Neuroscience Outlook Vol 13 Issue 2

A Triannual Publication of Augusta University

NEUROSCIENCE OUTLOOK News and Research from the Departments of Neurology and Neurosurgery

VOL. 13 | ISSUE 2

VOL. 13 | ISSUE 2 NEUROSCIENCE OUTLOOK

FROM THE CHAIRMEN

DEAR READERS,

In this issue of Neuroscience Outlook, we focus on the complex relationship between Chiari malformations and connective tissue disorders in the Clinical Spotlight section.

We also focus on multiple sclerosis and present a case illustration. We are proud to report that our newsletter won gold for Internal Publication at the Healthcare Advertising Awards (Department News section). In addition, our Epilepsy Center was recertified at the highest level, and one of our MCG Neurology-staffed affiliated hospitals in Savannah recertified as a Primary Stroke Center. This From left: Cargill H. Alleyne Jr., MD Professor and Marshall Allen Distinguished Chair of Neurosurgery David C. Hess, MD Professor and Presidential Distinguished Chair of Neurology

year, the Department of Neurosurgery celebrates its 60th anniversary, and in April, we sponsored a successful 60th anniversary reunion program which was thoroughly enjoyed by all. As usual, we also chronicle the various accomplishments of individual faculty from both departments and list our publications and presentations within the four-month period from January to April. Finally, we are saddened to report the passing of one of our illustrious alumni, Dr. William (“Billy�) Mayher. His stalwart support of both our Neurosurgery Department and, indeed, the medical school as a whole was much appreciated.

He will be greatly missed.

Cargill H. Alleyne Jr., MD Professor and Marshall Allen Distinguished Chair of Neurosurgery

David Hess, MD

Professor and Presidential Distinguished Chair of Neurology

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IN THIS ISSUE FACULTY & STAFF UPDATE________________4

VOL. 13 | ISSUE 2

DEPARTMENT NEWS_____________________5 PUBLICATIONS & PRESENTATIONS_________6

Neuroscience Outlook is produced triannually

SCHEDULES AND UPCOMING MEETINGS____7

by the Medical College of Georgia Departments of Neurology and Neurosurgery and the Augusta

CLINICAL SPOTLIGHT: THE RELATIONSHIP BETWEEN CHIARI MALFORMATIONS AND CONNECTIVE TISSUE DISORDERS:____________________________8

University Division of Communications and Marketing.

Please direct comments or questions to marketing@augusta.edu.

Editor-in-Chief: Cargill H. Alleyne Jr., MD

CLINICAL SPOTLIGHT: MULTIPLE SCLEROSIS ___________________10

Assistant Editor: Julie Kurek, MD

IN MEMORIAM__________________________14

Medical Illustrations: Colby Polonsky, MS

THE CLINICAL TEAM_____________________15

Design and Layout: Sergio Gallardo

THANK YOU DONORS ___________________16

Contributors: Ian Heger, MD, Suzanne H. Smith, MD, Rebeca Rahn, PA-C

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FACULTY & STAFF UPDATE Cargill H. Alleyne Jr., MD (Department of Neurosurgery) was a guest examiner at the Neurosurgical Oral Board Examinations in Houston, Texas, in April 2016. He was also co-organizer of the Larissa International Neurovascular Conference (Cerebral Aneurysms) at the Department of Neurosurgery, University of Thessaly, in Larissa, Greece, in March. In addition, he was a Castle Connolly Top Doctor and one of America’s Top Surgeons in 2016.

Krishnan Dhandapani, PhD (Department of Neurosurgery) was an ad hoc scientist reviewer for the American Heart Association Go Red for Women in Dallas, Texas, in January.

Mary Gregory MD, PhD (Department of Neurology) took on the role of clinical educator, a collaborative effort between the Office of Academic Affairs and the Department of Neurology.

Ian Heger, MD (Department of Neurosurgery) was named one of America’s Top Surgeons in 2016

Sergei A. Kirov, PhD (Department of Neurosurgery) participated in the NIH Neurodegeneration Study Section, Fellowships: Neurodevelopment, Synaptic Plasticity (ZRG1 F03A (20)), and the NIH Special Emphasis Panel, Brain Injury and Recovery (2016/05 ZRG1 BDCN-Y (02) M) in March

David C. Hess, MD (Department of Neurology) moderated a session (One, Two, Three Steps toward Cell Therapy for Stroke, and in the Future) and served on a panel (Clinical Trials of Cell Therapy for Stroke: Where Are We Now? - Safety and Efficacy of IV Stem Cell Therapy in Acute Stroke: What is the Evidence from the MultiStem Trial?) at the American Heart Association International Stroke Conference in Los Angeles, California, in February. He chaired a panel on cell therapies at the American Society of Neural Therapy and Repair (ASNTR) meeting in Clearwater, Florida, in April. In addition, he is a mentor for Mahesh Kates’ Intermediate Fellowship from Wellcome Trust, India, to conduct an early phase clinical trial titled, “Early Remote Ischemic Conditioning in Stroke (ERICS).” He also serves on the Lone Star Stroke Advisory Board and, in April, reviewed grants for the Lone Star Stroke network.

Jeffrey Switzer, DO (Department of Neurology) was the moderator at a session (The Nuts and Bolts of Organizing a Telestroke Network) at the American Heart Association International Stroke Conference in Los Angeles, California, in February.

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NEWS from the DEPARTMENTS (January-April 2016)

Affiliated hospital recertified as a Primary Stroke Center St. Joseph’s/Candler (SJC) Hospital in Savannah, which is staffed by MCG neurology faculty, was recertified as a Primary Stroke Center by the Joint Commission.

