affected members of his family. In comparison to the other

homozygous patients, however, his age of onset was

relatively later. Furthermore, his presentation with spastic

paraparesis without extra pyramidal features or significant

ataxia (subtype V) is unique. This patient expands the

clinical heterogeneity of homozygous MJD patients.

References1. Sudarsky L, Coutinho P. Machado-Joseph disease. Clin Neurosci.

1995; 3(1):17-22.

2. Carvalho DR, La Rocque-Ferreira A, Rizzo IM, Imamura EU,

Speck-Martins CE. Homozygosity enhances severity in

spinocerebellar ataxia type 3. Pediatr Neurol. 2008 Apr; 38(4):296-9.

3. Tsuda T, Hutterer J, St George-Hyslop P. Homozygous inheritance of

the Machado-Joseph disease gene.Lang AE, Rogaeva EA. Ann

Neurol. 1994 Sep;36(3):443-7.

4. Sobue G, Doyu M, Nakao N, Shimada N, Mitsuma T, Maruyama H,

Kawakami S, Nakamura S. Homozygosity for Machado-Joseph

disease gene enhances phenotypic severity. J Neurol Neurosurg

Psychiatry. 1996 Mar;60(3):354-6.

5. Lerer I, Merims D, Abeliovich D, Zlotogora J, Gadoth N. Machado

Joseph disease: correlation between the clinical features, the CAG

repeat length and homozygosity for the mutation. Eur J Hum Genet.

1996; 4(1):3-7.

6. Fukutake T, Shinotoh H, Nishino H, Ichikawa Y, Goto J, Kanazawa I,

Hattori T. Homozygous Machado-Joseph disease presenting as REM

sleep behaviour disorder and prominent psychiatric symptoms. Eur J

Neurol. 2002 Jan; 9(1):97-100.

7. Coutinho P, Guimarães A, Scaravilli F. The pathology of Machado

Joseph disease. Report of a possible homozygous case. Acta

Neuropathol. 1982; 58(1):48-54.

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t w e n t y - e i g h t

p a g e t w e n t y - n i n e

Introduction

Orbital myositis is an inflammatory process that

primarily involves the extraocular muscles and most

commonly affects young adults in the third decade of

life. Clinically, it is characterized by acute pain

exacerbated by eye movements. Diplopia, swelling of

the eyelid, conjunctival injection, and exophthalmos

may also be present.1, 2 The most common

presentation is acute and unilateral, which responds

to systemic corticosteroid therapy. Chronic and

recurrent cases may involve both orbits.3 Serologic

studies can exclude a systemic cause and biopsy is

reserved for cases with multiple recurrences or those

unresponsive to therapy.4 Orbital magnetic resonance

imaging (MRI) is the single most important diagnostic

test. MRI excludes other lesions such as neoplastic,

infectious, or vascular processes and provides

additional information such as apical extension,

cavernous sinus involvement, and/or intracranial

lesions. Typically it shows one or two extraocular

muscles enlarged in a single orbit with thickening of

ocular muscle tendons where the muscles insert onto

the globe. Inflammatory infiltrates generally show low

signal intensity on T1-weighted images, variable

intensity on T2, and marked, diffuse, and irregular

gadolinium enhancement.1-5 The main differential

diagnosis, thyroid eye disease, has distinct orbital

MRI findings, i.e., in one or both orbits, there is an

enlargement of the inferior and/or medial rectus

muscles and sparing of the ocular muscle tendons.6

Here we report a case of recurrent orbital

myositis in a patient with Crohn’s disease with atypical

MRI findings mimicking thyroid eye disease.

Case Report

The patient is a 33-year-old Caucasian man who

presented to the neuroophthalmology clinic with a

one-week history of diplopia, left eye pain,

photophobia and subjective numbness of his left

forehead. He has history of Crohn’s disease and

underwent intestine resection five years ago with no

subsequent recurrence. He had no history of head

injury and had no known allergies. He does not take

any regular medications and he smokes one-fourth of

a pack per day. Family history is unremarkable.

Three months prior he woke up with severe left

orbital and eye pain and left ptosis. He also had

conjunctival injection, lid swelling and throbbing pain

Ocular myositis in Crohn’s disease with MRI imaging mimicking thyroid ophthalmopathy

Shan Chen, MD, PhD; Mohammad Fouladvand, MD.

C a s e R e p o r t

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t h i r t y

in his left temporal region. He

was then diagnosed with

episcleritis and received

a Medrol Dose pack and

eye drops. Within days

his symptoms significantly

improved. One week later he

developed similar pain in his

right eye. He was treated

with Prednisone orally and

responded well. He was

well until a few days prior

to presentation when he

developed recurrent left

eye pain and ptosis.

He complained of vertical

diplopia, especially in extreme

downward gaze. He reported

mild left-sided headache and

numbness on the left side of his

face. There was no vision

change, tearing, discharge,

rhinorrhea, or other neurological

symptoms.

On examination his visual acuity was 20/20 in the

right eye and 20/25 in the left for distance and 20/20 at

near. Color vision was full. The pupils were 4 mm

bilaterally reactive with no relative afferent pupillary

defect (RAPD). He had limitation of the left eye in

inferoduction. All ocular movements, especially the

depression, were associated with pain in the left eye.

