Handbook of Neurosurgery 8th Edition-4

Endocrinology 149 Sign s: hypoten sion , bradycardia, hypon atrem ia, hypoglycem ia, hypoth erm ia, hypoven tilation , 8 occasionally seizures. Treatm ent Drugs m ay n eed to be given IV due to reduced gastric m otilit y. 1. general supportive care: a) hypoten sion : t reat w ith IV fluids (respon ds poorly to pressors un til thyroid replacem en t accom plish ed) b) hypon atrem ia: w ill correct w ith thyroid replacem en t; avoid hyperton ic salin e c) hypoglycem ia: IV glucose d) sym ptom s of hypocor tisolism : thyroid replacem en t m ay precipitate adren al crisis (see ca ution a bove); give 300–400 m g hydrocort ison e IV over 24 h rs e) hypoth erm ia: avoid active w arm ing sin ce th is in creases m etabolic dem an d, use blan kets to w arm gradually f) hypoven tilation : ch eck ABG, in tubate if n ecessar y 2. thyroid replacem en t (for average -sized adult): a) IV replacem en t: 0.5 m g of levothyroxin e IV, follow ed by 0.05–0.2 m g/d IV un t il patien t able to tolerate PO or NG m eds b) n asogastric replacem en t: liothyron in e (Cytom el®) is prim arily T3, h as a rapid on set of act ion , m uch sh orter h alf-life th an T4, an d sh ould be reserved for em ergen cies. : liothyron in e 0.05–0.1 m g per NG in itially, follow ed by 0.025 m g BID per NG 8.3 Pit uit ary em bryology and neuroendocrinology 8.3.1 Em bryology and derivat ion of t he pit uit ary gland Th e posterior pituitar y (n eurohypophysis) derives from dow nw ard evagin ation of n eural crest cells (brain n euroectoderm ) from th e floor of th e th ird ven tricle. Th e residual recess in th e floor of th e th ird ven tr icle is called th e m edian em in en ce. Th e an terior pituitar y glan d (aden ohypophysis) devel- ops from an evagin ation of epith elial ectoderm of th e oroph ar yn x, th e evagin ation is kn ow n as Rathke’s pouch an d is even tually separated from th e oroph ar yn x by th e sph en oid bon e. Cleft-like rem n an ts of Rath ke’s pouch separates th e aden ohypophysis an d n eurohypophysis. Th e aden ohy- pophysis is com prised of th e pars distalis (an terior lobe), th e pars in term edia (in term ediate lobe) and the pars tuberalis (extension of adenohypophyseal cells on th e anterior aspect of the pituitary stalk). Th e pituitar y glan d is fun ction ally outside th e blood-brain barrier. 8.3.2 Pit uit ary horm ones, t heir t arget s and t heir cont rols General inform at ion Th e pit uitar y glan d releases 8 h orm on es, 6 from th e an terior pituitar y, 2 from th e posterior pit uitar y ( Fig. 8.1). Th e an terior pituitar y is on e of on ly t w o sites in th e body h aving a por tal circulation (th e oth er bein g th e liver). 6 hypoth alam ic h orm on es released in a pulsat ile fash ion are conveyed in blood from hypoth alam ic capillaries th rough th is portal circulation via th e pit uitar y stalk to a secon d capillar y bed in the an terior pituitary w here they control release of horm ones by adenohypophyseal gland cells. Horm on es released from th e posterior pituitar y (ADH & oxytocin ) are syn th esized in neurons in th e hypoth alam us (not glan d cells) an d are conveyed alon g th eir a xons also in th e pituitar y stalk to th e posterior pituitar y glan d w h ere th ey are released. Th e com plete h om eostat ic loop (in cluding n egative feedback of th e hypoth alam ic h orm on es) w ill n ot be covered h ere, an d th e reader is referred to physiology texts. Propiom elanocort in (POMC), AKA proopiom elanocort in 241 am ino acid polypeptide horm on e precursor synth esized prim arily in cort icotroph cell of the an terior pituitar y (but also foun d in th e hypoth alam us). Con tain s am in o acid sequen ces for ACTH, alph a-m elan ocyte-stim ulating h orm on e (α -MSH), β-lipot ropin , γ-lipotropin , β-en dorph in an d m et- enkeph alin.

8 150 General and Neurology YROTI BI HNI YROTI BI HNI Fig. 8.1 Pituitary neuroendocrinology OHPPCHTCTAHHFAEHOIIECYOOORTTELRTANPGRRRUUDLGIOLTAMMMOIIBTTEAR-NNOOOAAATMORRCNNNLIYYKCEEE laiPPncr(frrhte(aPoooPiclIblletFRaattraioLcsacotLsaor)tttp)e*siiicrnnohy-ns TTtshhhhshtrT(ieyTygoPyhoymt((lrnhhrerrrTreeTooomoumytnyRraSthtttrmlrersrHoaeHorooeoiosotinnoisni))inpdipdpsinge-eshii)g,nns ACpSNhGro(oscotTSrmtiloyEnRoiaftwRa(dnteIessHitIrorntooOaoh)mm--R-haaPogttIoGorprTamLIotthnrUnirrhhworv(oo(rostIeGGIIeooelTuaptnnpGilrCfrlAherrHglihseeoiimmFne&nanRuo-rfstw-(lsaRa)i-Ylnool1GosiilcttnnHiisnn)htikHstougheeo)me)neers-,rI CCccHoooooh(rrhrrrraAeCetmo(ttto(SdsiloAdiiiCcrercccptremrrmoCrRaoooeeotoetsiTntttHononssrsirrrHonoosotoona)nsa-gpellpppeet,hii)iicnnss hgGhooosoLrthrnurmni(emFmoatGaloeoderdonumilnaonlonRliseatcoiteizHrtrln(noeioi(Fn)ngeLppSggHhiHns)) n e u rpoas er vcirceecHtloelYulrlPylsaOr THALAMnmUeauScgrenololsepsecmictemurilnelsieuttetdalaonarilrarkycyne cAorhnAPeKno(tWrOtiAistedrdtSemaDnnriTrtuiteioHceEioryotnreR)lisneoetIiO,nc R PMcIToOliUalrnUkBexcIttTfrylrteleeAaaetrtaoctRxidinstcoYiiotienonnwn, nsG tcaI rT – + + – – + + + + (b r. o f c a ve r n o u s ICA) I(CbpAsr.uh)opyfseienr iatorlarachrrtyaepnrioya-l *t♂dho:e?pma♀+ma:inBin?rPee IaFisst T3 +& T4 Epobifpolhonynessge s + + ♂cShe: ♀acTGferoG:ueasEnnorctsmdo+cnttetsaraiatrcrodeidyesnrsitloosliecnl sxe,, cbbv“colaeelhopopidin(AantoaipilgdscsNldaa”me()TrrvpnyseEoonRdrhtoIiaOsyultpRsa=olPisphnIToh=otUryuomsIsTciossAani)vnReeuYrss-e cPP(nrpeOIeTtauiSUnrrsTgpIoinTEnhhgAfReyeylRIasrrOpeivnYooaoRdrlpshcaaytseyroistlp=nleisdsour)uy-s ra l ) ni c ot yx O( ) HDA(

Endocrinology 151 Cort icot ropin AKA adrenocort icot rophic horm one (ACTH) 8 A 39 am in o acid t roph ic h orm on e syn th esized from POMC. Th e first 13 am in o acids at th e am in o term in al of ACTH are iden tical to α -MSH. Active h alf-life is ≈ 10 m in utes. Produces a diurn al peak in cort isol (th e h igh est peak occurs in th e early m orn in g, w ith a secon d, lesser peak in th e late after- noon) and also increases in response to stress. Con t r ol: CRH from th e hypoth alam us stim ulates th e release of ACTH. Prolact in (PRL) AKA som atom am m otropin . 199 am in o-acid protein w eigh in g 23,000 dalton s. Levels are h igh er in fem ales th an m ales, an d are h igh er st ill in pregn an cy (see Table 46.3). Secreted in pulsatile fash ion w ith a frequen cy an d am plitu de th at varies during m en strual cycle (range: 5–27 n g/m l) (≈ 9 pulses/ 24 h ours in th e late luteal ph ase, ≈ 14 pulses/24 h ours in th e late follicular ph ase, th e pulse am pli- t ude in creases from early to late follicular an d luteal ph ases). Th ere is also diurn al variation : levels begin to rise 1 h our after th e on set of sleep, peak ≈ 5:00–7:00 AM, an d n adir in m idm orn in g after aw aken in g. Heterogen eit y of th e m olecule m ay produce di eren t results betw een bioassays an d im m unoassays. Con trol: PRL is th e on ly pit uitar y h orm on e predom in an tly un der inhibitor y con trol from th e hypoth alam us by prolact in in h ibitor y factors (PRIFs), w ith dopam in e bein g th e prim ar y PRIF. Prolac- tin releasin g factors (PRFs) in clude: thyrotropin -releasin g h orm on e (TRH) an d vasoact ive in testin al peptide (VIP). Th e physiologic role of PRFs is n ot establish ed. For DDx of hyperprolact in em ia see Table 46.4. Grow t h horm one (GH) A 191 am in o-acid polypeptide t roph ic h orm on e. GH n orm ally h as pulsat ile secretion (≈ 5–10 pulses/ 24 h ours, prim ar ily at n igh t , up to 30 m cg/L), levels m ay be un detectable (< 0.2 m cg/L) by stan dard assays bet w een pulses.13 In sulin -like grow th factor-1 (IGF-1) (form erly AKA som atom edin -C) is th e protein secreted prim arily by th e liver in respon se to GH th at is respon sible for m ost of GH’s system ic e ect s (see levels (p.736)). GH also acts directly on epiphyseal en d-plates of lon g bon e to st im ulate ch on drocyte proliferation . Con trol: GH is un der dual hypoth alam ic con trol via th e hypophysial portal system . GH-releasing h orm on e (GHRH) from the arcuate n ucleus st im ulates pit uitary secretion an d synthesis of GH an d in duces GH gen e tran scription . Som atostatin from th e periven tricular n ucleus suppresses GH relea se on ly, an d h as n o e ect on syn th esis. GH relea se is also st im ulated by gh relin ,14 a peptide syn th esized prim arily in th e GI t ract in respon se to certain n utrien ts (m ay act part ially or totally via hypoth ala- m ic GHRH). Thyrot ropin AKA t hyroid st im ulat ing horm one (TSH) Glycoprotein troph ic h orm on e secreted by thyrotroph cells of th e an terior pituitar y. Con trol: TSH is also un der dual hypoth alam ic con trol. TRH stim ulates product ion an d release of TSH. Som atostatin in h ibits th e release of TSH. Gonadot ropins Follicle stim ulating h orm on e (FSH) an d lutein izin g h orm on e (LH) (AKA lut ropin ) are released from th e pit uitar y in respon se to gon adot ropin releasin g h orm on e 1 (Gn RH, form erly lutein izin g h orm on e releasin g h orm on e LH-RH) syn th esized prim arily in th e preoptic area of th e hypothalam us. Ant idiuret ic horm one (ADH) AKA argin in e vasopressin (AVP). Th e m ajor source of th is n an opept ide h orm on e is th e m agn ocellular port ion of th e supraoptic n ucleus of th e hypothalam us. It is conveyed alon g a xons in th e supraopt ic- hypophyseal t ract to th e posterior pit uitary glan d w h ere it is released in to th e system ic circulat ion . All action s of ADH result from bin din g of th e h orm on e to specific m em bran e boun d receptors on th e surface of target cells.15 On e of th e m ajor e ect s of ADH is to in crease th e perm eabilit y of th e distal renal tubules resultin g in in creased reabsorption of w ater, diluting th e circulatin g blood and produc- in g a con cen trated urin e. Th e m ost pow erful physiologic st im ulus for ADH release is an in crease in serum osm olality, a less poten t st im ulus is a reduct ion of in travascular volum e. ADH is also released in glucocorticoid deficien cy, an d is in h ibited by exogen ous glucocort icoids an d adren ergic drugs. ADH is also a poten t vasocon st rictor.

152 General and Neurology Oxyt ocin A n on apept ide. Oxytocin is a n eurotran sm itter as w ell as a h orm on e. Th e hypothalam us is th e m ain source of pituitar y oxytocin w h ich is stored in ner ve endings in the neurohypophysis and is involved in th e m ilk letdow n reflex for breastfeeding as w ell as in uterin e con traction durin g labor. Re fe r e n ce s [1] Byyn y RL. W ith draw al from Glu cocorticoid Th erapy. of Bone in System ic Lupus Er yth em atosus. Am J N En gl J Med . 1976; 295:30–32 Med. 1985; 79:597–603 [2] Szabo GC, W in kler SR. W ith d raw al of Glu cocort i- [10] Zizic TM. Avascu lar Necrosis of Bon e. Cu rren t Opin - coid Th erapy in Neurosurgical Pat ien ts. Surg Neurol. ion s in Rh eu m atology. 1990; 2:26–37 1995; 44 [11] Matsu o K, Hiroh ata T, Sugioka T, et al. In flu en ce of [3] Kou n t z DS. An Algorith m for Cor t icosteroid W ith - Alcoh ol In take, Cigarette Sm okin g an d Occu pation al drawal. Am Fam Physician . 1989; 39:250–254 Stat us on Idiopathic Necrosis of th e Fem oral Head. [4] Marshall LF, Kin g J, Lan gfitt TW . The Com plication Clin Orth op . 1988; 234:115–123 of High -Dose Cort icosteroid Th erapy in Neurosurgi- [12] Stru ys A, Sn eld er AA, Muld er H. Cyclical Etidron ate cal Patien ts: A Prospect ive St udy. An n Neurol. 1977; Reverses Bon e Loss of th e Sp in e an d Proxim al 1:201–203 Fem ur in Patients W ith Establish ed Cor t icosteroid- [5] Da Silva JA, Jacobs JW , Kir w an JR, Boers M, Saag KG, In duced Osteoporosis. Am J Med. 1995; 99:235–242 In es LB, de Kon in g EJ, But tgereit F, Cutolo M, Capell [13] Peacey SR, Toogood AA, Veld h uis JD, Th orn er MO, H, Rau R, Bijlsm a JW . Safet y of low dose glucocort i- Sh alet SM. Th e relation sh ip bet w een 24-h our coid treatm ent in rh eum atoid arth ritis: publish ed grow th horm on e secretion an d in sulin -like grow th eviden ce an d prospect ive t rial data. An n Rh eum factor I in patien ts w ith successfu lly t reated acro- Dis. 2006; 65:285–293 m egaly: im pact of surgery or radioth erapy. J Clin 8 [6] Braughler JM, Hall ED. Curren t Application of \"High-Dose\" Steroid Th erapy for CNS Injur y: A En docrinol Metab. 2001; 86:259–266 [14] Tan n enbaum GS, Epelbaum J, Bowers CY. Interrela- Ph arm acological Perspective. J Neurosurg. 1985; t ion sh ip bet w een th e n ovel peptide gh relin an d 62:806–810 som atostatin/grow th h orm on e-releasin g horm on e [7] Lu W Y, Rh on ey DH, Bolin g W B, et al. A Review of in regulation of pulsatile grow th h orm on e secre- Stress Ulcer Prophylaxis in the Neurosurgical Inten - t ion . En d ocrinology. 2003; 144:967–974 sive Care Unit. Neurosurger y. 1997; 41:416–426 [15] Th ibonn ier M, Barrow DL, Selm an W . In: Antidiuret- [8] Wein er HL, Rezai AR, Cooper PR. Sigm oid Divert icu- ic Horm on e: Regulation , Disord ers, an d Clin ical lar Perforation in Neurosurgical Patien ts Receiving Evalu ation . Neu roen d ocrin ology. Balt im ore: Wil- High-Dose Cor t icosteroids. Neurosurger y. 1993; liam s an d W ilkin s; 1992:19–30 33:40–43 [9] Zizic TM, Marcoux C, Hun gerfold DS, et al. Cort ico- steroid Th erap y Associated w ith Isch em ic Necrosis