Dr. Shannon Stewart, former MCG student, neurology resident and vascular neurology fellow, directs the Stroke Program at St. Joseph’s where he is assisted by Dr. Mihaela Saler, also a former MCG neurology resident and vascular neurology fellow. Dr. Brian Raj directs the program at Candler Hospital. The MCG Neurology Department continues to provide 24-7-365 telestroke consults to the SJC Stroke Network of seven hospitals.

Neurosurgery Department celebrates 60th anniversary reunion The Department of Neurosurgery at MCG had its origins as a division in 1956. To celebrate this event, we organized an alumni reunion, which coincided with the School of Medicine’s Alumni Weekend. By all accounts, the event was extremely successful. More than 27 neurosurgery alumni and guests attended in addition to our faculty and residents. Speakers at the event included Dean Peter Buckley and current faculty. Topics included a comprehensive history of our program and updates on a variety of subspecialties. Dr. Ernie Fokes, one of our alumni, made a monetary contribution for which we are extremely grateful.

Neuroscience Outlook wins award We are pleased to report that our very own newsletter, Neuroscience Outlook, won a Gold Award in the Internal category at the 33rd Annual Healthcare Advertising Awards.

Each year, a national panel of judges reviews entries based on creativity, quality, message effectiveness, consumer appeal, graphic design and overall impact. The Healthcare Advertising Awards is the oldest, largest and most widely respected health care advertising awards competition. The awards are sponsored by Healthcare Marketing Report, the leading publication covering all aspects of health care marketing, advertising and strategic business development.

Awards will be distributed in June.

Epilepsy Center receives Level 4 certification again The Epilepsy Center, led by Dr. Yong Park, medical director; Dr. Anthony Murro, co-medical director; and Donald Hamilton, administrative director, has once again received the highest level of certification (Level 4) by the National Association of Epilepsy Centers.

A subgroup of the reunion attendees. From left to right: Drs. Cargill Alleyne, William Sims (R ’85), Michael Cowan (R ’99), Ildemaro Volcan (R ’77), William Pritchard (R ’63), Ernest Fokes (R ’69), Hugh Smisson Jr. (R ’62), Hugh (“Trip”) Smisson III (R ’92), and Dennis McDonnell (chief of Neurosurgery ’94-’99)].

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PUBLICATIONS & PRESENTATIONS (January to April 2016) PRESENTATIONS:

Hess DC: Cerebrovascular disease and stroke. Augusta University Primary Care and Family Medicine symposium, MCG, Augusta University, Augusta, GA, April 2016.

Giller CA: A Random walk through the history of neurology and neurosurgery: Lessons from 35 years of collecting. Neurology Grand Rounds, Medical College of Georgia, Augusta University, Augusta, GA, February 2016.

Macomson SD: Minimally invasive cranial surgery. Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Hess DC: Final results of the B01-02 phase 2 trial testing the safety and efficacy of MultiStem® in treatment of ischemic stroke. American Heart Association International Stroke Conference, Los Angeles, CA, February 2016.

Park Y, Flamini R, Pearlman E, Mathur S, Gregory M, Long S, Starnes N, Wooldridge LJ, Diamond MP: Update from the Georgia Cannabidiol Intermediate Expanded Access Study: An open-label, multicenter study to investigate the safety of cannabidiol (GWP2003-P) in children with medication resistant epilepsy. American Academy of Neurology Meeting, Vancouver, Canada, April 2016.

Vender JR: Surgical management of trigeminal neuralgia and neuropathy. Konzelman Conference, School of Dental Medicine, Augusta University, Augusta, GA, February 2016.

Rahimi SY: Endovascular techniques for stroke. Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Alleyne CH: Risk of rupture and current trends in the management of unruptured aneurysms. Larissa International Neurovascular Conference: Cerebral aneurysms, Department of Neurosurgery, University of Thessaly, Larissa, Greece, March 2016.

Vender JR: Update on stereotactic radiosurgery. Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Alleyne CH: How I do it: Sylvian fissure splitting. Larissa International Neurovascular Conference: Cerebral aneurysms, Department of Neurosurgery, University of Thessaly, Larissa, Greece, March 2016.

Vender JR: Surgical management of trigeminal neuralgia. Augusta University Primary Care and Family Medicine symposium, MCG, Augusta University, Augusta, GA, April 2016.

Alleyne CH: Hybrid training: the way forward? Larissa International Neurovascular Conference: Cerebral aneurysms, Department of Neurosurgery, University of Thessaly, Larissa, Greece, March 2016.

PUBLICATIONS:

Vardjan N, Horvat A, Anderson JE, Yu D, Croom D, Zeng X, Lužnik Z, Kreft M, Teng YD, Kirov SA, Zorec R: Adrenergic attenuation of astrocyte swelling: a new strategy for rescuing cells in central nervous system edema. American Society for Neurochemistry, Denver, CO, March 2016 (poster).

Maugeri R, Antonella G, Graziano F, Visocchi M, Giller C, Iacopino DG: Delayed chronic intracranial subdural hematoma complicating resection of a tanycytic thoracic ependymoma. Surg Neurol Int 7(Suppl 1):S20-S22, 2016.

Kirov SA: Mechanisms of spreading depolarization-induced cytotoxic edema. American Society for Neurochemistry, Denver, CO, March 2016.