On examination of ocular

motility, he had left hypertropia

present for near and

distance vision in both primary

position and down gaze,

measuring with 4 prism-

diopters and 12 prism-diopters

respectively. He had left ptosis

measuring 2 mm without

obvious proptosis. Slit lamp

examination disclosed injection

in the left temporal margin of

the conjunctiva and left eyelid

swelling. He had decreased

sensation to pinprick and

temperature in the cranial

nerve V1 distribution. Visual

fields were full on Humphrey

visual field testing. Anterior

segment examination was

unremarkable. Dilated funduscopy

was normal with no evidence

of disc swelling.

Cranial MRI was unremarkable, with no evidence

of mass, infarct, edema, sinus disease or cavernous

sinus lesions. The orbital MRI showed enlargement of

left medial rectus, inferior rectus, inferior and

superior oblique muscles with muscle tendon sparing

and a normal optic nerve (Figures 1a, 1b). These

findings were consistent with thyroid ophthalmopathy.

Figure 1b. Axial fat-suppressed gadolinium-enhanced MR orbits T1-weighted image shows theenlargement of the extraocular muscles bellies ofmedial rectus and superior oblique with sparing oftheir tendinous insertions.

Figure 1a. Orbital myositis in Crohn’s disease.Coronal fat-suppressed gadolinium-enhanced MRorbits T1-weighted image shows enlargement ofthe superior oblique, medial rectus, inferior rectusas well as inferior oblique muscles with markedenhancement.

p a g e t h i r t y - o n e

His thyroid function tests (TSH, free T4, and total

T3), however, were all within normal limits. Complete

blood count showed slightly elevated platelet count of

404. His basic metabolic panel, erythrocyte

sedimentation rate (ESR: 11) and C-reactive protein

(CRP: 0.37) were all unremarkable. His antinuclear

antibody (ANA) titer was elevated at 80 in a speckled

pattern (seen in mixed connective tissue disorder,

some systemic lupus, Sjögren's syndrome and

scleroderma; lower levels are found in rheumatic

diseases) and the anti-Sjögren's syndrome A (anti-

SSA) and anti-Sjögren's syndrome B (anti-SSB)

antibodies were both negative.

He was given Prednisone one mg/kg daily. In a

follow-up visit he reported a response to steroids

within days and had no more pain or redness. He had

residual mild diplopia in extreme down gaze. He

was advised to continue Prednisone at 20 mg daily

for 10 days and then 10 mg for two months to

ensure remission.

Discussion

Orbital myositis in Crohn’s disease

Orbital myositis (OM) is an orbital inflammation

syndrome also known as orbital pseudotumor. There

are two categories of OM. One is specific orbital

inflammation (SOI) which is associated with specific

myositis either due to bacterial or viral infections (e.g.,

Lyme disease, cysticercosis, post-streptococcal, or

herpes zoster) or systemic immunomediated diseases

such as sarcoidosis, Sjögren’s syndrome, systemic

lupus erythematosus, giant cell arteritis, Wegener’s

granulomatosis and linear scleroderma.1-5 The second

category is idiopathic variant or nonspecific orbital

inflammation (NSOI) which includes nonspecific

histological forms. Muscle biopsies usually report

mixed infiltrates of plasma cells, lymphocytes,

macrophages, and polymorphonuclear cells. More

chronic forms are associated with fibrosis. Recently,

Harris provided a possible mechanism for NSOI.7

Some of the known findings of ocular myositis are in

line with the current model of the pathogenesis

of dermatomyositis as a complement-mediated

microangiopathy.8

Crohn’s disease is a chronic granulomatous

inflammatory disease of the gastrointestinal tract with

a pattern of remissions and relapses. The causes of

Crohn’s disease are unknown. It can be considered a

systemic disease and may be associated with

extraintestinal manifestations and other autoimmune

disorders. Fewer than 10% of patients have

ophthalmological symptoms;9. 10 episcleritis, scleritis,

and uveitis are the most common. They are

independent of the extent of bowel involvement and

often occur in the early years of the disease. One

explanation implicates an immune-complex-type

hypersensitivity reaction to a colonic antigen. Other

theories suggest that ocular inflammation is due to

cytotoxic antibodies or delayed-type hypersensitivity

reaction.

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t h i r t y - t w o

C a s e R e p o r t

The diagnosis of OM remains rare in Crohn’s

disease. There have been few reports of an association

between OM and Crohn’s disease, as in our patient.

OM in Crohn’s disease is considered a NSOI. OM can

precede the diagnosis of Crohn’s disease. Therefore, it

is important to recognize OM as a rare extraintestinal

manifestation of Crohn’s disease, especially if all

thyroid tests are negative, so that the diagnosis can be

made and appropriate therapy commenced.9-12

Orbital myositis vs. thyroid ophthalmopathy

Thyroid ophthalmopathy (TO), Graves’ disease, is the

most common cause of the extraocular muscle

enlargement, also leading to ophthalmoparesis and

diplopia. Clinically, thyroid ophthalmopathy is usually

painless at onset, symmetrical, slowly progressive, and

associated with systemic manifestations of Graves’

disease. Lid retraction, limitation of movement

opposite to the affected muscle, and deterioration of

visual function (including color perception) occur

more often in TO than in OM. In a cohort study,

eyelid retraction was found to be present in 91% of

cases. The frequencies of other symptoms are

exophthalmos (~62%), extraocular muscle dysfunction

(~43%), ocular pain (~30%), lacrimation (~23%) and

optic nerve dysfunction (~6%).14 In contrast, the

frequencies of major symptoms of OM are orbital

and/or retroorbital pain (~95%), diplopia (~85%),

conjunctival injection closely related to the affected

eye muscle (~70%), and proptosis (~60%).1, 2

More than 90% of patients with TO have

hyperthyroidism reflected in an abnormal thyroid

function test but a minority of patients (less than 10%)

are euthyroid or hypothyroid.13-17 Measurement of

thyrotropin-receptor antibodies may have diagnostic

value as well because of their high specificity and

sensitivity for Graves’ disease. Orbital MRI is very

useful to differentiate two disease entities.