Hem atology 153 9 Hem at ology 9.1 General inform at ion Circulatin g blood volum es for adults an d peds are sh ow n in Table 9.1. 9.2 Blood com ponent t herapy 9.2.1 Massive t ransfusions Defin ition : replacem en t of > 1 blood volum e (in average adult ≈ 20 U) in < 24 h rs for adult, or > 2 × cir- culatin g blood volum e in peds, m ay cause dilution of e ect ive platelets an d coagulation factors. W h en operatin g on a pediatric patien t, you can usually safely replace up to 1.5 × th e circulatin g blood volum e before problem s w ith coagulopathy en sue. Blood com pon en t th erapy required for m assive tran sfusion s: 1. PRBCs 2. platelets (4 U in adult) 3. FFP 9.2.2 Cellular com ponent 9 Red blood cell t herapy General inform ation Major h istocom patibilities of blood are sh ow n in Table 9.2. Whole blood 1 U (≈ 510 cc) = 450 cc blood + 63 cc preservative. Recom m en ded tran sfusion criteria: ● exch ange t ran sfusion s in n eon ates ● acute burn debridem en t an d graft ing in ch ildren Packed red blood cells (PRBCs) Recom m en ded t ran sfusion criteria: 1. acute blood loss ≥ 15%of patien t’s blood volum e 2. in asym ptom atic patient: h em oglobin (Hb) ≤ 8 gm or Hct ≤ 24% Table 9.1 Circulating blood volum e Vol (cc/kga) Ag e 85–100 prem ature infant 85 term infant < 1 month 75 infant > 1 m os (& adult) acc per kg of body weight Table 9.2 Blood com patibilit y (AB0) Blood t ype Antibody present Com patible blood Com patible plasm a Com pat ible platelets (PRBC) or cryoprecipitat e AB A, 0 A, AB 0 BA AB none B, 0 B, AB 0 A, B AB, A, B, 0 AB 0 AB, A, B, 0

154 General and Neurology 3. sym ptom s of an em ia at rest 4. preoperative Hb ≤ 15 gm or Hct < 45%in th e n eon ate Am oun t to t ran sfuse: Adult: 1 U (250–300 cc) raises Hct by 3–4%. For peds, use Eq (9.1). ml of PRBC to t ra n sfu se ¼ ðe st im a t e d blood volum e ½ml ÞÂ ðHct in cre m e n t desired ½% Þ 70% ð9:1Þ (where the Hct of PRBCs ranges 70–80%) Give n o faster th an 2–3 cc/kg/h r. Autologous blood transfusion Predon ated w h ole blood m ay be stored 35 days. PRBCs m ay be stored 42 days. Patients m ay don ate every 3 days to 1 w eek as long as they m aintain Hct ≥ 34%(supplem ent w ith ferrous sulfate). Th e follow in g patien ts require physician release before don atin g: patien ts w ith cor- onary artery disease, angina, cerebrovascular disease, seizure disorder, pregnan cy (because of possi- ble vasovagal episode) or patien ts w ith m align an cy. Tr y to t im e last don ation > 72 h rs prior to surger y to allow patien t to replen ish som e of th e depleted RBCs before surgery. 9 9.2.3 Plat elet s General inform at ion Norm al platelet coun t (PC) is 150K-400K (abbreviation used h ere: 150K= 150,000/m m 3 = 150 × 109/ l). Th rom bocytopen ia is defin ed as PC< 150K. Bleeding (spon tan eously or w ith invasive procedures) is rarely a problem w ith PC > 50K. Spon tan eous h em orrh age is ver y likely w ith PC< 5K. Spon tan eous in t racran ial h em orrh age is un com m on w ith PC> 30K, an d is m ore com m on in adults th an ch ildren . Based on patien ts w ith ITP, th e risk of fatal h em orrh age in patien ts w ith PC< 30K is 0.0162–0.0389 cases per pat ien t-year1 (risk of death from in fect ion is h igh er). In tracran ial bleeding is usually subar- ach n oid or in traparen chym al, w ith petech ial h em orrh ages com m on . 1 un it of platelets con tains 5.5 × 1010 (m in im um ) to 10 × 1010 platelets. Th e volum e of 6 un its is 250–300 m l. Platelets m ay be stored up to 5 days. Recom m ended plat elet t ransfusion crit eria In dication s for platelet t ran sfusion2: 1. th rom bocytopenia due to ↓ product ion (w ith or w ith out in creased destruction ) (th e m ost com - m on causes are aplastic an em ia an d leukem ia) a) PC< 10K even if n o bleedin g (prophylactic t ran sfusion to preven t bleedin g) b) PC< 20K and bleeding c) PC< 30K an d patien t at risk for bleedin g: com plain ts of H/A, presen ce of con fluen t (c.f. scat- tered) petech iae, con tin uous bleedin g from a w oun d, in creasing retin al h em orrh age d) PC< 50K AND ● m ajor surgery planned w ithin 12 hours ● PC rapidly fallin g ● patient < 48 hours post-op ● patient requires lum bar puncture ● acute blood loss of > 1 blood volum e in < 24 h ours 2. platelet t ran sfusion s h ave lim ited usefuln ess w h en th rom bocytopen ia is due to platelet destruc- tion (e.g. by an t ibodies as in ITTP) or con sum pt ion (if product ion is adequate or in creased, plate- let tran sfusion usually w ill n ot be useful) 3. docum en ted platelet dysfun ct ion in a patien t sch eduled for surger y or in a patien t w ith advan ced h epatic an d/or ren al in su cien cy (con sider ph arm acologic en h an cem en t of platelet fun ct ion , e.g. desm opressin3) Oth er in dication s for platelet t ran sfusion : 1. patients w ho have been on Plavix® or aspirin w ho need urgen t surgery th at can not be postponed for ≈ 5 days to allow n ew platelets to be syn th esized

Hem atology 155 Do s a g e 9 Approxim ately 25%of platelets are lost just w ith t ran sfusion . Peds: 1 U/m 2 raises PC by ≈ 10K, usually give 4 U/m 2. Adult: 1 U raises platelet coun t by ≈ 5–10K. Typical dose for th rom bocytopen ic bleedin g adult: 6– 10 U (usual order: “8-pack”). Altern atively, 1 U of ph eresed platelets m ay be given (obtain ed from a sin gle don or by aph eresis, equivalen t to 8–10 U of pooled don or platelets). Ch eck PC 1–2 h rs after tran sfusion . Th e in crease in PC w ill be less in DIC, sepsis, splen om egaly, w ith platelet an tibodies, or if th e patien t is on ch em otherapy. In th e absence of in creased con sum p - tion, platelets w ill be needed q 3–5 days. 9.2.4 Plasm a prot eins FFP (fresh frozen plasm a) General inform ation 1 bag = 200–250 m l (usually referred to as a “un it”, n ot to be con fused w ith 1 un it of factor activit y w h ich is defin ed as 1 m l). FFP is plasm a separated from RBCs an d platelets, an d con tain s all coagula- tion factors an d n atural in h ibitors. FFP h as an out-date period of 12 m on th s. Th e risk of AIDS an d h epatitis for each un it of FFP is equal to th at of a w h ole un it of blood. Recom m ended transfusion criteria Recom m en dat ion s (m odified2): 1. histor y or clin ical course suggestive of coagulopathy due to congenital or acquired coagulation factor deficien cy w ith act ive bleedin g or pre-op, w ith PT > 18 sec or APTT > 1.5 × upper lim it of n orm al (usually > 55 sec), fibrin ogen fun ct ion in g n orm ally an d level > 1 g/l, an d coagulation factor assay < 25%activity 2. proven coagulation factor deficien cy w ith act ive bleedin g or sch eduled for surgery or oth er inva- sive procedure a) congen ital deficien cy of factor II, V, VII, X, XI or XII b) deficien cy of factor VIII or IX if safe replacem en t factors un available c) von W illebran d’s disease un respon sive to DDAVP d) m ultiple coagulat ion factor deficien cy as in h epatic dysfun ct ion , vitam in K depletion or DIC 3. reversal of w arfarin (Coum adin ®) (p. 166) e ect (PT > 18 sec, or INR > 1.6) in patien t actively bleedin g or requiring em ergen cy surgery or procedure w ith in su cien t tim e for vitam in K to correct (w hich usually requires > 6–12 hrs) 4. deficien cy of an tith rom bin III, h eparin cofactor II, or protein C or S 5. m assive blood t ran sfusion : replacem en t of > 1 blood volum e (≈ 5 L in 70 kg adult) w ith in several h ours w ith evidence of coagulation deficiency as in (1) and w ith continued bleeding 6. treatm en t of th rom botic throm bocytopen ic purpura, h em olytic urem ic syndrom e 7. because of associated h azards an d suitable altern atives, th e use of FFP as a volum e expan der is relatively con traindicated Do sa g e Usual start in g dose is 2 bags of FFP (400–600 m l). If PT is 18–22 secs or APTT is 55–70 secs, 1 bag m ay su ce. Doses as h igh as 10–15 m l/kg m ay be n eeded for som e pat ien ts. Mon itor PT/PTT (or spe- cific factor assay) an d clin ical bleedin g. Sin ce factor VII h as a sh orter h alf-life (≈ 6 h rs) th an th e oth er factors, PT m ay becom e prolonged before APTT. Rem em ber: if patien t is also receivin g platelets, th at for ever y 5–6 un its of platelets th e patien t is also receivin g coagulat ion factors equivalen t to ≈ 1 bag of FFP. Album in and plasm a protein fraction (PPF, AKA Plasm anate®) Usually from outdated blood, treated to in act ivate h epatitis B virus. Ratio of album in :globulin per- centage in “album in ” is 96%:4%, in PPF it is 83%:17%. Available in 5% (on cotically an d osm ot ically equivalent to plasm a) and 25%(contraindicated in dehydrated patients). 25%album in m ay be diluted to 5%by m ixin g 1 volum e of 25%album in to 4 volum es of D5 W or 0.9%NS ( caution : m ixin g w ith sterile w ater w ill result in a hypoton ic solution th at can cause h em olysis an d possible ren al failure). Expen sive for use sim ply as a volum e expan der (≈ $60–80 per un it). In dicated on ly w h en total protein < 5.2 gm %(oth er w ise, use cr ystalloid w h ich is equally e ect ive). Rapid in fusion (> 10 cc/m in ) h as been reported to cause hypoten sion (due to Na-acetate an d Hagem an factor fragm en ts). Use in ARDS is con troversial. In n eurosurgical pat ien ts, m ay be con sidered as an adjun ct for volum e

156 General and Neurology expan sion (alon g w ith cr ystalloids) for hyperdyn am ic th erapy (p. 1186) w h en th e h em atocrit is < 40% follow in g SAH w h ere th ere is con cern about in creasin g th e risk of rebleedin g e.g. w ith th e use of hetastarch (p.1165). Cr yo p re cip it a t e Recom m en ded tran sfusion criteria: 1. h em oph ilia A 2. von Willebrand disease 3. docum en ted fibrin ogen /factor VIII deficien cy 4. docum en ted dissem in ated in travascular coagulation (DIC): alon g w ith oth er m odes of th erapy Prot hrom bin com plex concent rat e (PCC) (Kcent ra® and ot hers) Derived from fresh -frozen h um an plasm a, con tain s clot ting factors II, VII, IX an d X, w ith protein C & S to preven t th rom bosis. Prim ary in dication is to be given IV to reverse w arfarin in em ergen cy sit ua- t ion s. How ever it is also used in oth er settin gs. Requires m uch low er volum e th an FFP to w ork. Also, w h en th e INR gets dow n to about 1.4, PCC w ill con tin ue to reduce th e INR w h ereas FFP w ill h ave little or n o ben efit. Optim al dosin g is n ot kn ow n . Doses of 15-50 IU/kg h ave been given to h em oph iliacs but th e clot- t in g deficit di ers in vitam in -K depletion th an in clot t in g factor absen ce. A reason able dose th at is often used is 25 IU/kg. 9 9.2.5 Ant icoagulat ion considerat ions in neurosurgery General inform at ion Most of th ese issues h ave n ot been st udied in a rigorous, prospective fash ion . Yet, th ese question s frequen tly arise. Th e follow in g is to be con sidered a fram ework of guidelin es, an d is n ot to be con - st rued as a stan dard of care. Table 9.3 acts as an in dex to th e topics discussed below. Cont raindicat ions t o heparin Con train dication s to h eparin th erapy are con stan tly being reevaluated. Massive PE producing h em o- dyn am ic com prom ise sh ould be treated w ith an ticoagulat ion in m ost cases despite in tracran ial risks. Con train dication s to full an ticoagulation w ith h eparin in clude: ● recent severe head injury ● recent craniotom y: see below ● patients w ith coagulopath ies ● h em orrh agic in farct ion ● bleedin g ulcer or oth er in accessible bleedin g site Table 9.3 Anticoagulation issues in neurosurgery General neurosurgical contraindications to full anticoagulation with heparin (p. 156) St art ing/cont inuing ant icoagulation in t he presence of t he following neurosurgical condit ions ● incidental aneurysm (p. 157) ● subarachnoid hemorrhage (p. 157) ● brain tumor (p. 157) ● following craniotom y (p. 157) ● acute epidural/subdural hem atom a ● chronic subdural hem atom a ● ischemic stroke ○ after tPA (p. 1287) ○ for prevention of (p. 1270) ● intracerebral hemorrhage (p. 1341) Managing pat ients who are already ant icoagulat ed who need a neurosurgical procedure ● warfarin (Coum adin®) (p. 157) ● heparin (p. 160) ● LMW-heparin (p. 160) ● antiplatelet drugs (aspirin, Plavix, NSAIDs) (p. 160) Recom m endat ions for DVT prophylaxis in neurosurgical pat ient s (p. 168)