Sukumari Ramesh S, Alleyne C: Post injury administration of tert-butylhydroquinone attenuates acute neurological injury after intracerebral hemorrhage in mice. J Mol Neurosci 58(4):525-31, 2016 [doi: 10.1007/s12031-016-0722-y. Epub 2016 Feb 11].

Kirov SA: Live imaging of brain injury depolarizations and their impact on the integrity of synaptic circuitry. Tulane University, Neuroscience Seminar Series, New Orleans, LA, March 2016.

Vardjan N, Horvat A, Lužnik Z, Kreft M, Croom D, Teng T, Kirov SA, Zorec R: Cell edema attenuation by adrenergic receptors in astrocytes in vitro and in vivo: a new mechanism and strategy for neurotrauma treatment. Glia [Epub ahead of print; Mar 28], 2016.

Alleyne CH: An overview of the Department of Neurosurgery.

Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Sword J, Croom D, Wang PL, Thompson RJ, Kirov SA: Neuronal pannexin-1 channels are not molecular routes of water influx during spreading depolarization-induced dendritic beading. J Cereb Blood Flow Metab [Epub ahead of print; Mar 18], 2016.

Alleyne CH: Neurosurgery Research. Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Alleyne CH: How hybrid training influences aneurysm management.

Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Choudhri HF: Complex spine reconstruction. Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Giller CA: Update of Functional Neurosurgery. Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Heger I: Update on Pediatric Neurosurgery. Neurosurgery Department 60th Anniversary Alumni Reunion, Department of Neurosurgery, MCG, Augusta University, Augusta, GA, April 2016.

Hess DC: MultiStem: a Cell therapy for stroke. American Society of Neural Therapy and Repair (ASNTR) Meeting, Clearwater, FL, April 2016.

Members of the Augusta University Neurology and Neurosurgery departments are shown in bold 6

NEUROSURGERY CONFERENCE SCHEDULE May-August 2016 May 6 10 a.m. Journal Club 11 a.m. Pact Training 12 p.m. Faculty Meeting

July 8 10 a.m. Anatomy 11 a.m. Business-Dr. Giller 12 p.m. Case Conference

May 13 10 a.m. Oral Board Review 11 a.m. Neuro 101-Nathan Todnem 12 p.m. M&M

July 15 10 a.m. Radiology 11 a.m. Neuro 101-Dr. Rahimi 12 p.m. Case Conference

May 20 9 a.m. Pathology-Dr. Sharma 10 a.m. Radiology 11 a.m. Business-Dr. Giller 12 p.m. Case Conference

July 22 9 a.m. Pathology 10 a.m. Resident Meeting 11 a.m. Journal Club 12 p.m. M&M

May 27 NO CONFERENCEGeorgia Neurosurgical Society Meeting

July 29 NO CONFERENCE

June 3 11 a.m. Oral Board 12 p.m. Case Conference

August 5 11 a.m. Oral Board 12 p.m. Case Conference

June 10 NO CONFERENCE-Milestones

August 12 10 a.m. Anatomy 11 a.m. Functional/Gamma 12 p.m. Case Conference

June 17 10 a.m. Radiology 11 a.m. Neuro 101-Dr. Alleyne 12 p.m. Case Conference

August 19 10 a.m. Radiology 11 a.m. Neuro 101-Dr. Heger 12 p.m. Case Conference

June 24 10 a.m. Resident Meeting 11 a.m. Journal Club 12 p.m. M&M

August 26 9 a.m. Pathology 10 a.m. Resident Meeting 11 a.m. Journal Club 12 p.m. M&M

July 1 11 a.m. Oral Board 12 p.m. Case Conference

NEUROLOGY GRAND ROUNDS SCHEDULE May-August 2016

UPCOMING MEETINGS May 5 May 12 May 19 May 26 June 2 June 9 June 16 June 30 July 7 July 14 July 21 July 28 August 4 August 11 August 18 August 25

May-August 2016

Dr. Tom Swift: Case Presentation Dr. John Morgan: Movement Disorders Dr. Alfredo Garcia: Neuro Critical Care Dr. Mary Gregory : Child Neurology Resident: Nitzmari Melendez Vazquez Resident: James Shou Resident: Shaun Shaker No Grand Rounds No Grand Rounds Kiawah Conference-No Grand Rounds Dr. Ned Pruitt: Education Update Dr. Tom Swift: Case Presentation Dr. Yong Park: Epilepsy Dr. John Morgan: Movement Disorders Dr. Jeff Switzer: Stroke Dr. Mary Gregory: Child Neurology

April 30-May 4: American Assoc. of Neurological Surgeons

Washington, D.C.

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May 27-29:

Georgia Neurosurgical Society, Sea Island, Georgia

June 4-7:

Society of Neurological Surgeons, Indianapolis, Indiana

July 25-29 :

July 30-Aug 3:

Society of Neuro-Interventional Surgery Boston, Massachusetts National Medical Association, Los Angeles, California

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CLINICAL SPOTLIGHT

THE RELATIONSHIP BETWEEN CHIARI MALFORMATIONS AND CONNECTIVE TISSUE DISORDERS: Is it casual or causal?

Recently, there has been much interest in the association between Chiari malformations and connective tissue disorders (CTD) such as Ehlers-Danlos syndrome.

Whereas treating one of these disorders is in itself challenging, when they occur simultaneously, the decision is even more complex. Chiari malformations are a group of disorders with a broad range of signs and symptoms at presentation. A great deal of knowledge and experience is required of the clinician to determine if a correlation exists and if aggressive (surgical) treatment is an option. Further complicating the situation is the fact that the subset of patients with CTD are at high risk of treatment failure with the standard surgical treatment. This article will help the clinician to better understand these disorders, how to diagnose them properly, and will explore the different treatment options – both conservative and surgical.