Traditionally tendon-sparing, well-defined extraocular

muscle enlargement (fusiform configuration) strongly

suggests TO. An increase in orbital fibroadipose tissue

is another common finding. Late radiologic findings

include a dilated superior ophthalmic vein and apical

crowding of the optic nerve. The optic-nerve

compression is due to enlarged muscles, particularly at

the orbital apex, seen in dysthyroid optic neuropathy

(DON) indicating urgent referral to prevent vision

deterioration. Whereas in OM the muscles show

irregular contours and diffuse inflammation extends to

lacrimal glands, muscle tendons, and adjacent

intraconal fat (called “fat stranding” on MRI) forming

cylindrical configuration. OM tends to be unilateral

with bilateral involvement suggesting chronic and

recurrent cases. TO often has bilateral MRI findings

despite patients sometimes having only unilateral

symptoms (Table 1).

Extraocular muscles involved can further

distinguish the two conditions radiographically. In TO,

the inferior rectus and the medial rectus muscles are

most frequently involved. Isolated rectus muscle

involvement is rare (<6%). In this subgroup of

p a g e t h i r t y - t h r e e

Table 1. Clinical and radiographical differential diagnoses of thyroid ophthalmopathy and orbital myositis.

patients, the superior rectus may be the most

frequently involved muscle.2, 18, 19 Imaging studies in

OM showed that any of the extraocular muscles may

be involved in OM. The inflammation seems to

“jump” among muscles with each recurrence.

Siatkowski et al.20 conducted a retrospective chart

review of 100 patients with OM. They found that

single muscle involvement was found in 68% of

patients, 22% had two affected muscles and 10% had

three or more affected muscles. The lateral rectus

muscle was most commonly involved (33%), followed

by the medial rectus muscle (29%) and the superior

rectus muscle (23%). Oblique involvement was rare,

with the inferior oblique affected in 3% of cases and

the superior oblique (Brown’s syndrome) affected in

2% of cases.20 Multiple involvements at initial

presentation seemed to be a risk factor for recurrence,

as in this patient, particularly if bilateral. Optic

neuropathy occurs less commonly in OM than in TO

and is due to optic nerve sheath thickening and

intraconal fat inflammation rather than enlarged

muscles per se.2, 21

In this patient, not only was the tendon spared, but

there was enlargement of the medial rectus, inferior

rectus, and inferior and superior oblique muscle more

suggestive of TO (Figures 1a, 1b). The history, clinical

presentation, euthyroidism, and rapid response to

steroids, however, are most consistent with a diagnosis

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t h i r t y - f o u r

C a s e R e p o r t

of OM. Having orbital MRI mimicking the classic

findings of Graves’ disease does not exclude OM.

Patrinely et al.21 conducted a retrospective analysis

of the CT scans of 60 patients with nonthyroid

enlarged extraocular muscles of which 15 patients

were diagnosed with OM. Their data demonstrated

that OM has more bilateral involvement (40%, 6 out

of 15 patients) and less involvement of the tendons

(47%, 7 out of 15 patients) than previously

acknowledged.21 Another more recent retrospective

study suggested that extraocular muscle enlargement

with tendon involvement does not exclude the

diagnosis of TO.22 These authors reviewed 125

patients with TO. They defined tendon involvement

by a ratio of tendon to muscle width greater than 0.5.

Their study showed tendon involvement can be found

in 6.4% of TO cases (8 out of 125 patients), and in

such cases it may be more frequently associated with

primary gaze diplopia (37.5% vs. 25.3%).22 Thus, the

tendon involvement, while suggestive, cannot be

relied upon to definitively differentiate OM from TO.

Other differential diagnoses of OM include

primary or metastatic orbital tumor, orbital cellulitis,

sino-orbital aspergillosis or mucormycosis, carotid-

cavernous fistula and acromegaly, each of which has

its own distinct MRI findings. A dramatic clinical

response to corticosteroids confirms the diagnosis of

OM. Low-dose radiation therapy is beneficial in

patients with recurrent OM. If the orbital

inflammation is steroid resistant, systemic

immunosuppressive treatment may be considered.

Anecdotal reports have suggested the use of steroid-

sparing agents such as cyclophosphamide,

methotrexate, and cyclosporine. In selected cases,

particularly with recurrent and severe disease

manifestation, high doses of intravenous

immunoglobulin or rituximab (CD-20 antibody)

infusion may be helpful.2, 7, 8, 23

References

1. Schoser BGH. Ocular myositis: diagnostic assessment, differential

diagnoses, and therapy of a rare muscle disease – five new cases

and review. Clin Ophthalmol. 2007 March; 1(1): 37–42.

2. Lacey B, Chang W, Rootman J. Nonthyroid causes of extraocular

muscle disease. Surv Ophthalmol. 1999;44:187–213.

3. Costa RM, Dumitrascu OM, Gordon LK. Orbital myositis:

diagnosis and management. Curr Allergy Asthma Rep. 2009 Jul;

9(4): 316-23.

4. Gordon LK. Orbital inflammatory disease: a diagnostic and

therapeutic challenge. Eye. 2006 Oct;20(10):1196-206.

5. Weber AL, Romo LV, Sabates NR. Pseudotumor of the orbit.

Clinical, pathologic, and radiologic evaluation. Radiol Clin North

Am. 1999 Jan;37(1):151-68.