Hem atology 157 ● un controllable hypertension 9 ● severe hepatic or renal disease ● < 4–6 h ours before an invasive procedure (see below ) ● brain tum or: see below Pat ient s w it h unrupt ured (incident al) cerebral aneurysm s An ticoagulation m ay n ot in crease th e risk of h em orrh age (i.e. rupture), h ow ever, sh ould rupture occur, anticoagulation would m ost likely increase volum e of hem orrhage an d thus in crease m orbid- ity an d m ortalit y. Th e decision to star t/con tin ue an t icoagulan t depen ds on th e in dication for th e drugs, th e size of th e an eur ysm (a sm all an eur ysm < 4 m m is n ot as w orrisom e). Pat ien ts n eeding Plavix® for drug- elut in g cardiac sten ts sh ould probably be left on th eir drugs. Pat ient s on ant icoagulat ion/ant iplat elet drugs w ho develop SAH Coum adin an d an t iplatelet drugs are usually reversed. In pat ient s w it h brain t um or Som e auth ors are reluctan t to adm in ister full-dose h eparin to a patien t w ith a brain tum or,4 alth ough a n um ber of st udies foun d n o h igh er risk in th ese patien ts w h en t reated w ith h eparin or oral an ticoagulation 5,6,7 (PT sh ould be follow ed ver y closely, on e study recom m en ded m ain tain in g PT ≈ 1.25 × con trol7). Post -operat ively follow ing craniot om y Requires in dividualization based on th e reason for th e cran iotom y. Surgery for paren chym al lesion s w h ere th e surger y disrupts sm all vessels (e.g. brain tum or) is probably h igh er risk for h em orrh age th an e.g. an eur ysm surgery (expert opin ion ). Option s: Full an t icoagulation : m ost n eurosurgeon s w ould probably n ot fully an ticoagulate patien ts < 3–5 days follow in g cran iotom y,8 an d som e recom m en d at least 2 w eeks. How ever, on e st udy foun d n o in creased in ciden ce of bleeding w h en an t icoagulation w as resum ed 3 days post cran iotom y.9 Low -dose (prophylact ic) an ticoagulat ion : eith er w ith m in i-dose h eparin (5000 U SQ 2 h rs prior to cran iotom y an d con tin uing q 12 h rs post-op × 7 d) or en oxaparin (Loven ox) (30 m g SQ BID or as a single dose of 40 MG SQ q d). – RPDB study10: assessed sa fet y (n ot e cacy), 55 patien ts un dergoin g cran iotom y for t um or received m in i-dose h eparin as in dicated h ad n o in creased bleedin g ten den cy by any of th e param eters m easured. RPNB study11: in ciden ce of post-op h em orrh age in creased to 11%w ith enoxaparin. Managem ent of ant icoagulant s prior t o neurosurgical procedures Pre-operative laborator y assessm en t of th e coagulat ion path w ay an d platelet fun ct ion is routin ely used even th ough th ese studies rarely con tribute crit ical in form ation in th e patien t w ith a n egative h istor y for bleedin g ten den cies. Th ere are n o ran dom ized studies to assess th e value of coagulation laboratory m easurem en ts to patien t care. Th is sect ion en com passes th e use of an tiplatelet an d an ti- coagulation m edicines, their m onitoring, and th eir reversal. Table 9.4 sum m arizes th is in form at ion . Wa r fa r in Managem ent guidelines Pat ien ts on w arfarin w h o m ust be an ticoagulated as lon g as possible (e.g. m ech an ical h eart valves) m ay be “bridged“ to LMW h eparin inject ion s, e.g. Loven ox (p. 165), as follow s: stop w arfarin at least 3 days prior to th e procedure, an d begin self-adm in istered LMW h eparin inject ion s w h ich are dis- con tin ued as outlin ed in Table 9.4. Pat ien ts w ith less critical an t icoagulation n eeds (e.g. ch ron ic a-fib) can usually stop th e w arfarin at least 4–5 days before th e procedure, an d a PT/INR is th en ch ecked on adm ission to th e h ospital. Patients m ust be advised th at durin g th e tim e that th ey are n ot anticoagulated, th ey are at risk of possible com plication s from th e con dition for w h ich th ey are receivin g th e agen ts (a nnua l risk for m ech an ical valve: ≈ 6%; for a-fib: depen ds on several factors in cludin g age & h istor y of prior st roke, an average for patien ts > 65 years age is ≈ 5–6%; see details (p. 1304).

158 General and Neurology 9 UHA(FdG(SLA(ED(BIWT(DnAGLPMoqnBiovrlanaeongrraarlgnoureebbapufaWiv,esarraxndxihslidagkfeblaneBgttkaahtarHroancrrbdioraipripNe9saonxStnoi))it)Ss)aiain.,aabmgrmxot4mrra®(maoe,ini(ainnn)nirtlCS,Aate-huhaMotnKxenKutydliolmiciennforieaesa-))g uAlSSPlaalPaISaIttaaaVVhinnnndQQQOOenxxrtttdmniitff,oiissioosfffccctmBoootisrroooaanrIrrrDaannaebpwtisDDpgghgaddortitodreuuutVVsromhttrpaiolllTTshhaaaapthsettHteepihiippyiiionnnrroooeyIlrraaTntgaunnnloopppaxot;ppxaeeiifschhi-uusyytt --iicc MIaiVifpaBDVBptgIDitttnnahnnirierooiiyiiennchhttoorrrdd;nrraaeocteddii,ttbbommihccehmssanf→riirttaairettchsniiaaboscsnnncv:ttinnftibmhheeiCinfcIosKKttbaIirlrroiit,merbsoottrca&snardiihhVitmmXbnnanvnoetrrISlatdeohoIetbbpre,→.armrmiiesfXsIonngXinibabbmoao,diirciinnnnnniXbetnhhiisni,oovIIniitIIbbtf--II. .-- MPA1NP0(vcemdimTndAa3aamtaaPnPlrTh..oxoonnoho52olotrTT0t;er)psstteiinn6ipnmeeiiemoTTrr.fIlffr4iioNoaaihsaa,mnaetta((–g(pcruoyoccpRs)A01gwmlt0g/eltttrrea..onColiooaii(ui.42/)nunanct8rgoaPlT;rrt––h)elttgglTo)i,XiiXXecu;cc;1TaioafnaanAlf.lr;5eideCt c–vis-Tt/- MiLLLiucUw2vLu≈cLhhnniiiiiaae0rrrr2nvvvvvieiissrtus–uuneeenee2ktih≈tarrrrra6rreen%i;;;;;6biioCb≈;0nno;r5lereenorT9eweeeTehCxx%x1l;;)2n1ninciccr/lns/%aTT2asrrr2a;<meeel11l,n36pE(3//tttcc22hd90bxaeee0lleci––tiddde11gluimare95ae72herriii;rn10nnn––ailtlan/yTetn12mmmnesfd1c17ec/iiie2-ennn, Rr1p8b1ecF1NmmNePsrtVoaeehieaFnfxrr0rlidoommoftvvaoohoePvrad0eeaFeeeoxvdrtemragg/cmFrsosab;rrueedoriptesPs)amrisvirHespr;ineinptlhsVanonetync(treiowdirPrelrIgn1nisnoerooeInmsKmCpiaysig5ftes(vxaalgb1fftaCola,soeaemleomrrtmsel0rpobpeaddocanehiu(ednr,nlumett2gaifdide/leansearflbdtrk5etuyabacaulginegeryguinn(–pncidtlnogtp6xsype)ette1asoIimlgitbgdV0i;eaesusfr0tu,(irdr%soi≈abs3ilv10ncnonotfxuc1ttite2)eaianaukmeiefaompUlsnt03nugnodl;neprtl%IgxyVo,ewii/cs/dorenk/rwioIehi)ardsIenga-tnelynedai)-s-vrisnet Hbm2trr1ht1pF24“r5eeeiimu2r––l––hcoeepnnisdlnn4y462llidadaehanlt9aaallyao(ddrhhsif.ncts-sstt5fCsrraadiewtuetssemy)yraaiioe,nrcCcissfPtseoc,tclthTdeietaoh<anlT”ioorgnoneT5;snppr1sunoa0eSagia2rl-rd;aQpomm-eet2ehr-irlao4ur/ilsfn- CpdiCpHDi(3mudFwimotHaai2md2Lnmefahioonb%00sfroroeoveIoiscfCooaoorTetrmdlc–0pssein3p;feoiehybsrtvf;rdeea4rr59apssaueam“Ctee),tmceri3aoia0hrr;midldrwarenltn1eitniesnbtcems,e<noePsir,iecefro3iscvncidadiipitfncioCrnr2n1ne3lneetaeuehpteuoatmeCpa03g0renXldncrcrcscrne3ohsah%o3ttfetaitai,tm8espsntsfiui3i3ntiecidbovurlhvt1o,–iotmlof3Harpeeeaucer,nesrhoun391erwiineeraonscIl2n,taawsab3Tltiobstteendaliihnndn2sHiysfounfodddctsiprhii3nntsi5ciCIssuwolso2odiTtygsatb30t,runsvont2ae,iui1rtCi%tenea18ndo,tferdh3lbtocrn–-”kd2-eieert-er;

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160 General and Neurology Table 9.5 Recom m endations for holding new oral anticoagulants prior to invasive procedures related to renal fu n c t io n .3 1 Dabigat ran Ap ixa b a n Rivo r a xa b a n CrCl > 80 m l/m in ≥ 72 hr ≥ 48 hr ≥ 48 hr CrCl 50–80 ml/m in ≥ 72 hr ≥ 48 hr ≥ 48 hr CrCl 30–49 ml/m in ≥ 96 hr ≥ 72 hr ≥ 72 hr CrCl < 30 ml/m in ≥ 120 hr ≥ 96 hr ≥ 96 hr The recommended m inimum interval bet ween last dose and procedure is based on renal function and procedure risk. Generally, neurosurgical procedures including minor procedures such as LPs are considered interventions with a high bleeding risk For non-em ergent neurosurgical procedures For procedures w h ere post-op m ass e ect from bleedin g w ould pose serious risk (w h ich in cludes m ost n eurosurgical operation s), it is recom m en ded th at th e PT sh ould be ≈ ≤ 13.5 sec (i.e. ≤ upper lim its of n orm al) or th e INR sh ould be ≈ ≤ 1.4 (e.g. for referen ce, th is INR is con sidered safe for per- form ing a percutan eous n eedle liver biopsy). See also reversal of an t icoagulat ion (p.166). For em ergent neurosurgical procedures 9 Give FFP (start w ith 2 un its) an d vitam in K (10–20 m g IV at ≤ 1 m g/m in ) as soon as possible; see also reversal of an ticoagulat ion (p. 166). Th e tim ing of surger y is th en based on th e urgen cy of th e sit ua- t ion an d th e n ature of th e procedure (e.g. th e decision m igh t be to evacuate a spin al epidural h em a- tom a in an acutely paralyzed pat ien t before an ticoagulation is fully reversed). He p a r in For em ergen cies: if it w ould be deleterious to w ait 4–6 h ours after discon tin uing h eparin an d th en repeating th e PTT to verify th at an ticoagulation h as been corrected, th en h eparin can be reversed w ith protam in e (p.166). For non-em ergencies IV h eparin : stop th e drip ≈ 4–6 h ours prior to th e plan n ed procedure. Option : rech eck PTT just prior to starting the procedure. “Min i-dose” SQ h eparin : n ot m an dator y to stop for cran iotom y, but if desired to discon tin ue, th en give last dose ≥ 12 h ours prior to surger y. Low-m olecular weight heparins (LMWH) For em ergen cies: can be reversed w ith protam in e (p. 166). Non -em ergen cies: See Table 9.4. Lon ger t im es are n eeded in ren al failure. A factor Xa level can be used to ch eck an t icoagulation status, but th is usually m ust be sen t out , m akin g it un suitable for acute m anagem ent. Antiplatelet drugs and neurosurgical procedures Platelet m echanistics and platelet function tests Platelets are important for m aintaining vascular endothelial in tegrity and are constan tly involved w ith hem ostasis in conjunction w ith coagulation factors. Severe throm bocytopenia can result in petechial hem orrhages or spontaneous intracerebral hem orrhage (ICH). Vascular w all disturbance is the initial stim ulus for platelet deposition and activation. Platelets adhere to collagen via surface receptors GPIb- V-IX and von Willebrand factor. This adhesion sets o a cascade of reactions, w hich result in platelet aggregation form ing a hem ostatic plug. Historically, bleeding tim e (BT) was used as the screening test for abnorm alities of platelet function. Due to un reliabilit y, m any institutions have replaced the BT w ith the platelet function assay (PFA) using the PFA-100 (platelet function analyzer). There are lim ited stud- ies confirm ing its use according to the International Society of Throm bosis and Hem ostasis.12,13 In th e PFA-100, prim ar y h em ostasis is sim ulated un der “h igh -sh ear” flow by m ovem en t of citrated blood th rough a m em bran e-im pregn ated capillar y in t w o collagen -coated cart ridges; on e stim ulates platelets w ith aden osin e diph osph ate (ADP) an d th e oth er w ith epin eph rin e.14 Th is in ter- act ion w ith th e collagen in duces a platelet plug, w h ich closes an apert ure. Results are reported as

Hem atology 161 closure t im e in secon ds. Th is m eth od is eligible as a screen ing test for prim ar y h em ostatic disease 9 such as von W illebran d disease as w ell as for m on itorin g th e e ect of an tiplatelet th erapy. Th e PFA- 100 w orks for test in g w ith aspirin but n ot w ith th ien opyridin e drug class (e.g. clopidogrel). New ly available PFA cart ridges detect P2Y12 receptor blockade in patien ts on th ein opyridin e drugs.15 Veri- fyNow ® m easures agon ist-in duced aggregation as an in crease in ligh t tran sm itt an ce. Th e system con tain s a preparat ion of h um an fibrin ogen -coated beads, w h ich cause a ch ange in ligh t tran sm it- tan ce by ADP-in duced platelet aggregat ion .15 Th ere is lit tle correlation betw een PFA-100 results an d VerifyNow Assay. Agent s Plavix® (clop idogrel) (p.1275) an d asp irin . Cause perm anen t in hibition of platelet fun ction th at persists ≈ 5 days after discontin uation of th e drug an d can in crease the risk of bleeding. For elective cases, 5–7 days o th ese drugs is recom m ended (surveys of Germ an n eurosurgeons16,17: an average of 7 days was used for low -dose ASA, w ith a few w h o do spine surgery even w hile the patient is on ASA). Cardiac sten ts: dual an tiplatelet th erapy (e.g. ASA+ Plavix®) are m an datory for 4 w eeks (90 days is preferable18) after placem en t of a bare m etal cardiac stent , an d for at least 1 year w ith drug-elutin g stents (DES) (th e risk declin es from ≈ 6%to ≈ 3%).19 Even sh ort gaps in drug th erapy (e.g. to perform n eurosurgical procedures) is associated w ith sign ifican t risk of acute stent occlusion (an d th erefore elect ive surger y durin g th is tim e is discouraged20). DES are so e ect ive in suppressing en doth eliali- zation th at lifetim e dual an t iplatelet th erapy m ay be required. Bridgin g DES patien ts w ith an tith rom - bin , an ticoagulan ts, or glycoprotein IIb/IIIa agen ts has n ot been proven e ect ive.20 Reversal of an t ip latelet d r u gs: W h ile h eparin an d w arfarin can be reliably an d m easurably reversed, th e situation is less clear w ith an tiplatelet agen ts.21 Agents used pre-op to reverse th ese d rugs in clu de: Desm opressin (p. 166) (DDAVP®)16,17 an d FFP.16 Reversal of Plavix for em ergen cy surger y (p. 154): platelets m ay be given , h ow ever, Plavix e ects persists for up to a couple of days after th e last dose, an d can actually in h ibit platelets given after th e drug is discon tin ued (th e h alf-life of aspirin is low er an d sh ould n ot be an issue after 1 day). In cases w ith con tin ued oozing in th e first day or so after discon tin uing Plavix, th e follow in g regim en is an op t io n : 1. recom bin an t activated coagulation factor VII (rFVIIa): even th ough th e defect is in th e platelets, rFVIIa w orks, via a m ech an ism n ot m ediated by protein clot t ing factors. Ver y expen sive (≈ $10,000 per dose), but th is m ust be balan ced again st th e cost of repeat cran iotom y, in creased ICU stay an d addition al m orbidit y a) initial dose22: 90–120 m cg/kg b) sam e dose 2 hrs later c) 3rd dose 6 h rs after in itial dose 2. platelets ever y 8 h ours for 24 h ours, either a) 6 U of regular platelets b) if patien t is on fluid or volum e restriction: 1 unit of pheresed platelets Her bal p rod u ct s an d su p p lem en t s. Herbal products an d supplem en ts often a ect platelet aggre- gation an d th e coagulat ion cascade by m ean s th at can n ot be detected by laborator y tests. Th e in creasing popularit y of th ese un regulated products requires screen in g patien ts for th eir use. Th ere are lim ited studies regardin g th e use of h erbal supplem en ts in n eurosurger y an d for an elect ive ope- ration w ait in g 7–14 days after cessation of th eir use is w arran ted. Fish Oil (Om ega-3 Fatt y Acids) is w idely used am on g th e cardiac an d gen eral population for treat- m en t of dyslipidem ia an d hypert riglyceridem ia. Fish oil m ay a ect platelet aggregat ion by a reduc- tion in arach n adon ic acid an d th om boxan e an d aden osin e diph osph ate receptor blockade. Fish oil m ay also p oten tially len gth en bleed in g t im es.23,24,25 Garlic (Allium sativum ) h as in creased in popularit y as a supplem en t. Purported ben efits in clude: low erin g blood pressure, preven tin g in fect ion an d m yocardial in farct ion , an d treating hyperch oles- terolem ia. Garlic h as an an t iplatelet a ect th rough ADP receptor blockade, an d reducin g calcium an d th rom boxan e.26 Th ere is par ticular con cern w ith garlic as it m ay poten tiate th e an t iplatelet or an ti- coagulan t a ect of aspirin or w arfarin .27 Gin kgo (Gin kgo biloba)h as also becom e a popular supplem en t foun d in m any form ulat ion s from capsules to en ergy drin ks. Gin kgo h as been used to t reat a n um ber of ailm en ts in cludin g m em or y loss, depression , an xiet y, dizziness, claudication , erect ile dysfun ct ion , tin n itus an d h eadach e. Gin kgo a ects bleedin g via an an t iplatelet e ect an d an tagon ism of platelet-activating factor.28,29 See Gin kgo biloba un der Spon tan eous subdural h em atom a (p. 901). Gin sen g (Pan ax gin sen g)h as also been foun d to h ave an t iplatelet activit y th rough th rom boxan e in h ibition an d platelet-act ivatin g factor.30 Som e auth ors also advocate cautious use of gin ger an d vit am in E w h en plan n in g surger y, but th e exact an tiplatelet m ech an ism is un clear.25