Chiari malformations Chiari malformations are a heterogeneous group of disorders that produce herniation of the cerebellar tonsils below the level of the foramen magnum.

Increasingly, type III (cerebellar herniation into a high cervical meningocoele) and type IV (cerebellar agenesis) are thought to be due to a distinct dysembryogenesis from types I and II. Chiari malformation type II is generally found in association with spina bifida aperta.

Type I is a relatively rare disorder with an estimated prevalence in the range of one in 1000-5000. Although most cases are sporadic, familial inheritance either by an autosomal recessive or autosomal dominant with incomplete penetrance mechanism have been reported. This disorder is generally understood as one of unbalanced development of the paraxial mesoderm of the posterior fossa relative to the intracranial contents, resulting in a “too small” cavity for the cerebellar contents and resultant herniation. The most common complaint is headache, classically described as occurring suboccipitally with radiation to the vertex and behind the eyes. In many cases, the headaches are exacerbated

by Valsalva maneuvers such as sneezing, coughing or straining. Nearly any neurologic sign or symptom can be a part of the initial presentation. It is imperative that the treating physician be familiar with the disease to discern whether the symptoms are in fact due to the compression from the tonsillar herniation or are merely coincidental and not related. While some symptoms may respond to conservative treatment for which a trial may be appropriate prior to contemplating surgical intervention, other symptoms are best appropriately addressed surgically.

Ehlers-Danlos syndrome The Ehlers-Danlos syndrome (EDS) is a heterogeneous group of disorders of collagen metabolism which manifest through a wide variety of symptoms. The cardinal features include joint hypermobility, as well as skin hyperextensibility and fragility. This is a rare disease, which occurs in 1:5000 individuals. It is divided into six subtypes according to the Villefranche classification with the classical, hypermobile, and vascular types being the most common. The genetic basis for these disorders are quite diverse, and in some instances, the exact genetic mutation is unknown. Where the mutation is known, it usually involves dysfunction in either the formation or crosslinking of collagen fibrils.

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As the principle manifestation of this disease is joint hypermobility, the Beighton scale is used to assess the degree of hypermobility. As patients grow older, there is a tendency for flexibility to decrease; however, for children, generally a score of at least 5 out of 9 is considered diagnostic. Another characteristic of the disease is that patients frequently complain of joint pain and are prone to injuries such as joint subluxation and torn ligaments and tendons. Cutaneous manifestations such as marked skin hyperextensibility, widened atrophic cutaneous scars, and easy bruising with skin staining due to hemosiderin deposits are also prevalent. Furthermore, subcutaneous spheroids and molluscoid pseudotumors with scars over the knees and elbows can also be seen.

Due to the connective tissue abnormality, children with these disorders can experience problems with motor development, muscle weakness and proprioception.

Additionally, patients may be more prone to developing functional somatic syndromes such as fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome and orthostatic intolerance to name a few.

of cases. It is postulated that cervical hypermobility and resultant brain stem compression may be causative in some cases by activating cervical afferents that converge on the spinal nucleus of 5.

Connective tissue disorders may predispose patients to dural laxity or ectasias. CSF leaks are known to occur at sites of ectasias, resulting in intracranial hypotension.

These headaches tend to be position dependent and are worse sitting up and relieved while the patient lies flat.

Connective tissue disorders and headaches Headache and neck pain are common symptoms that patients with EDS report. The types of headaches they most commonly experience are migraines, cervicogenic headache, intracranial hypotension and new daily persistent headaches. The incidence of migraine headaches has been shown to be increased in EDS patients. It is speculated that this may be related to abnormalities in TGF-β signaling, such as has been found in patients with Marfan syndrome.

Association between Chiari malformation and EDS The association between Chiari malformation type I and connective tissue disorders (CTD) was initially described

by Milhorat et al in 2007. In their cohort of patients, family history data appeared to show a relationship between CMI and CTD. They observed that a subset of Chiari patients who also had CTD appeared to have what they referred to as functional cranial settling. This was manifested by a reducible increase in the basion-dens interval and posterior gliding of the occipital condyles.

This led to the conclusion that these patients suffer from occipitoatlantoaxial hypermobility, which is responsible for the treatment failure from decompression surgery in these patients. As a result, a belief that these patients require occipito-cervical fusion operations in order to achieve symptomatic relief has been developed.

Although their manuscript illustrated the dynamic changes which occur in patients with occipitoatlantoaxial hypermobility with the use of vertical or sitting MRI, further studies have not demonstrated the utility of upright MRI. Henderson has described the potential harmful effects of this type of cranial settling. In a finite analysis model, when the clivo-axial angle is less than 125 degrees, the forward angulation produces a distracting force on the neural elements, which can result

Cervicogenic headaches are experienced in the occipital region and tend to be mild to moderate in intensity. In children, this may be due to C2 neuralgia, mechanical instability or functional instability. In older patients, degenerative disease such as disc herniation, facet arthropathy, spinal stenosis or cervical spondylosis can be the cause. Cervical disc disease is known to be increased in these patients and is postulated that it is due to hypermobility and/or spinal deformity causing abnormal stress on the disc and supporting structures, leading to herniation.