6. Bijlsma WR, Mourits MP. Radiologic measurement of extraocular

muscle volumes in patients with Graves' orbitopathy: a review and

guideline. Orbit. 2006 Jun;25(2):83-91.

7. Harris GJ. Idiopathic orbital inflammation: a pathogenetic

construct and treatment strategy. Ophthal Plast Reconstr Surg.

2006;22:79–86.

8. Dalakas MC. Therapeutic targets in patients with inflammatory

myopathies: present approaches and a look to the future.

Neuromuscl Disord. 2006;16:223–36.

9. Ramalho J, Castillo M. Imaging of orbital myositis in Crohn's

disease. Clin Imaging. 2008 May-Jun;32(3):227-9.

10. Taylor S, McCluskey P, Lightman S. The ocular manifestations of

inflammatory bowel disease. Curr Opin Ophthalmol 2006;

17:538-44.

11. Maalouf T, Angioï K, George JL. Recurrent orbital myositis and

Crohn’s disease. Orbit. 2001 Mar;20(1): 75-80.

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12. Durno CA, Ehrlich R, Taylor R, Buncic JR, Hughes P, Griffiths

AM. Keeping an eye on Crohn’s disease: orbital myositis as the

presenting symptoms. Can J Gastroenterol. 1997 Sep:11(6):

497-500.

13. Bartalena L, Tanda ML. Clinical practice. Graves'

ophthalmopathy. N Engl J Med. 2009 Mar 5;360(10):994-1001.

14. Bartley GB, Fatourechi V, Kadrmas EF, et al. Clinical features of

Graves’ ophthalmopathy in an incidence cohort. Am J Ophthalmol

1996; 121:284-90.

15. Bahn RS, Heufelder AE. Pathogenesis of Graves'

ophthalmopathy. N Engl J Med. 1993 Nov 11;329(20):1468-75.

16. Garrity JA, Bahn RS. Pathogenesis of Graves’ ophthalmopathy:

implications for prediction, prevention, and treatment. Am J

Ophthalmol. 2006;142:147–53.

17. Nagy EV, Toth J, Kaldi I, Damjanovich J, Mezosi E, Lenkey A,

Toth L, Szabo J, Karanyi Z, Leovey A. Graves' ophthalmopathy:

eye muscle involvement in patients with diplopia. Eur J

Endocrinol. 2000 Jun;142(6):591-7.

18. Rothfus WE, Curtin HD. Extraocular Muscle Enlargement: a CT

review. Radiology 1984;151:677-681.

19. Hosten N, Sander B, Cordes M, Schubert CJ, Schorner W, Felix

R. Graves’ ophthalmopathy: MR imaging of the orbits. Radiology.

1989 Sep; 172 (3): 759-62.

20. Siatkowski RM, Capo H, Byrne SF, Gendron EK, Flynn JT,

Muñoz M, Feuer WJ. Clinical and echographic findings in

idiopathic orbital myositis. Am J Ophthalmol. 1994;118:343-350.

21. Patrinely JR, Osborn AG, Anderson RL, Whiting AS. Computed

tomographic features of nonthyroid extraocular muscle

enlargement. Ophthalmology 1989; 96:1038-1047.

22. Ben Simon GJ, Syed HM, Douglas R, McCann JD, Goldberg RA.

Extraocular Muscle Enlargement with Tendon Involvement in

Thyroid-associated Orbitopathy. Am J Ophthalmol. 2004

Jun;137(6):1145-7.

23. Franzco LL, Suhler EB, Smith JR. Biologic therapies for

inflammatory eye disease. Clin Experiment Ophthalmol.

2006;34:365–74.

Faculty/Authors: Aiesha Ahmed, MD, Attending Neurologist, NJ Neuroscience Institute at JFK Medical Center, Edison, NJ &Assistant Professor, Seton Hall University, South Orange, NJ.Max Lowden, MD, Assistant Professor, Department of Neurology, Penn State College of Medicine, Milton S.Hershey Medical Center, Hershey, PA.Gary Thomas, MD, Assistant Professor, Department of Neurology, Penn State College of Medicine, Milton S.Hershey Medical Center, Hershey, PA.

Editorial Committee for this CME Activity:Sudhansu Chokroverty, MD, FRCP, FACP, Co-Chair of Neurology (Clinical Neurophysiology and SleepMedicine), New Jersey Neuroscience Institute, JFK Medical Center, Edison, NJ; Professor of Neuroscience,Seton Hall University School of Graduate Medical Education, South Orange, NJ; and Co-Editor, Journal of theNew Jersey Neuroscience Institute.Annabella Drennan, Editorial Assistant, Journal of the New Jersey Neuroscience Institute, NJ NeuroscienceInstitute at JFK Medical Center, Edison, NJ.Martin Gizzi, MD, PhD, Chairperson, New Jersey Neuroscience Institute, JFK Medical Center, Edison, NJ;Professor and Chairperson, Neuroscience, Seton Hall University School of Graduate Medical Education, SouthOrange, NJ; and Co-Editor, Journal of the New Jersey Neuroscience Institute.Carole Kolber, PhD, Administrative Director, Professional Development/CME, JFK Medical Center & ClinicalAssistant Professor, Health Sciences, Seton Hall University School of Health & Medical Sciences, S. Orange, NJ.