162 General and Neurology 9 fP(DBg(iTnE(fCTAoAsTD(niiPTPaBpiireeoPlebsaicctorielAlapprtlcncraebiacualhrpcsiaooyvalivhitf,lgsgiuryexnireei),®ddiardibrAixlgiindnidii,mmENen9o,na®pcsr)tlaltR.etgta(giEioia)6i,mnasrAiolmnrledLrba)icSeecc(iereoZPi(lLeaEelhd(l,BlelyIifnRteaeln)-r-y)loet)yi-lle---)-le tCTCTGdCTcGflGhhhiOyuPPanciiiMnIIsXeeeeIIlsbbconnn-/P/1tP//poooTiII2oVeIIppapIIYnnaaryyyg1trrri2iiiynedddlthtiiinnnribieeeaisssxt///ooPPPrl222os YYpYy111 222r im i- MRRDDPPsPvPierrrreebiieoooorrrvvleecsddddeeeihccbrrrrrrttauuuussl-eiinggggaabbic,,,c,llseettiiirmiirrrenorrrveeegnevvv,, reeerisrrrreisssrbveiiibbble-elllreee- tAPPPPIPPIVVrdOOOOOOamt ioinnis - MaPPBNN(N(tNIVaPib(dIPPViPPbFFFlaemAooAoeoRReAAATTs/rwwennUUriIeeT,,,TfIidiiIdfy,,ctVVAaPPyiTTNonAAeerN22teeatragoerrCCYYecssioiicnwsffttsiTT11whdtyy))gt,,22s----) MLrcLbLLrrRlrGL2lbhhPTiiaaaaiiiiitver1ei0rrivvvvvuellennnnoss/eseeneeeee2ttm)≈cccctr;,arrrrra(e;eeeep3;;;;2;alTibpo;;rnr0c7errrce1T≈eolileeetTTaml/y%xxm1nel62innns11tvcic/;aas82m//iaaaaerr1ic22mrnlTeer%lll08aiamct14t1clccc,n–yei,/ll5–oh2lllee;fc1edeeeae5–nraaet32aaaTns--avi---.1dn7di7abnh/ a25gory%se9-s;; ReP(hNdParMDPnPDN1eecvllllroiAAeiaaaaaam0satevsttttl,)yilaeryveeeemy;ocynnsresllllboDveeeesiootis1eseanttttametp2dlgcsirttttrrseeemsorrrreehbataaatnmnnsmarrynnnnotssoiabrsoisssspondtatofffffvrbevuuuuotbileeaeiegessssrtsdldiiniiyeysoooou4seibnnnnnn8bnifsy;;,biiyott st H77 ––o 11ld00 tddimaa yyesa CPa≈uhPEtsdUarelliPCeaneiioffnfrrlpiier5ssttabsftfseeCctmeins2ee0eetinivvatseltdecct4ra%o(aagnti<msltto9s-aelliicfiheesen57ovnnpwofteednn3rofe0fcl5rnui1fawmaccrtepu–bticsthayeenesleen6iaoasdiioefsrloocsyc)0ree≈jni,keoutloff%8tto9c;isl1nsisodic–a;mpo36ntl0an3ol2s3anito%e7rdp%iehwr5nt,ypr3eoiie2e%fro-n1oiougaidrl4t,rfn3euf3afrusreoh72vtepepipcr,prgore3elnaeeilsl1rfnrrlaa-sruso,ecy3teicitlurn2set-eito-c--d-

TgcT(MlD(aACbaaeIurBrnsbbniHreD=aprrotulbnresaeoeeidfcgrtri)niglsuiikabed9nsmdrNmtv)ac.i),ti6lgonoaaii/Mnmrnmpto(ic,troAeeouieeMnndgnpsiusiss-it-:leiai-nntPnhuCdeeeCCnGdcrlhPa=eoaIscnpInsbotr/cr/moTeoIItasIlmhargrpgeorlenaomttduebeplied.n3t8tcaimodmheeptsloieoxwn catoiotn avcMRefetesneesvtcrerehaldratswiesinbca,ilosleIlmVnbt=yininiunticnr argevaetshneeodudtAIscrVrd,oaumtSngiQcoibenn=neissft-oruarbtecioudMnIVtoIbsaeoinn/ronIiegfIfiIyotaafNouantroscei,wntesoagtlerPcTVtTiIvMIfRhTI=ee1eraecps/n2onetaaapsd2rlbet.2cvi5oral5oaellih%tnastirmor;hsWanrTno1icilm/nl2ee bb2o6or–r5adp3%nela,drsttfioaRndMdceiietaaatvolillyiemyymrrs.sbseiiiDssena, elaArstesCemtmTrtaooh=tpveearegecedytsfisfvbienayctteinsdcorcfHeloatoshtletdeidndtgpirmultaigemt ea ele, t CardChl e=scior enaCiCri8rrtnnaaeutiohrnifhttmrnCmu3eeni2irlbs;;nasam<iiieoppntnt3enellodsaac0dnottlDi≈eteenmawsa5/llhdeeCrii0itzjattb’uh%edncfisidtu3cnote42enatdih5,ncrgritDfmafsuiuool/lasiarnininfto3,tiroen–baenron- tdish Hem atology 163 9

164 General and Neurology Table 9.7 Recom m ended INRs39 INR 2.5–3.5 Indicat ion ≥3 ● m echanical prosthetic heart valve 2–3 ● prevention of recurrent MI antiphospholipid antibody syndrom e (p. 1270) 40 all other indications (DVT prophylaxis and treatm ent, PE, atrial fibrillation, recurrent system ic em bolism , tissue heart valves) Ant icoagulant s See also platelet fun ction in h ibitors (p. 164). Wa r fa r in Drug info : Warfarin (Coum adin®) An oral vitam in Kantagonist. To anticoagulate average weight patient, give 10 mg PO q d × 2–4 days, then ≈ 5 mg q d. Follow coagulation studies, titrate to PT= 1.2–1.5 × control (or INR ≈ 2–3) for most conditions (e.g. DVT, single TIA). Higher PT ratios of 1.5–2 × control (INR ≈ 3–4) may be needed for 9 recurrent systemic embolism , m echanical heart valves…(the recommended ranges for the Interna- tional Normalized Ratio (INR) are shown in Table 9.7). Starting warfarin: During the first ≈ 3 days of warfarin therapy, patients may actually be hypercoagu- lable (secondary to reduction of vitamin-K dependent anticoagulation factors protein C and protein S), putting them at risk of “Coumadin necrosis.” Therefore patients should be “bridged” by starting either Lovenox (p. 165) which can be self-administered as an outpatient, or heparain (with a therapeutic PTT). Supplied: scored tabs of 1, 2, 2.5, 5, 7.5 and 10 mg. IV form: 5 m g/vial. He p a r in Drug info : Heparin Full anticoagulation in an average weight patient, give 5000 U bolus IV, follow with 1000 U/hr IV drip. Titrate to therapeutic anticoagulation of APTT= 2–2.5 × control (for DVT, some recommend 1.5–2 × control41). prophylactic AKA low-dose (“mini-dose”) heparin: 5000 IU SQ q 8 or 12 hrs. Routine monitoring of APTT is usually not done, although occasionally patients may become fully anticoagulated on this regimen. Side e ect s: (see Anticoagulant considerations in neurosurgery above): hem orrhage, throm bosis42 (heparin activates anti-throm bin III and can cause platelet aggregation) which can result in MIs, DVTs, PEs, strokes, etc. Heparin induced thrombocytopenia (HIT): transient m ild throm bocytopenia is fairly comm on in the first few days after initiating heparin therapy, however severe throm bocytopenia occurs in 1–2%of patients receiving heparin > 4 days (usually has a delayed onset of 6–12 days, and is due to consumption in heparin-induced throm bosis or to antibodies formed against a heparin-platelet protein complex). The incidence of HIT in SAH is 5–6%and was similar with enoxaparin.43 Consider use of fondaparinux in thrombocytopenic patients. Chronic therapy may cause osteoporosis. Low m olecular weight heparins See referen ces.44,45 Low m olecular w eigh t h eparin s (LMWH) (average m olecular w eigh t = 3000–8000 daltons) are derived from un fraction ated h eparin (average MW = 12,000–15,000 dalton s). LMW Hs di er from un fract ion ated h eparin because th ey h ave a h igh er ratio of an ti-factor Xa to an t i-factor IIa (an tith - rom bin ) act ivity w h ich th eoretically sh ould produce an tith rom bic e ect s w ith fewer h em orrh agic com plicat ion s. Realization of th is ben efit h as been ver y m in or in clin ical t rials. LMW H h ave greater bioavailabilit y after sub-Q inject ion leadin g to m ore predictable plasm a levels w h ich elim in ates th e n eed to m on itor biologic act ivity (such as APTT). LMWH h ave a lon ger h alf-life an d th erefore require

Hem atology 165 few er doses per day. LMW H h ave a low er in ciden ce of th rom bocytopen ia. More e ect ive in DVT pro- phylaxis th an w arfarin in orth opedic surgery.46 Sp in al ep id u r al h em at om as: Th ere h ave been a n um ber of case reports of spin al epidural h em a- tom as occurrin g in patien ts on LMW H (prim arily en oxaparin ) w h o also un derw en t spin al/epidural an esth esia or lum bar pun ct ure, prim arily in elderly w om en un dergoing orth opedic surger y. Som e h ave h ad sign ifican t n eurologic sequelae, in cludin g perm an en t paralysis.47 Th e risk is fur th er in creased by th e use of NSAIDs, platelet in h ibitors, or oth er an ticoagulan ts, an d w ith t raum atic or repeated epidural or spin al pun ct ure. Available low m olecu lar w eigh t h ep ar in s. Drugs in clude: ● en oxaparin (Loven ox®): see below ● dalteparin (Fragm in ®): 2500 an ti-Xa U SQ q d ● ardeparin (Norm iflo®): h alf-life = 3.3 h rs. 50 an ti-Xa U/kg SQ q 12 h rs ● dan aparoid (Orgaran ®): a h eparin oid. Even h igh er an ti-Xa:an ti-IIa ratio th an LMW Hs. Does n ot require laboratory m on itorin g. 750 an t i-Xa U SQ BID ● tin zaparin (Logiparin ®, In n oh ep®): n ot available in U.S. 175 an ti-Xa U per kg SQ on ce daily Drug info : Enoxaparin (Lovenox®) 9 dosage established following hip replacem ent is 30 m g SQ BID × 7–14 days (alternative: 40 mg SQ q d). Pharmacokinetics: After SQ injection, peak serum concentration occurs in 3–5 hrs. Half-life: 4.5 hrs. Direct throm bin inhibitors Drug info : Dabigat ran (Pradaxa®, Rendix®) An oral anticoagulant in the class of direct thrombin inhibitors. Administered as the prodrug dabiga- tran etexilate. Must be stopped 24 hrs prior to surgery. Reversal of an t icoagu lat ion : Praxbin d (idarucizum ab) IV for em ergen cies. Reverses pradaxa w ith in 4 h rs, lasts 24 h rs.48 Drug info : Bivalirudin (Angiom ax® or Angiox®) A reversible direct thrombin inhibitor (DTI) that increases the rapidit y of plasm inogen activator-m edi- ated recanalization. No e ective reversal. : IV loading dose of 0.5 m g/kg IV, followed by continuous infusion of 1.75 m g/kg/hr. Intraarterial: inject 15 mg in 10 ml of heparinized saline via a m icrocatheter. Factor Xa inhibitors Drug info : Fondaparinux (Arixt ra®) A synthetic analog of the pentasaccharide binding sequence of heparin. Increases factor Xa inhibition without a ecting factor IIa (thrombin).49 Unlike heparin, fondaparinux does not bind to other plasma proteins or platelet factor-4 and does not cause heparin-induced thrombocytopenia (HIT) and can therefore be used in patients with HIT. May be more e ective than enoxaparin (Lovenox®) for pre- venting post-op DVTs. Side e ect s: Bleeding is the m ost common side e ect (m ay be increased by concurrent NSAID use). Contraindicated with severe renal impairment (CrCl < 30 ml/min).50 : 2.5 mg SQ injection q d. Supplied: 2.5 mg single-dose syringes. Pharm acokinet ics: Peak activ- it y occurs in 2–3 hrs. Half-life: 17-21 hrs. Anticoagulation e ect lasts 3-5 half-lives. Elim ination: in urine (in renal insu ciency reduce dose by 50%for CrCl 30-50 ml/min). STOP: 2-4 days pre-op (longer with kidney dysfunction)