New daily persistent headaches begin on a specific day and are then continuous. They are bilateral 64 percent of the time and are described as throbbing or pressure in nature. They are usually located in the occipitonuchal or retro-orbital region but can be generalized in 18 percent

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CLINICAL SPOTLIGHT

MULTIPLE SCLEROSIS

Clinical Vignette:

A 16 year-old African-American girl presented with initial symptoms of stomach pain, vomiting, weight loss, right lower extremity numbness, fatigue and generalized weakness. She was treated with steroids for possible Crohn’s disease and improved. Four months later, however, she developed numbness in her hands, legs and torso with concomitant bowel and bladder incontinence. She was admitted to the MCG PICU for a more extensive work-up. Cervical MRI showed extensive cervical spinal cord lesion burden with enlargement of the cord, whereas MRI of the brain was unremarkable.

CSF studies revealed elevated IgG synthesis and oligoclonal bands, and visual evoked potentials showed some mild abnormalities in the left eye. Laboratory tests for infectious and rheumatologic disorders was unrevealing. Due to concern for a neoplastic process, she underwent cervical spine biopsy, which showed demyelination, and furthermore, Aquaporin-4 antibody testing came back positive. Based on the above results, she was diagnosed with neuromyelitis optica (NMO), aka Devic’s disease, in March of 2009, at the age of 17.

She had minimal improvement with IV SoluMedrol, plasmapheresis (PLEX) and IVIG. She suffered a reaction with her initial dose of Rituxan, and her parents refused further treatment with this drug. She was subsequently started on Imuran and had gradual improvement with inpatient rehabilitation. She went on to have two relapses in the fall of 2009 with unilateral vision loss and sensory changes, which improved partially with SoluMedrol. Imuran was titrated up to 150 mg BID, and she was referred to the Center for Pediatric Onset Demyelinating Disease at the University of Alabama, for a second opinion; the diagnosis of NMO was confirmed, and the recommendation was to continue Imuran.

For the next several years, she continued on Imuran 150 mg BID with intermittent noncompliance leading to a relapse in 2011. However, she restarted Imuran and was stable for two years, until January 2013, when she had a severe relapse marked by the development of a new cervicomedullary lesion. She was critically ill, and her course was complicated by both pancreatitis and neutropenia. She had an extended hospitalization requiring intubation and PEG tube placement. Imuran 10

was held during the time because of neutropenia.

Following discharge, she restarted Imuran 100 mg BID with plan to titrate to her usual dose of 150 mg BID. However, several months later in November of 2013, she had a relapse consisting of blurred vision with increased nystagmus, decreased motor control of her left upper extremity and difficulty in ambulation. MRIs demonstrated a new cervical enhancement and optic neuritis of her right eye. Despite additional treatment with PLEX, her symptoms worsened, her cervical lesion progressed and she required re-admission to the hospital in December. Imuran was again discontinued, and she was given her first dose of Mitoxantrone without complications. Prior to infusion, her cardiac ejection fraction was normal, and she tolerated the medication well. Despite this new treatment, she again relapsed shortly after the infusion and was treated with IVIG rather than PLEX due to the recent Mitoxantrone infusion. Following the hospitalization, she continued to receive Mitoxantrone infusions every three months.

Follow-up MRIs remained stable. By January 2015, she had completed five rounds of Mitoxantrone and had received close to half the recommended cumulative lifetime dose. Given her clinical and radiographic stability combined with total-dose limitations, a decision was made to spread her infusions to every six months.

Two months later, in March 2015, she unfortunately relapsed once again with cervical enhancement. She was treated once again with IVIG and continued with the Mitoxantrone in April 2015. Despite this, she relapsed six weeks later with extensive enhancement of the lesion from C1-6. At that time, Alexion was enrolling patients in a trial evaluating the efficacy of Eculizumab for NMO, and we decided to try it. However, before the Augusta University MS Center could be enrolled as a site, the patient relapsed yet again. She was treated with Methylprednisolone and PLEX. Rituxan was retried with premedication of diphenhydramine, acetaminophen and SoluMedrol given her previous infusion reaction. She tolerated it very well and was discharged to inpatient rehab a week later. She has been clinically and radiographically stable on a regimen of Rituxan 1g every three months since that time.

Here at the Augusta University Multiple Sclerosis (MS) Center, we strive to provide the very best care possible by offering both proven and cutting-edge therapies to achieve optimal outcomes. We embrace a multidisciplinary and comprehensive approach to treat our diverse and often very ill population. We participate in clinical trials to help bring better medications to the market.

She is improving clinically, but at the young age of 23, she unfortunately has to cope with daily symptoms of gait impairment, neurogenic bladder and bowel dysfunction, dysesthesias, muscle spasm, vision impairment, headaches, arm tremor and fatigue. Both her strength and sensation are reduced in the extremities, and she ambulates with a hemi-walker. She continues to participate in physical and occupational therapy at home. She is followed closely by neuro-ophthalmology for rotatory nystagmus at rest and in all directions of gaze.

Despite her limitations, she possesses an admirable and infectious grit going so far as to organize fundraisers to expand NMO research.

The Augusta University MS Center was recently selected as a participating center for a phase 3 trial to confirm the safety and efficacy of Eculizumab for the treatment of NMO. Eculizumab is a recombinant, humanized monoclonal IgG2/4 antibody approved by the FDA for treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. It is a terminal complement inhibitor, suggesting it may reduce relapse and prevent disability accumulation in NMO. In a recently reported, investigator-initiated trial of a highly relapsing NMO patient population, Eculizumab reduced the annual relapse rate from a median of three relapses per year to zero relapses per year (p<0.0001). The trial is a randomized double-blind, parallel-group, placebocontrolled, multicenter, time-to-event study. The good news is that patients may remain on a stable maintenance dose of immunosuppressive therapy while in this trial.