Activity Description/Need/Practice Gap: Venous air embolism can occur due to instrumentation in patients undergoing laparoscopic procedures,particularly during insertion of catheters or trocars. The resultant entrapment of intravascular gas can lead tosevere neurologic injury, cardiovascular collapse, and even death. This case study highlights the discussionregarding the assessment of factors, pre and intraoperatively that can lead to air embolism. The goal is to addressidentified practice gaps in identifying and managing venous air embolism through physician education related tothe knowledge, strategies, and performance in practice necessary for optimal patient care.

Objective: At the conclusion of this CME activity, participants should be able to:1. Discuss the possibility of instrumentation causing venous air embolism that can lead to ischemic injury

to vital organs.2. Evaluate for a patent foramen ovale (PFO), which may pose risk for development of venous air embolism

during surgery, through transthoracic echocardiogram with saline infusion.

Audience:Neurologists, gastrointestional surgeons, internists including gastroenterologists, family physicians, and sleep specialists

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t h i r t y - s i x

CME Activity: Cerebral Ischemia Due To Venous Air Embolism During Laparoscopic SurgeryIntroductory Required Reading

p a g e t h i r t y - s e v e n

Accreditation Information:JFK Medical Center is accredited by the Accreditation Council for Continuing Medical Education to providecontinuing medical education for physicians. Credit: JFK Medical Center designates this educational activity for a maximum of .50 AMA PRA Category 1Credit(s).TM Physicians should only claim credit commensurate with the extent of their participation in theactivity.

Conflict of Interest/Content Validation: The Office of CME of JFK Medical Center utilizes the followingmechanisms to identify and resolve conflicts of interest and validate content: 1) Disclosures by faculty andplanning committee of any relationships that might create a potential, apparent or real conflict of interest; 2)Disclosures of off-label drug uses to audience; 3) Participant evaluation of CME activity’s freedom fromcommercial bias; and 4) Faculty Attestation of best available evidence.

Disclosure: The authors for this Journal CME activity, Aiesha Ahmed, MD, Max R. Lowden, MD, GaryThomas, MD, did not indicate any financial interest/arrangement or affiliation with any corporate organizationrelevant to this journal article. The members of the Editorial Committee, Sudhansu Chokroverty, MD,Annabella Drennan, Martin Gizzi, MD, PhD, and Carole Kolber, PhD, did not indicate any financialinterest/arrangement or affiliation with any corporate organization relevant to this journal article. The contentdoes not include information on experimental or off-label uses of pharmaceutical products.

Educational Media: This self-study CME activity entails reading a selected article from the Journal of the New Jersey NeuroscienceInstitute and completing a post-test and evaluation form which demonstrate reflection on the article content,including changes in knowledge, and intended changes in practice patterns. It has been developed as a JournalCME activity through the Office of CME of JFK Medical Center in collaboration with the authors.

Learner Responsibility: The learner is responsible for the following:1. Reading the activity description, learning objectives, target audience, disclosure information,

and printed article.2. Completing a 5 question post-test with a minimum score of 80% and completing an evaluation form.3. Completion of the post-test and evaluation form serves as validation of participation in this activity.

Participants will be issued certificates of completion/entered into the JFK/ MSL physician participation database.

Instructions for Receiving Post-Test and Evaluation FormPlease email your request for the post-test and evaluation form to kdecamp@solarishs.org. Upon receipt, linksto access the post-test and evaluation form will be forwarded to your email address. After successful completion,you will receive an electronic certificate.

Estimated Time To Complete: 30 minutes (This includes required reading of introductory information,journal article and completion of post-test and participant evaluation form).

Release Date: December 1, 2009

Termination Date: November 30, 2012

Abstract

Venous air embolism (VAE) is the entry of air into the

central or peripheral vasculature. In patients

undergoing laparoscopic procedures, venous air

embolism can occur due to instrumentation,

particularly during insertion of catheters or trocars.

The resultant entrapment of intravascular gas can lead

to severe neurologic injury, cardiovascular collapse,

and even death.

Introduction

This article presents the case of a 44-year-old woman

who was undergoing laparoscopic surgery to remove

the gastric banding with intention for further

conversion to gastric bypass. She suffered an inferior

vena cava laceration due to presumable trocar injury.

As she had an unknown patent foramen ovale (PFO),

she developed infarctions affecting both cerebral

hemispheres due to paradoxical embolism. The

factors that determine the subsequent morbidity and

mortality in VAE include the rate of air entrainment,

the volume of air introduced, the position of the

patient at the time of the embolism and presence of a

PFO. This case highlights the discussion regarding the

assessment of factors, pre and intraoperatively, that

can lead to air embolism.

Case Presentation

A 44-year-old woman with history of obesity had a

laparoscopic gastric banding procedure done one year

ago with resultant dysphagia, reflux symptoms and

inadequate weight loss. For these complaints the

patient was scheduled for an elective laparoscopic

removal of the gastric band with further conversion to

a gastric bypass. Preoperative evaluation including

physical examination was unrevealing.

Surgery was complicated by intraperitoneal scar

tissue that made optical trocar entry difficult; this

approach was aborted with removal of the trocar. A

subcutaneous dissection was started in order to

perform an open port placement. At that time the

patient’s blood pressure was noted to drop

dramatically requiring fluid resuscitation. In view of a

potential vascular injury, the peritoneal cavity was

rapidly opened and free blood was seen with

laceration of the inferior vena cava (IVC).

The peritoneal cavity was packed with laparotomy

pads and the IVC was compressed. An

emergent transesophageal echocardiogram (TEE)

demonstrated air in the cardiac chambers and a

large PFO.