166 General and Neurology Coagulopat hies Correction of coagulopathies or reversal of anticoagulants Also refer to recom m en ded n orm al values for coagulat ion studies in n eurosurger y (p. 157). Pla t e le t s See in dication s an d adm in istration guidelin es (p.154). Fresh frozen plasm a To reverse w arfarin an ticoagulat ion , use th e follow in g as a start in g poin t an d rech eck PT/PTT after w ards: ● w h en patien t is “th erapeutically an t icoagulated” start w ith 2–3 un its FFP (approxim ately 15 m l/kg is usually n eeded) ● for severely prolonged PT/PTT, start w ith 6 un its FFP Prothrom bin com plex concentrate (PCC) Warfarin induced anticoagulation m ay be reversed up to 4 or 5 tim es m ore quickly w ith PCC (Kcentra) (contain s coag factors II, IX, and X) than w ith FFP.51 Patient m ay becom e hyperth rom botic w ith this. Drug info : Vit am in K (Mephyt on®) To reverse elevated PT from warfarin , give aqueous colloidal solution of vitamin K1 (phytonadione, 9 Mephyton®). Doses > 10 mg may produce warfarin resistance for up to 1 week. FFP may be adm inis- tered concurrently for m ore rapid correction (see above). See recommended levels of PT (p. 157). adult: start with 10–15 mg IM; the e ect takes 6–12 hrs (in absence of liver disease). Repeat dose if needed. The average total dose needed to reverse therapeutic anticoagulation is 25–35 m g. IV administration has been associated with severe reactions (possibly anaphylactic), including hypotension and even fatalities (even with proper precautions to dilute and administer slowly), there- fore IV route is reserved only for situations where other routes are not feasible and the serious risk is justified. IV (when IM route not feasible): 10–20 mg IV at a rate of injection not to exceed 1 mg/min (e.g. put 10 m g in 50 m l of D5 W and give over 30 m inutes). Drug info : Prot am ine sulfat e For heparin: 1 mg protam ine reverses ≈ 100 U heparin (give slowly, not to exceed 50 mg in any 10 m in period). Therapy should be guided by coagulation studies. Reversal of low m olecular weight heparins (LMWH): slow IV injection of a 1%solution of prot- am ine can also be used to reverse LMWHs as follows: Enoxaparin (Lovenox®): ≈ 60%of Lovenox can be reversed with 1 mg of protamine for every mg of Lovenox given (maximum dose = 50 mg) within the last 8 hrs, and 0.5 m g of protamine for every mg of Lovenox given from 8–12 hrs prior. Protamine is probably not needed for Lovenox given > 12 hrs earlier. Dalteparin (Fragmin®) or ardeparin (Normiflo®): 1 mg of protamine for every 100 anti-Xa IU of the LMWH (maximum dose = 50 mg) with a second infusion of 0.5 mg protam ine for every 100 anti- Xa IU of LMWH if the APTT rem ains elevated 2–4 hours after the first dose is com pleted. Danaparoid and Hirudin: no known reversing agent. Drug info : Desm opressin (DDAVP®) Causes an increase in factor III coagulant activit y and von Willebrand factor which helps coagulation and platelet activit y in hemophilia A and in von Willebrand’s disease Type I (where the factors are norm al in makeup but low in concentration, but may cause throm bocytopenia in von Willebrand’s disease Type IIB where factors m ay be abnorm al or missing). 0.3 mcg/kg (use 50 ml of diluent for doses ≤ 3 mcg, use 10 m l for doses > 3 mcg) given over 15– 30 m inutes 30 minutes prior to a surgical procedure.

Hem atology 167 Elevated pre-op PTT 9 In a patien t w ith n o h istory of coagulopathy, a sign ifican tly elevated pre-op PTT is com m on ly due to eith er a factor deficien cy or to lupus an ticoagulan t. Work-up: 1. m ixing study 2. lupus coagulant If th e m ixin g st udy corrects th e elevated PTT, th en th ere is probably a factor deficien cy. Con sult a hem atologist. Lu p u s an t icoagu lan t : If th e test for lupus an t icoagulan t is positive, th en th e m ajor risk to th e pa- tient w ith surgery is not bleeding, rather it is throm boem bolism . Managem ent recom m endations: 1. as soon as feasible post-op, start patient on heparin (p.164) or LMW heparin (p.164), e.g. Lovenox 2. at th e sam e tim e start w arfarin , an d m ain tain th erapeutic an t icoagulat ion for 3–4 w eeks (th e risk of DVT/PE is act ually h igh est in th e first few w eeks post-op) 3. m obilize as soon as possible post-op 4. con sider ven a-cava in terruption filter in patien ts for w h om an ticoagulation is con train dicated Dissem inated intravascular coagulation (DIC) Abn orm al in travascular coagulat ion w h ich con sum es clotting factors an d platelets, coupled w ith abn orm al act ivation of fibrin olytic system . Head t raum a is an in depen den t risk factor for DIC, possi- bly because th e brain is rich in th rom boplast in w h ich m ay be released in to system ic circulat ion w ith t raum a.52 Oth er risk factors: sh ock, sepsis. Pre se n t a t io n Di use bleedin g, cutan eous petech ia, sh ock. La b s 1. fibrin ogen degradation products (FDP) > 16 m cg/m l (1–8 = n orm al; 8–16 = borderlin e; 32 = defi- n itely abn orm al; som e labs require > 40 for diagn osis of DIC) (th e m ost com m on abn orm alit y) 2. fibrinogen < 100 m cg/dl (som e use 130) 3. PT > 16; PTT > 50 4. platelets < 50,000 (relatively un com m on ) Chronic DIC PT & PTT m ay be n orm al; platelet & fibrin ogen low, fibrin split products elevated. Treatm en t 1. rem ove in cit in g st im ulus if possible (treat in fect ion s, debride injured t issue, stop t ran sfusion s if suspected) 2. vigorous fluid resuscitation 3. an ticoagulan ts, if not con traindicated (p.156) 4. FFP if PT or PTT elevated, or fibrin ogen < 130 5. platelet t ran sfusion if platelet coun t < 100 K Pse u d o - DIC In creased fibrin split products, n orm al fibrin ogen . Seen in con dition s such as liver failure. Throm boem bolism in neurosurgery Deep-vein throm bosis (DVT) DVT is of con cern prim arily because of th e poten tial for m aterial (clot, platelet clum ps…) to dislodge an d form em boli (in cludin g pulm on ar y em boli, (PE)) w h ich m ay cause pulm on ar y in farct ion , sudden death (from cardiac arrest), or cerebral in farct ion (from a paradoxical em bolus, w h ich m ay occur in th e presen ce of a paten t foram en ovale, see Cardiogen ic brain em bolism (p. 1304)). Th e reported m ortalit y from DVT in th e LEs ran ges from 9–50%.53 DVT lim ited to th e calf h as a low th reat (< 1%) of em bolization , h ow ever, th ese clots later exten d in to th e proxim al deep vein s in 30–50% of cases,53 from w h ere em bolizat ion m ay occur (in 40–50%), or th ey m ay produce postph lebit ic syn drom e. Neurosurgical patien ts are particularly pron e to developin g DVTs (estim ated risk: 19–50%) due at least in par t to th e relatively h igh frequen cy of th e follow in g: 1. long operating tim es of som e procedures 2. prolonged bed rest pre- an d/or post-op

168 General and Neurology 3. alterations in coagulation status a) in patien ts w ith brain tum ors (see below ) or h ead injur y54 ● related to the condition itself ● due to release of brain th rom boplastin s during brain surgery b) in creased blood viscosit y w ith con com itan t “sludging” ● from dehydration th erapy som etim es used to reduce cerebral edem a ● from volum e loss follow in g SAH (cerebral salt w astin g) c) use of h igh -dose glucocort icoids Specific “n eurological” risk factors for DVT an d PE in clude53: 1. spinal cord injury (p.952) 2. brain tum or: autopsy prevalen ce of DVT = 28%, of PE = 8.4%. In ciden ce using 125I-fibrin ogen 55: m en in giom a 72%, m align an t gliom a 60%, m etastasis 20%. Risk m ay be reduced by pre-op use of a sp ir in 56 3. subarachnoid hem orrhage 4. h ead traum a: especially severe TBI (p. 918) 5. st roke: in ciden ce of PE = 1–19.8%, w ith m or talit y of 25–100% 6. n eurosurgical operat ion : risk is h igh er follow in g cran iotom y for supraten torial tum ors (7%of 492 patien ts) th an p -fossa t um ors (0 out of 141)57 Prophylaxis against DVT Option s in clude: 9 1. general measures a) passive range of m otion b) am bulate appropriate patien ts as early as possible 2. m echan ical tech niques (m inim al risk of com plication s): a) pn eum at ic com pression boots58 (PCBs) or sequen t ial com pression devices (SCDs): reduces th e in ciden ce of DVTs an d probably PEs. Do n ot use if DVTs already presen t. Con tin ue use un t il patient able to w alk 3–4 hrs per day b) TED Stockin gs®: (TEDS) applies graduated pressure, h igh er distally. As e ect ive as PCB. No evidence th at th e ben efit is additive.53 Care sh ould be taken to avoid a tourn iquet e ect at th e proxim al en d (n ote: TEDS® is a registered tradem ark. “TED” stan ds for th rom boem bolic d ise a se ) c) elect rical stim ulation of calf m uscles d) rotating beds 3. anticoagulation ; see also contraindications and considerations of an ticoagulation in neurosur- gery (p.156) a) full an t icoagulation is associated w ith perioperative com plication s59 b) “low -dose” an t icoagulation 60 (low -dose h eparin ): 5000 IU SQ q 8 or 12 h rs, startin g 2 h rs pre- op or on adm ission to h ospital. Poten tial for h azardous h em orrh age w ith in brain or spin al canal has lim ited its use c) low m olecular w eigh t h eparins an d h eparin oids (p. 164): n ot a h om ogen eous group. E cacy in n eurosurgical prophylaxis has n ot been determ in ed d) aspirin : role in DVT prophylaxis is lim ited because ASA in h ibits platelet aggregation , an d pla- telets play on ly a m in or role in DVT 4. com bin ation of PCBs an d “m in i-dose” h eparin start in g on th e m orn in g of post-op day 1 (w ith n o evidence of sign ifican t com plication s)61 Recom m endations Table 9.8.53 See Recom m en ded prophylaxis varies w ith th e risk of developin g DVT, as illustrated in also details of prophylaxis in cer vical spin al cord injuries (p. 952). Diagnosis of DVT (For PE, see below ). Th e clin ical diagn osis of DVT is ver y un reliable. A patien t w ith th e “classic sign s” of a h ot, sw ollen , an d ten der calf, or a positive Hom an s’ sign (calf pain on dorsiflexion of th e an kle) w ill h ave a DVT on ly 20–50%of th e tim e.53 50–60%of patien ts w ith DVT w ill n ot h ave th ese fin din gs. Laboratory t est s ● con trast ven ography: th e “gold stan dard”, h ow ever it is invasive an d carr ies risk of iodin e reac- tion , occasion ally produces ph lebit is, n ot readily repeated

Hem atology 169 Table 9.8 Risk & prophylaxis of DVT in neurosurgical patientsa Risk group Est im ated risk Typical neurosurgical patients Treatment recom - of calf DVT m endat ion low risk <10% age < 40 yrs, m inim al general risk factors, no prophylaxis, or surgery with < 30 m inutes general anesthesia PCB/ TEDS m o d e rat e 10–40% age ≥ 40 yrs, m alignancy, prolonged bed rest, PCB/TEDs; or for pa- risk extensive surgery, varicose veins, obesit y, sur- tients without ICH or gery > 30 minutes duration (except simple SAH, mini-dose lum bar discectomy), SAH, head injury heparin high risk 40–80% history of DVT or PE, paralysisb (para- or PCB/TEDS + (in pa- quadriplegia or hemiparesis), brain tum or tients without ICH or (especially meningiom a or m alignant gliom a) SAH) mini-dose heparin aabbreviations: DVT= deep venous throm bosis, PCB= pneumatic com pression device, TEDS = TED (thromboem - bolic disease) Stockings®, ICH = intracerebral hem orrhage, SAH = subarachnoid hem orrhage bsee specifics regarding DVT prophylaxis in cervical SCI (p. 952) ● Doppler ult rasoun d w ith h igh -resolution real-tim e B-m ode im agin g: 95%sen sitive an d 99%spe- 9 cific for proxim al DVT. Less e ect ive for calf DVT.62 As a result , it is recom m en ded th at patien ts w ith in itially n egative studies un dergo repeat st udies over th e n ext 7–10 days to R/O proxim al ex- ten sion . Requires m ore skill on th e part of th e tester th an IPG. May be used in im m obilized or casted LE (un like IPG). Widely accepted as th e n on -invasive test of ch oice for DVT63 ● im pedan ce plethysm ography (IPG): looks for reduced electrical im pedan ce produced by blood flow from th e calf follow in g relaxation of a pn eum at ic tourn iquet. Good in detect in g proxim al DVT, n ot sen sitive for calf DVT. A positive st udy in dicates DVT th at sh ould be t reated, a n egative st udy can occur w ith n on -occlusive DVT or w ith good collaterals, an d sh ould be repeated over a 2 week period ● 125I-fibrin ogen : radiolabeled fibrin ogen is in corporated in to th e developin g th rom bus. Better for calf DVT th an proxim al DVT. Expen sive, an d m any false positives. Risk of HIV t ran sm ission h as resulted in w ith draw al of use ● D-dim er (a specific fibrin degradation product): h igh levels are associated w ith DVT an d PE64 Treatm ent of DVT 1. bed rest, w ith elevation of involved leg(s) 2. un less an ticoagulat ion is con train dicated (p.156): start h eparin as outlin ed in An ticoagulation (p. 156), aim for APTT = 1.5–2 × con trol; or fixed dose of LMW h eparin oids, e.g. tin zaparin (Logi- parin ®,65 or in th e U.S. en oxaparin (Loven ox®) (p.165). Simulta neously in itiate w arfarin th erapy. Heparin can be stopped after ≈ 5 days66 3. in patien ts w h ere an t icoagulat ion is con train dicated, con sider in ferior ven a cava in terruption or placem en t of a filter (e.g. Green field filter) 4. in n on -paralyzed patien ts, cautiously begin to am bulate after ≈ 7–10 days 5. w ear an ti-em bolic stockin g on a ected LE in defin itely (lim b is alw ays at risk of recurren t DVT) Pulm onary em bolism (PE) See referen ce.67 Prevention of PE Preven tion of PE is best accom plish ed by preven tion of DVT (p.168).68 Presentation of PE Post-op PE gen erally occurs 10–14 days follow in g surger y.68 Th e reported in ciden ce68 ran ges from 0.4–5%. A series (on a ser vice w ith routin e use of elastic stockings an d, in h igh risk pat ien ts, “m in i- dose” h eparin ) foun d a post-op in ciden ce of ≈ 0.4%, w ith a doublin g of th is n um ber if on ly patien ts w ith m ajor path ology (brain tum or, h ead t raum a, or cerebrovascular or spin al path ology) w ere con - sidered68 (an oth er series dealing on ly w ith brain tum ors foun d a 4%in ciden ce57). Clin ical diagn osis is n on specific (di eren tial diagn osis of sym ptom s is large, an d ran ges from ate- lect asis to MI or cardiac tam pon ade).