The primary endpoint of the trial is to assess the efficacy of Eculizumab treatment as compared with placebo in relapsing NMO patients based on the time to first relapse and relapse risk reduction. The secondary endpoints are to characterize the overall safety and tolerability of Eculizumab and to evaluate the efficacy by additional measures including disease-related disability, quality of life, neurologic function and annual relapse. Our hope is that by participating in this trial, among others, we can realize better treatments for our NMO patients. We welcome referrals for treatment of all demyelinating disease and are currently also enrolling in a number of clinical trials for both disease-modifying therapies and symptomatic management of multiple sclerosis.

Discussion: Neuromyelitis optica is a rare, disabling autoimmune disorder that causes demyelination to the central nervous system and is characterized by relapses. NMO predominately affects the optic nerves, spinal cord and brainstem often causing symptoms of sudden vision loss, weakness, sensory loss, bowel or bladder dysfunction, vomiting and hiccups as seen in the case example above.

Patients rarely recover fully from relapses, leading to rapid accumulation of disability. Neuromyelitis optica spectrum disorder (NMOSD) is an inclusive term referring to both patients with NMO and patients who have aquaporin-4 antibodies with either recurrent transverse myelitis without optic neuritis or recurrent optic neuritis without a history of transverse myelitis. Similar to multiple sclerosis, NMO affects women more commonly than men with a female-to-male ratio of at least 3:1. Although many patients receive immunosuppressive therapies to prevent relapses, currently, there are no approved therapies for the treatment of NMO. As in this case, acute relapses are typically treated with high-dose corticosteroids, plasma exchange, IVIG, immunosuppressant or a combination of all the above. Unfortunately, this combination is not enough to prevent relapses and progressive disability as highlighted by this case. Further research into effective disease-modifying treatments is desperately needed.

To learn more about our trials or to participate, please contact the clinic at 706-721-1411.

Pittock SJ1, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, Oâ&#x20AC;&#x2122;Toole O, Wingerchuk DM: Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol. 2013 Jun;12(6):554-62. [doi: 10.1016/S1474-4422(13)70076-0. Epub 2013 Apr 26].

Rebeca Rahn, PA-C, and Suzanne H. Smith, MD

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(Continued from page 9.)

Figure 1 – Instrumentation and fusion from the occiput to C3. There is anterior angulation of C3 on C4 as well as separation of the spinous processes at that level indicative of ligamentous instability.

Figure 2 – After anterior cervical discectomy and fusion at C3/C4, there is stabilization at that level. At C4/C5, there is now splaying of the spinous processes illustrating adjacent level disease.

in neurologic dysfunction. Other authors sought to elucidate which patients would benefit from a decompression alone and which patients would progress to treatment failure if their surgical intervention did not include an occipital-cervical fusion. Brockmeyer et al. determined that a subgroup of “complex” pediatric Chiari malformation patients exist that indeed have a higher rate of requiring occipital-cervical fusion. These patients include those that present with basilar invagination, Chiari malformation 1.5 (tonsillar herniation along with brainstem herniation), and a clival-axial angle less than 125 degrees. Although it was initially thought that ventral brainstem compression, as defined by the pB-C2 line, is an independent predictor for treatment failure, further studies have not shown this to be the case.

However, the pB-C2 line is still useful as a quantitative measure of ventral brainstem compression.

Treatment of EDS-related, CM1-related symptoms For many patients, the initial treatment strategy employed is one of conservative management. Physiotherapy is an option for most patients as it has been shown to improve muscle tone, thereby stabilizing joints and reducing postural sway. With respect to the cervical spine, treatment strategies are employed to improve proprioception in addition to activity modification and postural training to stabilize the hypermobile cervical segments. In addition, many patients with a hypermobile spine tend to have tightened muscle groups, in particular the trapezius, which may require controlled stretching.

With respect to headaches, different treatments are available for migraines.

Topiramate, tricyclic antidepressants, gabapentin and valproic acid are good preventative agents. Angiotensin receptor blockers have been shown to be effective migraine preventative agents in patients with Marfan syndrome due to abnormalities in TGF-β signaling. As there is speculation that there are many similarities between Marfan’s and the other CTD, it is possible that these agents may be efficacious in these disorders as well.

As previously mentioned, those patients with dural ectasia or laxity may develop intracranial hypotension due to CSF leakage. The primary treatment is with caffeine, hydration and a lumbar epidural blood patch. If a definitive leak site can be identified, a targeted epidural blood patch can be tried, or direct surgical repair can be performed.

Figure 3 – Resolution of symptoms following revision of the instrumentation to extend to the T2.

Patients who suffer from dysautonomia (postural orthostatic tachycardia syndrome or POTS) often develop a variant of migraines called “coat hanger” headaches. These are described as occurring in the occiput, neck and shoulders and occur while sitting or arising. β-blockers in small doses can be used to treat both the headaches and the dysautonomia. Other treatment options include support stockings, fludrocortisone or midodrine.

Given the chronic nature of CTD and the multiple pain-producing conditions that are associated with it, many patients ultimately suffer from the effects of polypharmacy. Where possible, it is best to avoid narcotics and instead use nonsteroidal anti-inflammatory medications. Conservative treatments such as physical therapy, biofeedback and acupuncture should be utilized in an attempt to avoid medications. When medications are required, those that are preventative in nature should be employed. Many of these patients suffer from diffuse pain throughout the body and should be evaluated for central sensitization syndrome. Central sensitization is a chronic pain condition where the 12

functional state of sensory neurons is altered such that the central nervous system abnormally amplifies sensory input. This leads to patients having a hypersensitivity to nonpainful stimuli or experiencing the â&#x20AC;&#x153;gainâ&#x20AC;? being turned up on painful stimuli. Although complex, identifying patients with central sensitization is the first step in treatment.