The patient’s condition continued to deteriorate

requiring vasoactive medications and ultimately

complete cardiac bypass after performing a

C a s e R e p o r t

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e t h i r t y - e i g h t

Cerebral ischemia due to venous air embolism during laparoscopic surgery Aiesha Ahmed, MD; 1Max R. Lowden, MD; 2Gary Thomas, MD1, 2Department of Neurology, Penn State College of Medicine, EC037, 30 Hope Drive, Hershey, PA 17033

sternotomy. The IVC was explored carefully and a

through-and-through injury to the vessel was noted.

Initial attempts to repair both aspects of the vessel

failed requiring ligation by the vascular surgery team

to allow a careful repair. Return of homeostasis was

achieved after this and discontinuation of cardiac

bypass was possible.

Physical Examination

On examination after surgery,

the patient was comatose on

ventilator support. Neurologic

examination revealed 4mm

dilated pupils bilaterally

which were sluggishly reactive;

no facial asymmetry nor

purposeful movements to

verbal or pain stimulation were

noted.

Imaging Studies

Based on the neurological

examination and in the setting

of a complicated surgery, a

severe neurological insult was

suspected and a computerized

tomography (CT) scan of the

brain was obtained. This

demonstrated diffuse cerebral

edema with large areas of

hypoattenuation in both

cerebral hemispheres that

were most consistent with

evolving infarcts (Figure 1).

Magnetic resonance imaging (MRI) obtained three

3 days after surgery (Figure 2) showed extensive areas

of restricted diffusion involving the gray matter of the

cerebral hemispheres bilaterally right more than left

consistent with cortical ischemia.

Clinical Course

Ten days after surgery, our patient continued to

be ventilator-dependent requiring a tracheostomy.

Neurological evaluation revealed

continued unresponsiveness to

verbal stimuli. Cranial nerves

showed no facial asymmetry and

3 mm pupils bilaterally which

were reactive. Motor testing

showed a left hemiplegia and a

right hemiparesis. Palliative

medicine was involved for

continued support and plans for

long term care.

Figure 2. Axial MRI diffusion weighted image (A) and apparent diffusion coefficient (B)obtained 3 days after surgery showing extensive areas of restricted diffusion involving the graymatter of the cerebral hemispheres bilaterally right more than left consistent with embolicinfarcts.

Figure 1. CT scan of the brain non-contrastshowing diffuse cerebral edema with largeevolving infarct noted on the righthemisphere. There is 9 mm of right to lefttranstentorial herniation and significanteffacement of the suprasellar cistern.

p a g e t h i r t y - n i n e

Discussion

Early complications associated with laparoscopic

gastric procedures are pulmonary embolism or death in

less than one percent of patients. Late complications

include gastric prolapse, band slippage, and access port

problems.1 Saunders et al. mention that technical

complications due to surgery (such as perforation,

bleeding, stricture, bowel obstruction, etc.) are the

leading reasons for readmission after bariatric surgery.2

VAE is the entrainment of air into the venous system

producing a broad array of outcomes such as

circulatory obstruction. A circulatory arrest occurs

ultimately due to the trapping of air in the right

ventricular outflow tract. Large emboli may cause

arterial embolization by acutely increasing the right

atrial pressure and facilitating a right to left shunt

through a PFO.3 Gas embolism can occur through a

tear in a vessel on the abdominal wall or on the

peritoneum. This can occur due to inadvertent

placement of the Veress needle into a vein or an organ.

In patients undergoing gastrointestinal and urologic

laparoscopic procedures, the incidence of major

vascular injuries is approximately 0.03-0.06%. Vascular

complications occur due to instrumentation,

particularly during insertion of the Veress needle or

tocar.4 Insertion of the Veress needle or trocar into

major vessels such as aorta, common iliac, or inferior

vena cave have been reported. Injuries to the vessels

in the abdominal wall (such as epigastric vessels) are

becoming increasingly common due to the use of

multiple trocars. Stretching of vascular adhesions

because of the expansion caused by

pneumoperitonium can tear vessel walls and lead to

bleeding.4 Marked embolism is noted in the distal

inferior vena cava occlusion or when there has been

significant blood loss.5 In addition, manipulation of the

venotomy hole and higher intraperitoneal pressures

leads to a higher degree of embolization.5 Material

coming from the IVC is directed against the fossa

ovalis, causing paradoxical embolization if the foramen

ovale is open.6 Approximately 27% of the adult

population is known to have a PFO, which tends to

increase with age.6 This risk can be assessed with TEE.

The presenting signs of gas embolism during

laparoscopy include sudden hypotension, hypoxemia,

tachycardia and pulmonary edema. Neurologic

impairment can occur because of anoxic damage or

paradoxic embolism through a PFO.4 Clinically

significant gas embolism is rare during gynecologic

laparoscopic procedures. In contrast, emboli are seen

at a higher rate in laparoscopic cholecystectomy and

nephrectomy.7 The degree of embolization is thought

to be proportional to the decrease in central venous

pressure from blood loss or distal venous compression,

the time the venotomy was open, the intraperitoneal

pressure, and the amount of manipulation during

repair.5 Factors that may decrease the incidence of gas

embolism include increase in central venous pressure

due to adequate hydration and head-down position

which may reduce gas embolism to the head as bubbles

are buoyant.7 Tuppurainen et al.6 used TEE to assess

hydration. The movement of the mobile part of the

interatrial septum can provide information on the

volume status of the patient. Hypovolemia can bend

the septum to the left. By expanding the intravascular

volume the shunt can be reduced.6 Management

C a s e R e p o r t

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e f o r t y

p a g e f o r t y - o n e

involves expeditious control of bleeding, distal and

proximal compression or vascular clamping.5 This

brings up the discussion of routine use of TEE during

the procedure to assess the volume status of the

patient and to monitor other entities such as air

embolism and valvular regurgitation which could

cause hemodynamic compromise.6. 7 The other

alternative would be to perform a preoperative

transthoracic echocardiogram with saline infusion to

evaluate for a PFO which may pose a risk for

development of complications during surgery.