170 General and Neurology Com m on fin din gs: sudden dyspn ea (th e m ost frequen t fin ding), tachypn ea, tachycardia, fever, hypoten sion , 3rd or 4th h eart soun d. Tr ia d (rare): h em opt ysis, pleurit ic ch est pain , dyspn ea. Auscul- tation : pleurit ic friction rub or rales (rare). Sh ock an d CHF (m im ics MI) in dicates m assive life-th reat- en in g PE. Mor talit y reported ran ges from 9–60%,68 w ith a sign ifican t n um ber of deaths w ith in th e first hour. Diagnosis of PE A n egative D-dim er test (see above) reliably excludes PE in patien ts w ith a low clin ical probabilit y of PE69 or in th ose w ith n on diagn ostic VQ scan .64 Altern at ively, on e can ch eck for DVT ut ilizin g IPG, Doppler, or ven ography (see above). If positive, th is in dicates a possible source of PE, an d sin ce th e t reatm en t is sim ilar for both , n o furth er search for PE n eed be m ade an d treatm en t is started. If n egative, furth er test in g m ay be n eeded (e.g.VQ scan , see below ). Laboratory t est s D-dim er: see above. General diagnost ic test s Non e are ver y sen sitive or specific. ● EKG: “classic” S1Q3T3 is rare. Usually just n on specific-ST & T ch anges occur. Tachycardia m ay be the only findin g ● CXR: n orm al in 25–30%. W h en abn orm al, usually sh ow s in filtrate an d elevated h em idiaph ragm ● ABG: n ot ver y sen sitive. pO2 > 90 on room air vir t ually excludes ma ssive PE 9 Specific radiograph ic evaluation ● Test of ch oice: con t r ast en h an ced ch est CT. Occasion ally ch est CTA m ay be em ployed . Can p ro- vide in sigh t in to altern ate diagn oses ● pulm on ar y an giogram : h istorically, th e “gold stan dard.” Invasive, expen sive, an d labor in ten sive. 3–4%risk of sign ifican t com plication s. Not in dicated in m ost cases ● ven tilation -perfusion scan (VQ scan ): CXR is also n eeded. A perfusion defect w ith n o ven tilation defect in a pat ien t w ith n o previous h istor y of PE st ron gly suggests acute PE. Equivocal st udies occur w hen an area of m alperfusion correspon ds to an area of reduced ven tilation (on ven tilation scan ) or in filtrate (on CXR). Probabilities of PE based on VQ scan are sh ow n in Table 9.9.70 A tech n ically adequate n orm al VQ scan virt ually rules out PE. Pat ien ts w ith low or in term ediate probabilit y scan s sh ould h ave a test for DVT or quan t itative D-dim er (see above). If test for DVT is positive, treat; if it is n egative, th e ch oice is to follow serial IPG or Doppler st udies for 2 w eeks, or (rarely) to do a pulm onary angiogram ● th in -section con trast-en h anced ch est CT: m ore accurate in pat ien ts w ith COPD w h o often h ave an in determ in ate VQ scan Treatm en t If diagn osis is seriously en ter tain ed, start hepa r in – un less con train dicated (p. 156) – w ith out w aitin g for results of diagn ost ic st udies. For an average 70 kg patien t, begin w ith 5000–7500 un it IV bolus, follow ed by 1000 U/h r drip (less for sm aller pat ien t). Follow PTT an d titrate drip rate for PTT 1.5 to 2 × con trol. Th e use of h eparin sh ortly after surger y an d in pat ien ts w ith brain t um ors is con troversial, an d ven a caval in terruption m ay be an altern ate con siderat ion (e.g. Green field filter). Pat ien ts w ith m assive PEs m ay be h em odyn am ically un stable. Th ey usually require ICU care, often w ith PA cath eter an d pressors. Table 9.9 Probabilit y of PE based on VQ scan Incidence of PE Scan result s 90–95% high probabilit y 30–40% intermediate probabilit y or indeterminate 10–15% low probabilit y 0–5% norm al

Hem atology 171 9.3 Ext ram edullary hem at opoiesis 9.3.1 General inform at ion In ch ron ic an em ias (especially th alassem ia m ajor, AKA Cooley’s an em ia), low h em atocrit results in ch ronic over-stim ulation of bon e m arrow to produce RBCs. Th is results in system ic bony abn orm al- ities, cardiom yopathy (due to h em och rom atosis caused by in creased breakdow n of defect ive RBCs). Pert in en t to th e CNS, th ere are th ree sites w h ere extram edullar y h em atopoiesis (EMH) can cause fin d in gs: ● skull: produces “h air-on -en d” appearan ce on skull x-ray ● vertebral bodies: m ay result in epidural cord com pression 71 (see below ) ● choroid plexus 9.3.2 Epidural cord com pression from EMH Th e exuberan t tissue is ver y radiosen sitive, h ow ever, th e pat ien t m ay be som ew hat depen den t on the hem atopoietic capacit y of th e tissue. 9.3.3 Treat m ent 9 Surgical excision follow ed by radiation th erapy h as been th e recom m en ded treatm en t. 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Hem atology 173 [63] Wells PS, An derson DR, Borm an is J, et al. Value of [68] In ci S, Erbengi A, Berker M. Pulm on ar y Em bolism in Assessm en t of Pretest Probabilit y of Deep -Vein Neu rosu rgical Patien ts. Su rg Neu rol. 1995; 43:123– Throm bosis in Clin ical Man agem en t . Lan cet. 1997; 129 350:1795–1798 [69] Wells PS, Gin sberg JS, An derson DR, et al. Use of a [64] Ginsberg JS, Wells PS, Kearon C, An derson D, et al. Clin ical Mod el for Safe Man agem en t of Patien ts Sen sitivit y and Specificit y of a Rapid W h ole-Blood w ith Suspected Pulm onar y Em bolism . An n In tern Assay for D-dim er in th e Diagn osis of Pulm on ar y Med. 1998; 129:997–1005 Em bolism . An n In tern Med . 1998; 129:1006–1011 [70] The PIOPED In vestigators. Value of th e Ven tilation/ [65] Hull RD, Raskob GE, Pin eo GF, et al. Subcutan eous Perfu sion Scan in Acu te Pu lm on ar y Em bolism . Results of th e Prosp ect ive In vestigation of Pulm o- Low -Molecular-Weigh t Hep arin Com pared w ith n ar y Em bolism Diagn osis (PIOPED). JAMA. 1990; Con t in uous Int ravenous Heparin in th e Treatm en t 263:2753–2759 of Proxim al-Vein Th rom bosis. N En gl J Med. 1992; 326:975–982 [71] Man n KS, Yue CP, Ch an KH, et al. Paraplegia due to [66] Hu ll RD, Raskob GE, Rosen bloom D, et al. Hep arin Ext ram ed u llar y Hem atop oiesis in Th alassem ia: for Five Days as Com pared w ith Ten Days in th e In i- t ial Treatm en t of Proxim al Ven ou s Th rom bosis. N Case Repor t. J Neu rosurg. 1987; 66:938–940 En gl J Med . 1990; 322:1260–1264 [67] Wen ger NK, Sch w art z GR. In : Prin ciples an d Prac- tice of Em ergen cy Med icin e. Ph iladelph ia: W .B. Sau n ders; 1978:949–952 9

174 General and Neurology 10 Neurology for Neurosurgeons 10.1 Dem ent ia Defin it ion . Loss of in tellect ual abilities previously attain ed (m em or y, judgem en t, abstract th ough t, an d oth er h igh er cortical fun ct ion s) severe en ough to in terfere w ith social an d/or occupa- t ion al fun ct ion in g.1 Mem or y deficit is th e cardin al feature, h ow ever, th e DSM-IV defin ition requires im pairm en t in at least on e oth er dom ain (lan guage, perception , visuospatial fun ct ion , calculation , judgem ent, abstraction, problem -solving skills). A ects 3–11% of com m unity-dwelling adults > 65 yrs of age, w ith a greater presen ce am ong in stitut ion alized residen ts.2 Risk factors: advan ced age, fam ily h istor y of dem en tia, an d apolipoprotein E-4 allele. Delir iu m vs. d em en t ia (cr it ical d ist in ct ion ). Delirium AKA acute con fusion al state. Distin ct from dem en tia, h ow ever, patien ts w ith dem en tia are at in creased risk of developin g delirium .3,4 A prim ar y disorder of atten tion th at subsequen tly a ects all oth er aspects of cogn ition .5 Often represents life- th reaten in g illn ess, e.g. hypoxia, sepsis, urem ic en ceph alopathy, elect rolyte abnorm alit y, drug in tox- ication , MI. 50%of pat ien ts die w ith in 2 yrs of th is diagn osis. Un like dem en tia, delirium h as acute on set, m otor sign s (trem or, m yoclonus, asterixis), slurred speech, altered con sciousn ess (hyperalert/agitated or leth argic, or fluctuations), hallucinations m ay be florid. EEG sh ow s pron oun ced di use slow in g. Br ain biop sy for d em en t ia. Clin ical criteria are usually su cien t for th e diagn osis of m ost dem en - t ias. Biopsy sh ould be reser ved for cases of a ch ron ic progressive cerebral disorder w ith an un usual clin ical course w h ere all oth er possible diagn ostic m eth ods h ave been exh austed an d h ave failed to provide adequate diagn ostic certain t y.6 Biopsy m ay disclose CJD, low grade astrocytom a, an d AD 1 0 am ong oth ers. Th e h igh in ciden ce of CJD am on g patien ts selected for biopsy un der th ese criteria n ecessitates appropriate precaution s; see Creutzfeldt-Jakob disease (p. 367).In a report of 50 brain biopsies perform ed to assess progressive n eurodegen erative disease of un clear etiology,7 th e diag- n ostic yield w as on ly 20%(6%w ere on ly suggest ive of a diagn osis, 66%w ere abn orm al but n on spe- cific, 8% w ere n orm al). Th e yield w as h igh est in th ose w ith focal MRI abn orm alit ies. Am on g th e 10 patien ts w ith diagn ostic biopsies, th e biopsy result led to a m ean in gful th erapeutic in terven t ion in only 4. Recom m en d at ion s. Based on th e above, th e follow in g recom m en dation s are m ade for patien ts w ith an otherw ise un explained neurodegen erative disease: 1. th ose w ith a focal abn orm alit y on MRI: stereotactic biopsy 2. th ose w ith out focal abn orm alit y (possibly in cludin g SPECT or PET scan ): brain biopsy sh ould on ly be perform ed w ith in an investigat ive protocol Recom m en d at ion s for specim en . Ideally th e biopsy specim en sh ould8: 1. be large en ough (usually 1 cm 3) 2. be taken from an a ected area 3. in clude grey an d w h ite m atter, pia an d dura 4. be h an dled carefully to m in im ize artifact (elect rocauter y sh ould n ot be used on th e specim en side of the incision) 10.2 Headache 10.2.1 General inform at ion Headach e (H/A) m ay be broadly categorized as follow s: 1. chronic recurring headaches a) vascular t ype (m igrain e): see below b) m uscle con traction (ten sion ) h eadach es 2. headache due to pathology a) system ic pathology b) in tracran ial path ology: a w ide variety of etiologies in cludin g: ● subarach noid h em orrh age: sudden on set, severe, usually w ith vom it in g, apoplexy, focal def- icits possible;see di eren tial diagnosis of paroxysm al H/A (p. 1158)

Neurology for Neurosurgeons 175 ● in creased in tracran ial pressure from any cause (tum or, com m un icatin g hydroceph alus, in flam m at ion , pseudot um or cerebri…) ● irritation or inflam m ation of m eninges: m eningitis ● t um or (p.590): w ith or w ith out elevated ICP c) local path ology of th e eye, n asoph aryn x, or extracran ial tissues (in cludin g gian t cell arteritis (p . 1 9 5 ) d) follow in g h ead t raum a: postcon cussive syn drom e (p. 923) e) follow in g cran iotom y: “syn drom e of th e treph in ed ” (p. 1431) A severe new H/A, or a ch ange in th e pattern of a lon gstan din g or recurren t H/A (in cludin g develop - in g associated N/V, or an abn orm al n eurologic exam ) w arran ts fur th er invest igation w ith CT or MRI.9 Un ilateral H/A th at n ever ch anges side over a period ≥ 1 year w arran ts an MRI; th is w ould be atypical in m igrain e an d m ay be a presentation of an occipital AVM (p. 1239). 10.2.2 Migraine General inform at ion Migrain e attacks usually occur in in dividuals predisposed to th e con dition , an d m ay be act ivated by factors such as brigh t ligh t, stress, diet ch anges, t raum a, adm in istration of radiologic con trast m edia (especially an giography) an d vasodilators. Classificat ion 10 Based on th e 1962 ad h oc com m ittee on h eadache (H/A). See also in dex un der Headach e, e.g. for: crash m igrain e (th un derclap h eadach e) (p. 1158), post-m yelogram h eadach e (p. 1508)... Com m on m igraine Episodic H/A w ith N/V an d ph otoph obia, w ith out aura or n eurologic deficit . Classic m igraine Com m on m igrain e + aura. May h ave H/A w ith occasion al focal n eurologic deficit(s) th at resolve com - pletely in ≤ 24 hrs. Over h alf of th e tran sien t n eurologic dist urban ces are visual, an d usually con sist of positive ph e- n om en a (spark ph otopsia, stars, com plex geom etric pattern s, fort ification spectra) w h ich m ay leave n egative ph en om en a (scotom a, h em ian opia, m on ocular or bin ocular visual loss…) in th eir w ake. Th e secon d m ost com m on sym ptom s are som atosen sor y involving th e h an d an d low er face. Less fre- quen tly, deficits m ay con sist of aph asia, h em iparesis, or un ilateral clum sin ess. A slow ma rch-like pro- gression of deficit is ch aracteristic. Th e risk of stroke is probably in creased in pat ien ts w ith m igrain e.10 Com plicated m igraine Occasion al attacks of classic m igrain e w ith m in im al or n o associated H/A, an d com plete resolut ion of neurologic deficit in ≤ 30 days. Migraine equivalent Neurologic sym ptom s (N/V, visual aura, etc.) w ith out H/A (aceph algic m igrain e). Seen m ostly in ch il- dren . Usually develops in to t ypical m igrain e w ith age. Aura m ay be sh or ten ed by open in g an d sw al- low in g con ten ts of a 10 m g n ifedipin e capsule.11 Hem iplegic m igraine H/A t ypically precedes h em iplegia w h ich m ay persist even after H/A resolves. Cluster headache AKA h istam in ic m igrain e. Actu ally a n eurovascular even t, distin ct from true m igrain e. Recurren t un i- lateral attacks of severe pain . Usually oculofron tal or oculotem poral w ith occasion al radiation in to th e jaw, usually recurrin g on th e sam e side of th e h ead. Ipsilateral auton om ic sym ptom s (conjun cti- val inject ion , n asal congest ion , rh in orrh ea, lacrim ation , facial flush ing) are com m on . Part ial Horn er’s