Surgical treatment The symptoms that respond most optimally to surgical intervention are those related to neural compression and CSF circulation disturbance. Ataxia, hyperreflexia, swallowing dysfunction and central sleep apnea are examples of neural compression symptoms that are amenable to surgical decompression. Headaches that are related to perturbations in CSF flow, such as those that are worsened by coughing, sneezing or straining, many times respond favorably to a posterior fossa decompression.

Although many different variations of this procedure exist, generally the objective of any surgical correction is to relieve the neural compression at the foramen magnum and to restore normal anatomy and CSF circulation across the craniovertebral junction. When the intracranial pressure is elevated, an underlying defect in CSF absorption may be present, which usually responds well to CSF shunting. Intracranial hypotension responds well to a lumbar epidural blood patch or, when the actual leakage point can be discerned, direct repair.

involved a posterior fossa craniectomy with C1 laminectomy and duraplasty only involving the outer layer of dura. Initially, his headaches resolved, but ultimately, they returned along with upper extremity dysesthesias.

His decompression was therefore revised, where a duraplasty, lysis of adhesions and tonsillar shrinkage was performed. Subsequently, he underwent a vascular bypass procedure for symptomatic vascular insufficiency, and a ventriculoperitoneal shunt was performed for hydrocephalus. He developed intractable neck pain for which an O-3 fusion was performed. His symptomatic improvement was short lived as he developed signs of cervical instability at the adjacent level (Figure 2). A C4/5 ACDF and extension of his posterior fusion to the thoracic spine (Figure 3) was required to achieve stability and symptomatic improvement.

When significant instability is present preoperatively or if the risk of developing it postoperatively is high, the decompression is paired with an instrumentation and fusion procedure (Figure 1). To treat cranial settling, the techniques described by Rekate and others to reduce the deformity are performed as part of the procedure prior to the instrumentation. If there is cranial settling or other anterior compression present that is not reducible, then an anterior decompression should be considered in addition to the posterior fusion. When a posterior fusion is contemplated for a patient with CTD, a longer construct than would otherwise be thought necessary should be considered. Due to connective tissue laxity in these patients, the ligaments at adjacent spinal levels to the fusion construct may not be strong enough and fail, leading to adjacent level failure and instability (Figure 2).

Conclusion When treating patients with Chiari malformations, it must be considered that a subset of patients will also meet the diagnostic criteria of connective tissue disorders such as EDS. Failure to recognize this can easily lead to treatment failure. The well-educated and experienced clinician will evaluate the patient for both of these conditions, as treatments may change depending on their presence or absence. If evaluated properly, many conservative as well as surgical treatments are available with good outcomes should these patients be diagnosed appropriately.

Case vignette Patient BW is a complex patient who presented at the age of 8 with headaches that were refractory to conservative treatment. His initial surgical procedure

(References page 14)

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VOL. 13 | ISSUE 2 NEUROSCIENCE OUTLOOK

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2. Bollo RJ, Riva-Cambrin J, Brockmeyer MM, Brockmeyer DL. Complex Chiari malformations in children: an analysis of preoperative risk factors for occipitocervical fusion. J Neurosurg Pediatr. 2012 Aug;10(2):134-41.

3. Bonney PA, Maurer AJ, Cheema AA, Duong Q, Glenn CA, Safavi-Abbasi S, Stoner JA, Mapstone TB. Clinical significance of changes in pB-C2 distance in patients with Chiari Type I malformations following posterior fossa decompression: a single-institution experience. J Neurosurg Pediatr. 2016 Mar;17(3):336-42.

4. Brockmeyer DL. The complex Chiari: issues and management strategies. Neurol Sci. 2011 Dec;32 Suppl 3:S345-7. doi: 10.1007/s10072-011-0690-5.

5. Castori M, Camerota F, Celletti C, Danese C, Santilli V, Saraceni VM, Grammatico P. Natural history and manifestations of the hypermobility type Ehlers-Danlos syndrome: a pilot study on 21 patients. Am J Med Genet A. 2010 Mar;152A(3):556-64.

6. Castori M, Morlino S, Celletti C, Ghibellini G, Bruschini M, Grammatico P, Blundo C, Camerota F. Re-writing the natural history of pain and related symptoms in the joint hypermobility syndrome/Ehlers-Danlos syndrome, hypermobility type. Am J Med Genet A. 2013 Dec;161A(12):2989-3004.

7. Castori M, Morlino S, Ghibellini G, Celletti C, Camerota F, Grammatico P. Connective tissue, Ehlers-Danlos syndrome(s), and head and cervical pain.

Am J Med Genet C Semin Med Genet. 2015 Mar;169C(1):84-96.

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10. Henderson J, Thoreson A, Yoshii Y, Zhao KD, Amadio PC, An KN. Finite element model of subsynovial connective tissue deformation due to tendon excursion in the human carpal tunnel. J Biomech. 2011 Jan 4;44(1):150-5.

11. Jacome DE. Headache in Ehlers-Danlos syndrome. Cephalalgia. 1999 Nov;19(9):791-6.

12. Kim LJ, Rekate HL, Klopfenstein JD, Sonntag VK. Treatment of basilar invagination associated with Chiari I malformations in the pediatric population: cervical reduction and posterior occipitocervical fusion. J Neurosurg. 2004 Nov;101(2 Suppl):189-95.