References

1. Sarker S, Herold K, Creech S, Shayani V. Early and late

complications following laparoscopic adjustable gastric banding.

Am Surg. Feb 2004;70(2):146-149; discussion 149-150.

2. Saunders JK, Ballantyne GH, Belsley S, et al. 30-day readmission

rates at a high volume bariatric surgery center: laparoscopic

adjustable gastric banding, laparoscopic gastric bypass, and

vertical banded gastroplasty-Roux-en-Y gastric bypass. Obes Surg.

Sep 2007;17(9):1171-1177.

3. Palmon SC, Moore LE, Lundberg J, Toung T. Venous air

embolism: a review. J Clin Anesth. May 1997;9(3):251-257.

4. Joshi GP. Complications of laparoscopy. Anesthesiol Clin North

America. Mar 2001;19(1):89-105.

5. O'Sullivan DC, Micali S, Averch TD, et al. Factors involved in gas

embolism after laparoscopic injury to inferior vena cava.

J Endourol. Apr 1998;12(2):149-154.

6. Tuppurainen T, Makinen J, Salonen M. Reducing the risk of

systemic embolization during gynecologic laparoscopy--effect of

volume preload. Acta Anaesthesiol Scand. Jan 2002;46(1):37-42.

7. Fahy BG, Hasnain JU, Flowers JL, Plotkin JS, Odonkor P,

Ferguson MK. Transesophageal echocardiographic detection of

gas embolism and cardiac valvular dysfunction during laparoscopic

nephrectomy. Anesth Analg. Mar 1999;88(3):500-504.

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e f o r t y - t w o

What’s New in Neuroscience? Sudhansu Chokroverty, MD, FRCP, FACP

Under this heading in this issue we are directing

attention of the practicing neurologist to three

important topics published recently.

Blood pressure monitoring for diagnosis and

treatment after acute ischemic stroke and

intracerebral hemorrhage.

Tikhonoff V, Zhang H, Richart T, Staessen J. Blood

pressure as a prognostic factor after acute stroke.

Lancet Neurol 2009;8:938-48.

In a review article based on a literature survey

Tikhonoff et al. briefly outlined the role of blood

pressure monitoring for prognosis and treatment after

acute ischemic stroke and intracerebral hemorrhage.

In a world-wide survey it was found that there were 16

million first-ever strokes in 2005, and the number is

predicted to rise to 18 million in 2015 and 23 million

in 2030. Stroke is the second leading cause of death

world-wide and hypertension as a risk factor is most

directed link to the occurrence of stroke. In nearly

30% of the world’s population hypertension is noted.

In at least 50% of all patients with acute stroke, there

is an acute rise of blood pressure which is associated

with poor prognosis. The outcome of acute stroke and

blood pressure measurement is reflected in an U-

shaped curve with the best outcome occurring with a

systolic blood pressure ranging from 140 to 180 mm

Hg. Whether decreasing blood pressure in

hypertensive patients with acute ischemic or

hemorrhagic stroke improves prognosis and whether

raising blood pressure to improve perfusion of

ischemic brain areas is beneficial remain uncertain

and need further confirmation. Current guidelines in

the management of hypertension in patients with

acute stroke are not evidence-based but are based on

expert opinion and general principles identified in

observational studies or in small clinical trials. Present

guidelines include not treating hypertension in most

patients with ischemic stroke unless blood pressure

exceeds 200 to 220 mm Hg systolic or 120 mm Hg to

140 mm Hg diastolic pressure. Alteplase, a tissue

plasminogen activator produced by recombinant DNA

technology for clot lysis, is recommended to be given

if the blood pressure is lower than 185 mm Hg systolic

and 105 to 110 mm Hg diastolic pressure. If the

systolic blood pressure is higher than 180 to 200 mm

Hg or if the diastolic pressure exceeds 105 mm Hg,

anti-hypertensive medications can then be given in

patients with primary intracerebral hemorrhage.

There is no support in the current guidelines to

intervene to increase blood pressure in patients with

acute ischemic stroke. The authors concluded that

more than 50% of patients with acute stroke have an

acute hypertensive response associated with poor

prognosis, and lowering blood pressure is feasible in

these patients and carries little risk. Results of ongoing

trials for lowering blood pressure in patients with new

onset stroke might translate into absolute benefit

in the future.

p a g e f o r t y - t h r e e

The neuroanatomical regions associated with

the spelling system.

Cloutman L, Gingis L, Newhart M, et al. A neural

network critical for spelling. Ann Neural

2009;63:249-253.

Cloutman et al. tried to identify neuroanatomical

regions associated with the spelling system by

evaluating 331 patients with left hemispheric

ischemic stroke with various spelling tests. They used

magnetic resonance diffusion-weighted imaging and

perfusion-weighted imaging within 48 hours of stroke

onset to outline the extent of the regions involved in

stroke. Based on a voxel-wise statistical map, these

authors identified a cortical-subcortical network of

areas in left posterior frontal, parietal, and lateral

occipital lobes in addition to extensive areas of

subcortical white matter underlying prefrontal cortex,

lateral occipital gyrus or caudeate nucleus associated

with impairment in maintaining the sequence of letter

identities while spelling. The authors suggested that

future studies with more patients with and without

dysfunction in each of these regions may reveal which

areas are critical.