176 General and Neurology syn drom e (ptosis an d m iosis) som et im es occurs. Male:fem ale ratio is ≈ 5:1. 25% of patien ts h ave a person al or fam ily h istor y of m igrain e. Headaches ch aracteristically h ave no prodrom e, last 30–90 m in utes, an d recur on e or m ore tim es daily usually for 4–12 w eeks, often at a sim ilar tim e of day, follow in g w h ich th ere is typically a rem ission for an average of 12 m on th s.12 Prophylaxis for cluster H/A is on ly m in im ally e ect ive: 1. β-adrenergic blockers are less e ect ive 2. lith ium : becom ing drug of ch oice (respon se rate 60–80%). 300 m g PO TID an d follow levels (desired: 0.7–1.2 m Eq/L) 3. occasionally ergotam ines are used 4. n aproxen (Naprosyn ®) 5. m ethysergide (San sert®) 2–4 m g PO TID is e ect ive in 20–40%of cases, m ust cycle pat ien t o th e drug to prevent retroperitoneal fibrosis, etc. (also see below ) Treatm en t for cluster H/A (prophylaxis is on ly m in im ally e ect ive): Treatm en t is di cult because th ere is n o prodrom e an d th e H/A often stop after 1–2 h rs. Treat- m en t of acute attacks in cludes: ● 100%O2 by face m ask w ith pat ien t sit tin g for ≤ 15 m in or un til attack aborted ● ergotam ine: see below ● SQ sum atriptan : usually aborts attack w ith in 15 m in utes (see below ) ● steroids: see below ● refractor y cases m ay be con sidered for: ○ percutan eous radiofrequen cy sph en opalatin e ganglion blockade13 ○ occipital ner ve stim ulation 14 ○ hypothalam ic deep brain stim ulation 10 Basilar artery m igraine Essen tially restricted to adolescen ce. Recurren t episodes lastin g m in utes to h ours of tran sien t n euro- logic deficits in dist ribut ion of vertebrobasilar system . Deficits in clude: ver tigo (m ost com m on ), gait ataxia, visual dist urban ce (scotom ata, bilateral blin dn ess), dysarth ria, follow ed by severe H/A an d occasion ally n ausea an d vom it in g.15 Fam ily h istor y of m igrain e is present in 86%. 10.3 Parkinsonism 10.3.1 General inform at ion Parkin son ism m ay be prim ar y or secon dar y to oth er con dition s. All result from a relative loss of dop - am in e m ediated in h ibition of th e e ect s of acet ylch olin e in th e basal gan glia. 10.3.2 Idiopat hic paralysis agit ans (IPA) Clin ica l Classical Parkin son’s disease AKA sh aking palsy. A ect s ≈ 1% of Am erican s > age 50 yrs,16 it is fre- quen tly un derdiagnosed.17 Male:fem ale ratio is 3:2. Not clearly environ m en tally or gen etically in duced, but m ay be in fluen ced by th ese factors. Th e classic t riad is sh ow n in Table 10.1. Oth er sign s m ay in clude: postural in stabilit y, m icrogra- ph ia, m ask-like facies. Gait con sists of sm all, sh u in g steps (m arch e á petits pas) or festin atin g gait. Clinically dist inguishing IPA from secondary parkinsonism (see below ) May be di cult early. IPA gen erally exh ibits gradual on set of bradykin esia w ith t rem or th at is often asym m etrical, an d in itially respon ds w ell to levodopa. Oth er disorders are suggested w ith rapid pro- gression of sym ptom s, w hen the initial response to levodopa is equivocal, or w hen there is early m idlin e sym ptom s (ataxia or im pairm en t of gait an d balan ce, sph in cter disturban ce…) or th e Table 10.1 Classic triad of Parkinson’s disease ● trem or (resting, 4–7/second) ● rigidit y (cogwheel) ● bradykinesia

Neurology for Neurosurgeons 177 presen ce of oth er features such as early dem en tia, sen sor y fin din gs, profoun d orth ostatic hypoten - sion , or abn orm alit ies of extraocu lar m ovem en ts.18,19 Pat hophysiology Degen erat ion p r im ar ily of p igm en ted (n eu rom elan in -lad en ) d op am in ergic n eu ron s of t h e p ars com pacta of th e subst ant ia nigra, result ing in redu ced levels of d opam in e in th e n eost riat um (cau d at e n u cle u s, p u t am en , globu s p allid u s). Th is d ecreases t h e act ivit y of in h ibitor y n eu ron s w ith p redom in an t ly D2 class of dop am in e receptors w h ich p roject directly to the intern al seg- m en t of t h e glob u s p allid u s (GPi), an d also in creases (by loss of in h ibit ion ) act ivit y of n eu ron s w it h p red om in an t ly D1 rece ptors w h ich p roject in d irect ly t o t h e globu s p allid u s exter n a (GPe) an d su bt h alam ic n u cleu s.20 Th e n et resu lt is in creased act ivit y in GPi w h ich h as in h ibit or y p ro - jection s to the thalam us w hich then suppresses act ivit y in th e supplem ental m otor cortex am ong other locations. Histologically: Lew y bodies (eosinophilic intraneuronal hyaline inclusions) are th e hallm ark of IPA. 10.3.3 Secondary parkinsonism 10 General inform at ion Th e di eren tial diagn osis of Parkin son’s disease in cludes th e follow in g etiologies of secon dar y par- kin son ism or Parkin son -like con dition s (som et im es of th ese are occasion ally referred to as “Parkin - son plus” syn drom es or parkin son ian disorders) (see above for dist in guish in g features): 1. olivopon tocerebellar degen eration (OPC) 2. st riato-n igral degen eration (SND): m ore aggressive th an parkin son ism 3. posten ceph alitic parkin son ism : follow ed an epidem ic of en ceph alit is leth argica (von Econ om o disease) in th e 1920s, vict im s are n o lon ger living. Dist inguish in g features: oculogyric crisis, trem or involves n ot on ly extrem ities but also trun k an d h ead, asym m et rical, n o Lew y bodies 4. progressive supran uclear palsy (PSNP): im paired vert ical gaze (see below ) 5. m ultiple system atrophy (Shy-Drager syn drom e): see below 6. drug induced: in cludes: a) prescription drugs (elderly fem ales seem m ore susceptible) ● an tipsych ot ics (AKA n eurolept ics): h aloperidol (Haldol®) w h ich w orks by blockin g post- syn aptic dopam in e receptors ● ph en oth iazin e an t iem et ics: proch lorperazin e (Com pazin e®) ● m etoclopram ide (Reglan ®) ● reserpine b) MPTP (1-m et h yl- 4-p h e n yl- 1,2,3,6-tet rah yd ropyr id in e): a com m ercially available ch em i- cal in term ed iate w h ich is also a by-p rod u ct of t h e syn t h esis of MPPP (a m ep erid in e an a- log) th at w as syn th esized an d self-in jected by a grad u ate st u d en t ,21 an d later p rod u ced by illicit d r ug m an u fact u rers to be sold as “syn t h et ic h eroin ” an d u nw it t in gly in ject ed by som e IV d rug abu sers in n or t h er n Califor n ia in 198322 (t h ere is also a case rep or t of a ch em ist w h o w orked w it h MPTP w h o d evelop ed p arkin son ism ).23 MPTP w as su bse - quen t ly d iscover ed to be a p ot en t n eu rotoxin for d op am in ergic n euron s (w it h con t in u ed toxic e ect s th at p ersisted for years24). As a r u le, t h e resp on se to levod op a is d ram at ic, bu t sh or t-lived w it h fre quen t sid e e ects. In con t rast to classic IPA, t h e locu s coer u leu s an d d orsal m otor vagus n ucleu s w ere essent ially n orm al, an d t he sym ptom s d i er sligh t ly c) th ere is an as yet un proven assert ion that m ethylen edioxym eth am ph etam in e (MDMA) AKA “ecstasy” (on th e st reet), m ay h asten the on set of Parkin son ism (a st udy dem on st ratin g a link had to be w ithdraw n because of a m islabeling of drugs) 7. toxic: poison in g w ith a) carbon m on oxide: sym m et ric low den sities in th e globus pallidus on CT b) m anganese: m ay be seen in m iners, w elders, an d pyrotechnics workers. Manganese is excreted by th e liver, people w ith h epatic in su cien cy are m ore susceptible. Im agin g: sym m etrical h igh sign al abn orm alit ies on T1W I prim arily in th e globus pallidus w ith essen - t ially n o fin din gs on T2W I or GRASS (alm ost path ogn om on ic) 8. isch em ic (lacun es in basal gan glia): produces so-called arteriosclerotic parkin son ism AKA vascu- lar parkin son ism : “low er-h alf” parkin son ism (gait dist urban ce predom in ates17). Also causes pseudobulbar deficits, em otion al labilit y. Trem or is rare 9. postt raum atic: parkin son ian sym ptom s m ay occur in ch ron ic t raum atic en cephalopathy, see dem en tia pugilistica (p. 924). Th ere are usually oth er features n ot n orm ally present in IPA (e.g. cerebellar findin gs)

178 General and Neurology 10. norm al pressure hydrocephalus (NPH): urinary incontinen ce (p.404)… 11. n eoplasm in th e region of th e substan tia n igra 12. Riley-Day (fam ilial dysautonom ia) 13. parkin son -dem en t ia com plex of Guam : classic IPA+ am yot roph ic lateral sclerosis (ALS). Path o- logically h as features of parkin son ism an d Alzh eim er’s disease but n o Lew y bodies n or sen ile p la q u e s 14. Hun tin gton’s disease (HD): w h ereas adults t ypically sh ow ch orea, w h en HD m an ifests in a youn g person it m ay resem ble IPA 15. (spon tan eous) in tracran ial hypoten sion (p. 389) m ay present w ith fin din gs m im icking IPA Mult iple syst em at rophy (MSA) AKA Shy-Drager syn drom e. Parkin son ism (in distin guish able from IPA), PLUS idiopath ic or th ostatic hypoten sion , PLUS oth er sign s of autonom ic n er vous system (ANS) dysfun ct ion (ANS fin dings m ay precede parkin son ism an d m ay in clude urin ar y sph in cter disturban ce an d hypersen sitivit y to n ora- dren alin e or t yram in e in fusion s). Degen eration of pregan glion ic lateral h orn n euron s of th oracic spi- n al cord. Unlike IPA, m ost do n ot respon d to dopa th erapy. NB: classic IPA m ay even tually produce orth ostatic hypoten sion from in act ivit y or as a result of progressive auton om ic failure. Progressive supranuclear palsy (PSNP) AKA Steele-Rich ardson -Olszew ski syn drom e.25 Tr ia d : 1. progressive supran uclear oph th alm oplegia (ch iefly vert ical gaze): paresis of volun tar y ver tical eye m ovem en t, but still m oves to vert ical doll’s eyes m an euver 2. pseudobulbar palsy (m ask-like facies w ith m arked dysarth ria an d dysph agia, hyperact ive jaw 10 jerk, em otional incontinence usually m ild) 3. axial dyston ia (especially of n eck an d upper trun k) Associated fin din gs: subcort ical dem en tia (in con stan t), m otor fin dings of pyram idal, extrapyram idal an d cerebellar system s. Average age of on set: 60 yrs. Males com prise 60%. Respon se to an ti-parkin - son drugs is usually ver y sh ort lived. Average sur vival after diagn osis: 5.7 yrs. Di eren tiatin g from Parkin son’s disease (IPA): Pat ien ts w ith PSNP h ave a pseudo-parkin son ism . Th ey h ave m ask facies, but do n ot w alk ben t for- w ard (th ey w alk erect), an d th ey do n ot h ave a t rem or. Th ey ten d to fall backw ards. Co u r se 1. early: a) m any falls: due to dysequilibrium + dow n gaze palsy (can’t see floor) b) eye fin din gs m ay be n orm al in itially, subsequen tly m ay develop di cult y lookin g dow n (especially to com m an d, less to follow in g), calorics h ave n orm al ton ic com pon en t but absen t nystagm us (cortical component) c) slurred speech d) personality changes e) di cult y eatin g: due to pseudobulbar palsy + in abilit y to look dow n at food on plate 2. late: a) eyes fixed centrally (n o respon se to oculoceph alics or oculovestibulars): ocular im m otility is due to fron tal lobe lesions b) n eck st i en s in exten sion (retrocollis) Treat m ent for Parkinson’s disease Medical t reatm en t for Parkin son’s disease is beyon d th e scope of th is book. Surgical treatm ent Before th e in troduct ion of L-dopa in th e late 1960’s, stereotactic th alam otom y w as w idely used for Parkin son’s disease. Th e locat ion ultim ately targeted for lesionin g w as th e ven trolateral n ucleus. Th e procedure w orked better for relieving th e trem or th an for th e bradykin esia, h ow ever it w as th e latter sym ptom th at w as m ost disablin g. Th is procedure can n ot be don e bilaterally w ith out sign ifican t risk to speech fun ct ion . Th e procedure fell out of favor w h en m ore e ect ive drugs becam e available.26 See Surgical t reatm en t of Parkin son’s disease (p.1524) for fur th er in form at ion .

Neurology for Neurosurgeons 179 10.4 Mult iple sclerosis Key concept s ● an idiopathic dem yelinating disease of the CNS producing exacerbating and rem itting sym ptom s disseminated in space and time ● classic clinical findings: optic neuritis, paresthesias, INO and bladder symptoms ● diagnostic criteria (McDonald criteria) use clinical and/or lab results (MRI, CSF…) to stratify patients as: MS, probable MS, or not MS ● MRI: m ultiple usually enhancing lesions involving optic nerves & white matter of brain (especially periventricular white mat ter), cerebellum and spinal cord 10.4.1 General inform at ion An id iop at h ic d em yelin at in g d isease (t h u s a ect in g on ly w h ite m at ter) of t h e cerebru m , opt ic n er ves, an d sp in al cord (esp ecially t h e cor t icosp in al t ract s an d t h e p osterior colu m n s). Does not a ect periph eral m yelin . Path ologically p rod u ces m ult ip le p laques of var iou s age in d i u se loca- t ion s in th e CNS, esp ecially in t h e p eriven t ricu lar w h ite m at ter. Lesion s in it ially evoke an in flam - m ator y resp onse w ith m onocytes an d lym ph ocytic perivascular cu ng, but w ith age set tle dow n to glial scars. 10.4.2 Epidem iology 10 Usual age of on set: 10–59 years, w ith th e greatest peak betw een ages 20–40 years. Th e fem ale:m ale in ciden ce is approxim ately 2:1.27 Prevalen ce varies w ith latitude, an d is < 1 per 100,000 n ear th e equator, an d is ≈ 30–80 per 100,000 in th e n orth ern U.S. an d Can ada. 10.4.3 Classificat ion Typically causes exacerbation s an d rem ission s in various location s in th e CNS (dissemina tion in spa ce a nd t ime). Com m on sym ptom s: visual dist urban ces (diplopia, blurring, field cuts or scotom a), spastic paraparesis, an d bladder disturban ces. Nom en clature for th e tim e course of MS is sh ow n in Table 10.2.28 Relapsin g-rem it t ing MS is th e m ost com m on pattern (≥ 70%) at on set, an d h as th e best respon se to th erapy, but > 50%of cases even tu ally becom e secon dar y progressive MS. On ly 10% h ave prim ar y progressive MS, an d th ese patien ts ten d to be older at on set (40–60 years) an d fre- quen tly develop progressive m yelopathy.29 Progressive relapsin g MS is ver y un com m on . Deficits presen t > 6 m on th s usually persist. Table 10.2 Clinical categories of MS Cat egory Definit ion re la psin g -re m it t in g episodes of acute worsening with recovery and a stable course bet ween relapses secondary progressive gradual neurologic deterioration ± superim posed acute relapses in a patient who previously had relapsing-rem it ting MS primary progressive gradual, nearly continuous neurologic deterioration from the onset of sym p t o m s progressive relapsing gradual neurologic deterioration from the onset of symptom s, but with subsequent superim posed relapses