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14. Milhorat TH, Bolognese PA, Nishikawa M, McDonnell NB, Francomano CA. Syndrome of occipitoatlantoaxial hypermobility, cranial settling, and chiari malformation type I in patients with hereditary disorders of connective tissue. J Neurosurg Spine. 2007 Dec;7(6):601-9.

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19. Scheper MC, de Vries JE, Verbunt J, Engelbert RH. Chronic pain in hypermobility syndrome and Ehlers-Danlos syndrome (hypermobility type): it is a challenge. J Pain Res. 2015 Aug 20;8:591-601.

20. Scheper MC, Engelbert RH, Rameckers EA, Verbunt J, Remvig L, Juul-Kristensen B. Children with generalised joint hypermobility and musculoskeletal complaints: state of the art on diagnostics, clinical characteristics, and treatment. Biomed Res Int. 2013;2013:121054.

21. Smits-Engelsman B, Klerks M, Kirby A. Beighton score: a valid measure for generalized hypermobility in children. J Pediatr. 2011 Jan;158(1):119-23, 123.e1-4.

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IN MEMORIAM

DR. WILLIAM B. MAYHER III, MD Medical College of Georgia Alumni

In Memoriam Dr. Willam B. Mayher III (MD ’64, R ’70) of Albany, Georgia, passed away at age 77 on Jan. 31, 2016, in Athens, Georgia. Dr. Mayher was born in Columbus, Georgia. After graduating from the University of Georgia in 1960 and the Medical College of Georgia in 1964, he had a long and distinguished career as a neurosurgeon in Albany from 1970 to 1998. He maintained close ties with MCG throughout his life and was affiliated with the Medical College of Georgia Foundation for 20 years, including serving as chairman of the board.

on numerous other boards, including the American 2016 January-April Association of Neurological Surgeons and the Georgia Aviation Hall of Fame Board. Mayher was an avid lover of aviation, earning his pilot’s license at age 15. After 52 years of flying, the FAA awarded him the Wright Brothers Master Pilot Award to acknowledge over 55,000 piloting hours. He was known for his quick wit and great sense of humor. He will be greatly missed by his colleagues, family and friends.

He is survived by his wife, JoAnne; his son, William R. Mayher of Jacksonville, Florida; his daughter, Anne M. Mayher of Greenville, South Carolina; his daughter-in-law, Holli W. Mayher of Greenville, South Carolina; four grandchildren; and his sister, Frances M. Buckland of Atlanta.

Among his many civic responsibilities, he served as chairman of Blue Cross Blue Shield of Georgia, chairman of the Albany Regional Airport Commission, and chairman of the board of Gray Television Inc. He served

Dr. Vender in the Gamma Knife suite

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THE CLINICAL TEAM ALS CLINIC Michael H. Rivner, MD EPILEPSY CENTER Cole A. Giller, MD, PhD Mary Gregory, MD, PhD Debra Moore-Hill, MD Anthony M. Murro, MD Yong Park, MD Gregory Lee, PhD GAMMA KNIFE CENTER Cargill H. Alleyne Jr., MD Cole A. Giller, MD, PhD John R. Vender, MD MEMORY DISORDERS John C. Morgan, MD, PhD MOVEMENT DISORDERS Cole A. Giller, MD, PhD Julie A. Kurek, MD John C. Morgan, MD, PhD Kapil D. Sethi, MD MULTIPLE SCLEROSIS CENTER Suzanne H. Smith, MD

NEUROLOGISTS Askiel Bruno, MD James Carroll, MD K. Alfredo Garcia, MD J. Edward Hartmann, MD David C. Hess, MD Julie A. Kurek, MD Gregory Lee, PhD Debra Moore-Hill, MD John C. Morgan, MD, PhD Anthony M. Murro, MD Fenwick T. Nichols III, MD Yong Park, MD J. Ned Pruitt II, MD Michael H. Rivner, MD Elizabeth Sekul, MD Kapil D. Sethi, MD Suzanne H. Smith, MD Thomas Swift, MD Jeffrey A. Switzer, DO NEUROMUSCULAR DISEASES J. Edward Hartmann, MD J. Ned Pruitt II, MD Michael H. Rivner, MD NEUROSURGEONS Cargill H. Alleyne Jr., MD Haroon F. Choudhri, MD J. Dan Dillon, MD Cole A. Giller, MD, PhD Ian Heger, MD S. Dion Macomson, MD Scott Rahimi, MD John R. Vender, MD

NEURO CRITICAL CARE K. Alfredo Garcia, MD PEDIATRIC NEUROSCIENCES James Carroll, MD Morris Cohen, EdD Mary Gregory, MD, PhD Ian Heger, MD Yong Park, MD Elizabeth Sekul, MD SKULL BASE TUMOR CENTER Cargill H. Alleyne Jr., MD John R. Vender, MD SLEEP MEDICINE Anthony M. Murro, MD Yong Park, MD SPINE CENTER Cargill H. Alleyne Jr., MD Haroon F. Choudhri, MD Ian Heger, MD S. Dion Macomson, MD Scott Rahimi, MD John R. Vender, MD STROKE AND CEREBROVASCULAR CENTER Cargill H. Alleyne Jr., MD Askiel Bruno, MD David C. Hess, MD Fenwick T. Nichols III, MD Scott Rahimi, MD Jeffrey A. Switzer, DO

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