Eating Yourself to a Stroke?

This was the title of an editorial by Goldstein

(Goldstein LB. Ann Neurol 2009; 66:129-131) in

reference to an epidemiological study conducted in a

Texas county by Morgenstern and colleagues (Fast

food and neighborhood stroke risk. Morgenstern LB,

Escobar JE, Sanchez BN, et al. Ann Neuro 2009;

66:165-170).

Morgenstern and colleagues found a significant

association between the number of fast food

restaurants and risk of stroke in the residents of a

community in Nueces County, Texas. This

observation was based on an epidemiological study

conducted from January 2000 through June 2003. The

risk of stroke in this neighborhood increased by one

percent for every fast food restaurant, however, this

statistical association does not necessarily indicate a

causal relationship. As there is an established

relationship between diet and stroke (Goldstein LB,

et al. Stroke 2006;37:1583), it is plausible to suggest a

biological relationship between stroke and the

number of fast food restaurants (as a surrogate for

level of fast food consumption). This study raises

more questions than it answers and further research is

needed to understand possible reasons for this

association.

T H E N E W J E R S E Y N E U R O S C I E N C E I N S T I T U T E A T J F K M E D I C A L C E N T E Rp a g e f o r t y - f o u r

Article TypesOriginal research articles and reviews should belimited to a maximum of 2000 words with 20references, 1 table and 2 figures.

Editorials should be limited to 1000 words with 10references.

Case reports may contain up to 1000 words, 1 tableand 1 figure.

What’s new in neuroscience should include a briefsummary and pertinent comments on some recentarticles in neuroscience that are clinically relevant forthe practicing physicians.

Images in neuroscience articles should consist ofhigh-resolution images (e.g., neuroimaging,polysomnographic tracing, actigraphic recording,EMG tracing, eye movement and vestibularrecordings, evoked potential and EEG tracings,interesting neurosurgical specimens, etc.) derivedfrom a specific clinical situation.

Original research articles should be organized asfollows: title page, abstract (50 words), introduction,method, result, discussion, references, legends, tables,and figures.

Keywords of 4-6 items must be included on the title page.

Reference style should follow the Vancouver style asdescribed in the “Uniform Requirements forManuscripts Submitted to Biomedical Journals”(published in N Engl J Med 1997;336:309-315). Thetitles of journals should be abbreviated in conformitywith Index Medicus. The following are a fewexamples:

[1] Bondi M, Kaszniak A. Implicit and explicitmemory in Alzheimer's disease and Parkinson'sdisease. J Clin Exp Neuropsychol 1991;13:339-358.[2] Wechsler D. Wechsler Adult Intelligence Scale.New York: Grune & Stratton, 1976.[3] Hirst W, Volpe B. Automatic and effortfulencoding in amnesia. In: Gazzaniga M, editor.Handbook of cognitive neuroscience. New York:Plenum Press, 1984; p. 369-386.

Articles dealing with human experiments mustconform to the principles enumerated in the HelsinkiDeclaration of 1975 and must include a statementthat informed consent was obtained after fullexplanation of the procedure.

Authors must disclose any conflicts of interest whensubmitting their manuscript.

Authors must submit all figures as either .jpeg or .tiff files.

Each table, figure, graph, etc. should have its relativeplacement noted within the text.

Papers should be submitted electronically to theeditorial office (abdrennan@solarishs.org).

Instructions to Authors

6 5 J a m e s S t r e e t | E d i s o n | N e w J e r s e y | 0 8 8 1 8 | 7 3 2 - 3 2 1 - 7 0 1 0 | w w w. n j n e u r o . o r g

New Jersey Neuroscience Institute at JFK Medical Center . . . . . . . . . . . . . . . . . . . . 2

Aim and Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Editors’ Corner . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4

Evolving treatment options for pain after spinal cord injury . . . . . . . . . . . . . . . . . . . 6

Poli Francois Kouya, D.MSci, PhD and Ratan Banik, MBBS, PhD

**A pediatrician’s approach to basic seizure principles . . . . . . . . . . . . . . . . . . . . 14

Gary N. McAbee, D.O., J.D. and Kavitha Velicheti, M.D.

Evaluation of risk factors for seizures in patients with subarachnoid hemorrhage . . . . . . . . . 22

Abuhuziefa Abubakr, MD, FRCP

A case of homozygous Machado Joseph Disease . . . . . . . . . . . . . . . . . . . . . . . 26

Liudmila Lysenko, MD; Leema Reddy Peddareddygari, MD; Wei Ma, MD; Raji P.Grewal, MD

Ocular myositis in Crohn’s disease with MRI imaging mimicking thyroid ophthalmopathy . . . . . 29

Shan Chen, MD, PhD; Mohammad Fouladvand, MD

**Cerebral ischemia due to venous air embolism during laparoscopic surgery . . . . . . . . . . 36

Aiesha Ahmed, MD; Max R. Lowden, MD; Gary Thomas, MD

What’s New in Neuroscience? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42

Sudhansu Chokroverty, MD, FRCP, FACP

Instructions to the Authors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44

Table of Contents

** JNJNI CME ActivityReaders interested in earning CME credit are directed to the introductory pages preceding thearticles marked with the asterisks; these pages will provide all the necessary information to getstarted. For more information, please contact Kathleen DeCamp (kdecamp@solarishs.org).