180 General and Neurology 10.4.4 Clinical signs and sym pt om s Visual dist urbances Dist urban ces of visual acuit y m ay be caused by opt ic or retrobulbar n eurit is w h ich is th e presen ting sym ptom of MS in 15%of cases, an d w h ich occurs at som e tim e in 50%of MS patien ts. Th e percen t- age of patients w ith an attack of optic n euritis and no prior attack that w ill go on to develop MS ran ges from 17–87%depen din g on th e series.30 Sym ptom s: acute visual loss in on e or both eyes w ith m ild pain (often on eye m ovem en t). Dip lop ia m ay be d u e t o in ter n u clear op h t h alm op legia (INO) (p. 565) from a p laqu e in t h e MLF. INO is an im p or t an t sign becau se it rarely occu rs in ot h er con d it ion s besid es MS or brain stem stroke. Mot or findings Ext rem it y w eakn ess (m on o, para, or quadriparesis) an d gait ataxia are am on g th e m ost com m on sym ptom s of MS. Spasticit y of th e LEs is often due to pyram idal tract involvem en t. Scan n in g speech results from cerebellar lesion s. Sensory findings Posterior colum n involvem en t often causes loss of propriocept ion . Paresth esias of extrem ities, t run k, or face occur. Lh erm it te’s sign (elect ric sh ock-like pain radiatin g dow n th e spin e on n eck flexion ) is com m on , but is n ot path ogn om on ic. Trigem in al n euralgia occurs in ≈ 2%, an d is m ore often bilateral an d occurs at a youn ger age th an th e population in general.31 Ment al dist urbances 1 0 Euph oria (la belle in di eren ce) an d depression occur in ≈ 50%of patien ts. Reflex changes Hyperreflexia an d Babin ski sign s are com m on . Abdomina l cuta neous reflexes disappear in 70–80%. GU sym pt om s Urin ar y frequen cy, urgen cy, an d in con tin en ce are com m on . Im poten ce in m ales an d reduced libido in eith er sex is often seen . 10.4.5 Di erent ial diagnosis Th e plethora of possible sign s an d sym ptom s in MS causes th e di eren tial diagn osis to exten d to alm ost all con dition s causin g focal or di use dysfun ct ion of th e CNS. Con dit ion s th at m ay closely m im ic MS clin ically an d on diagn ostic test in g in clude: 1. acute dissem in ated en ceph alom yelit is (ADEM) (p. 182): gen erally m on oph asic. May also h ave CSF- OCB (p. 182). Corpus callosum involvem en t is un com m on 2. CNS lym ph om a (p. 710) 3. oth er closely related dem yelin atin g diseases: e.g. Devic syn drom e (p. 1409) 4. vasculitis 5. encephalitis: patients are usually very ill 6. chronic w hite m atter changes: seen in older patients 10.4.6 Diagnost ic crit eria No sin gle clin ical feat u re or d iagn ost ic test is ad equ ate for t h e accu rate d iagn osis of MS. Th er e- fore, clin ical in for m at ion is in tegrat ed w ith p araclin ical st u d ies. Diagn osin g MS after a sin gle, acu te rem it t in g clin ically isolated syn d rom e (CIS) is ver y r isky. 50–70% of p at ien t s w it h a CIS suggest ive of MS w ill h ave m u lt ifocal MRI abn or m alit ies ch aracter ist ic of MS. Th e p rese n ce of t h ese MRI abn or m alit ies in creases t h e r isk of d evelop in g MS in 1–3 years (w ith greater p rogn os- t ic sign ifican ce t h an CSF- OCB). Th e m ore MRI lesion s, t h e h igh er th e r isk.32 Criteria for t h e d iag- n osis of MS33 follow s.

Neurology for Neurosurgeons 181 Definit ions See referen ces.33,34 Th e follow in g defin ition s are used in th e classification system th at follow s: 1. attack (exacerbation , relapse): neurologic disturbance lasting > 24 hrs35 t ypical of MS w h en clini- copath ological st udies determ in e th at th e cause is dem yelin atin g or in flam m atory lesion s 2. rem ission : ≥ 30 days sh ould separate th e on set of th e first attack from the on set of a secon d 3. h istorical in form at ion : reportin g of sym ptom s by th e patien t (con firm ation by obser ver desir- able), adequate to locate a lesion of MS, an d h as n o oth er explan ation (i.e. m an ifestat ion s m ust not be attributable to anoth er condition) 4. clin ical evidence (signs): n euro dysfun ct ion recorded by com peten t exam in er 5. paraclin ical eviden ce: tests or procedures dem on stratin g CNS lesion w hich h as n ot produced sign s; e.g. Uh th o ph en om en on or sign (w orsen ing of sym ptom s w ith h ot bath or sh ow er), BAER, im agin g procedures (CT, MRI), expert urological assessm en t 6. t ypical of MS: sign s & sym ptom s (S/S) kn ow n to occur frequen tly in MS. Th us excludes gray m at- ter lesion s, periph eral n er vous system lesion s, an d n on -specific com plain ts such as H/A, depres- sion , convulsive seizures, etc. 7. separate lesion s: S/S can n ot be explain ed on basis of sin gle lesion (optic n eurit is of both eyes sim ultan eously or w ith in 15 days represen ts single lesion ) 8. laboratory support: in th is st udy, th e on ly con siderat ion s w ere CSF oligoclon al ban ds (CSF-OCB) (see below ) (OCB m ust n ot be presen t in serum ) or in creased CSF IgG product ion (CSF-IgG) (se- rum IgG m ust be n orm al). Th is assum es th at syph ilis, SSPE, sarcoidosis, etc. h ave been ruled out Diagnosis of MS 10 Th e 2010“McDon ald MS Diagn ostic criteria”36 are sh ow n in Table 10.3. MRI MRI is th e preferred im agin g st udy in evaluating MS39 an d can dem on strate dissem in at ion of lesion s in t im e an d space. Recom m en ded33 brain MRI criteria for diagn osin g MS are sh ow n in Table 10.3.40, 41 Lesion s are n or m ally > 3 m m d iam eter.33 MRI sh ow s m u lt ip le w h ite m at te r abn orm alit ies in 80% of p at ie n t s w it h MS (com p ar ed to 29% for CT).42,43 Lesion s are h igh sign al on T2, an d acu t e lesion s te n d to en h an ce w it h gad olin iu m m ore t h an old lesion s d o. Per iven t ricu lar lesion s m ay blen d in w ith t h e sign al from CSF in t h e ven t r icles on T2, t h ese lesion s are sh ow n to bet ter advan tage on FLAIR (flu id at ten u at ion ) MRI (p. 229). These lesion s are ovoid an d are or ien ted p er p en d icu lar to t h e ep en dym al su r face an d are som et im es called Daw son ’s fin gers (after n eu - rop at h ologist Jam es Daw son ). Spin al cord lesion s n orm ally sh ow lit tle or n o sw ellin g, sh ould be ≥ 3 m m but < 2 ver tebral seg- m en ts, occupy on ly a portion of th e cross-sect ion of th e cord, an d m ust be hyperin ten se on T2.44 Specificit y of MRI is ≈ 94%,45 h ow ever, en ceph alit is as w ell as UBOs seen in aging m ay m im ic MS lesion s. DW I sh ould be n orm al, how ever plaques can som etim es exh ibit “sh in e th rough” (p. 232) so th e ADC m ap m ust be ch ecked to rule-out in farct. Focal tum efactive dem yelin atin g lesion s (TDL) m ay occur in isolation or, m ore com m on ly, in patien ts w ith establish ed MS (con cen tr ic sclerosis of Balo). TDL m ay represen t an in term ediate posi- tion betw een MS an d ADEM (p.182).46 TDLs ten d to be sym m etric. TDLs m ay en h an ce, an d sh ow perilesion al edem a (but less th an MS) and th us be m istaken for n eoplasm s. Biopsy results m ay be con fusin g. MRS m ay n ot be able to di eren tiate from n eoplasm .47 CSF CSF an alysis can support th e diagn osis in som e cases, but can n ot docum en t dissem in ation of lesion s in t im e or space. Th e CSF in MS is clear an d colorless. Th e OP is n orm al. Total CSF protein is < 55 m g/ dl in ≈ 75% of patien ts, an d < 108 m g/dl in 99.7% (values n ear 100 sh ould prom pt a search for an altern ative diagn osis). Th e W BC coun t is ≤ 5 cells/m cl in 70%of patien ts, an d on ly 1% h ave a coun t > 20 cells/m cl (h igh values m ay be seen in th e acute m yelit is). In ≈ 90%of patien ts w ith MS, CSF-IgG is in creased relative to oth er CSF protein s, an d a ch aracter- ist ic pattern occurs. Agarose gel elect roph oresis sh ow s a few IgG ban ds in th e gam m a region (oligo- clonal ban ds) th at are n ot presen t in th e serum (h igh er resolution isoelect ric focusin g can dem on strate 10–15 ban ds). CSF-OCB are n ot specific for MS, an d can occur in CNS in fect ion s an d less com m on ly w ith strokes or tum ors. Th e predictive value of th e absen ce of IgG in a patien t w ith sus- pected MS h as n ot been satisfactorily elucidated.

182 General and Neurology Table 10.3 2010 McDonald MS Diagnostic Criteria36 The diagnosis of MS requires elim ination of m ore likely diagnoses and dem onstration of lesions dissem inated in space (DIS) and t im e (DIT) Clinical (at t acks) Le sio n s Additional crit eria to m ake t he diagnosis ≥ 2 Objective clinical evidence of ≥ 2 lesions None. If additional tests are done, or objective clinical evidence of 1 lesion results m ust still be consistent with MS with reasonable historical evidence of a prior attack ≥ 2 Objective clinical evidence of 1 lesion DIS; or wait for further clinical attack im plicating a different CNS location 1 Objective clinical evidence of ≥ 2 lesions DIT; or wait for a second clinical attack 1 Objective clinical evidence of 1 lesion DIS or wait for further clinical attack implicating a different CNS location and DIT; or wait for a second clinical at tack 0 (progression from onset) One year of disease progression (retro- spective or prospective) and at least 2 of: ● DIS in the brain based on ≥ 1 T2 MRI lesion in periventricular, juxtacortical or infratentorial regions ● DIS in the spinal cord based on ≥ 2 T2 MRI lesions ● or positive CSF 1 0 Paraclinical evidence in diagnosis of MS Evidence for DIS37 ≥ 1 T2 MRI lesion in at least 2 out of 4 areas of the CNS: periventricular, juxtacortical, infratentorial or spinal cord ● Gadolinium enhancement of lesions is not required ● If the patient has a brainstem or spinal cord syndrome, the sym ptom atic lesions are excluded and do not contribute to lesion count Evidence for DIT38 ● New T2 and/or gadolinium -enhancing MRI lesion(s) on follow-up MRI, with reference to a baseline study, irrespective of the tim ing of the baseline MRI or ● Simultaneous presence of asym ptomatic gadolinium-enhancing and non- enhancing lesions at any tim e Evidence for positive CSF Oligoclonal bands in CSF (and not serum ) or elevated IgG index Recom m en ded criteria h ave been publish ed,48 m ost of w h ich pertain to specifics of laborator y an alysis, pert in en t clin ical excerpts are sh ow n in Table 10.4. 10.5 Acut e dissem inat ed encephalom yelit is AKA ADEM. Acu te d em yelin at in g con d it ion , h as been associate d w it h relat ively recen t h ist or y of vaccin at ion . Like MS, m ay also d em on st rate oligoclon al ban d s in CSF. ADEM is gen erally m on o - p h asic, an d lesion s occu r w it h in a cou p le of w eeks. Th e re is u su allly a good resp on se to h igh - d ose IV cor t icosteroid s. 10.6 Mot or neuron diseases 10.6.1 General inform at ion Degen erative diseases of m otor n euron s. See also com parison of upper m otor n euron (UMN) w ith low er m otor n euron (LMN) (p. 504) an d th e paralysis th ey produce. Five subt ypes of w h ich ALS is th e m ost com m on (see below ).

Neurology for Neurosurgeons 183 Table 10.4 CSF criteria for MS 1. qualitative assessment of IgG is the most informative analysis and is best perform ed using IEF with some form of imm unodetection (blotting or fixation) 2. analysis should be perform ed on unconcentrated CSF and m ust be compared to sim ultaneously run serum sample in the sam e assay 3. runs should use the sam e amount of IgG from serum and CSF 4. each run should contain positive and negative controls 5. quantitative analysis should be m ade in term s of one of the 5 recognized staining patterns for OCB 6. an individual experienced in the techniques should report the result s 7. all other tests perform ed on the CSF (including WBC, protein & glucose, lactate) should be taken into co n sid e ra t io n 8. evaluation using light chains for im m unodetection may be helpful in certain cases to resolve equivocal oligoclonal IgG pat terns 9. if clinical suspicion is high but CSF results are equivocal, negative or show only a single band, consider repeating the LP 10. to m easure IgG levels, nonlinear form ulas that consider integrit y of the blood-CSF barrier should be used (e. g. the ratio of CSF to serum albumin (AKA Qalb) is a m easure of leakiness) 11. labs analyzing CSF should have internal as well as external qualit y assessm ent controls 12. quantitative IgG is a complementary test, but is not a substitute for qualitative IgG testing which has the highest sensitivit y and specificit y Th ree pattern s of involvem en t: 10 1. m ixed UMN & LMN degen eration : am yotroph ic lateral sclerosis (ALS) (see below ). Th e m ost com - m on of the m otor neuron diseases 2. UMN degen eration : prim ar y lateral sclerosis. Rare, on set after age 50. No LMN sign s. Slow er pro- gression th an ALS (yrs to decades). Pseudobulbar palsy is com m on .49 Usually does n ot sh orten lon gevity. May present w ith falling due to balan ce problem s or low back an d n eck pain due to axial m uscle w eakn ess 3. LMN degen eration : progressive m uscular atrophy (PMA) an d spin al m uscular atrophy (SMA) 10.6.2 Am yot rophic lat eral sclerosis Key concept s ● degeneration of anterior horn cells and corticospinal tracts in the cervical spine and medulla (bulb) of unknown etiology ● a m ixed upper and lower motor neuron disease (UMN → mild spasticit y in LEs; LMN → atrophy and fasciculations in UEs) ● clinically: progressive muscle wasting, weakness, and fasciculations ● no cognitive, sensory, nor autonomic dysfunction In t h e U.S. am yot rop h ic lateral sclerosis (ALS) is AKA Lou Geh rig’s d isease n am ed after th e New York Yan kee first basem an w h o an n ou n ced t h at h e h ad t h e d isease in 1939. AKA m otor n eu ron disease (singular). Epidem iology See referen ce.30 Prevalen ce: 4–6/100,000. In ciden ce: 0.8–1.2/100,000. Fam ilial in 8–10% of cases. Fam ilial cases usually follow autosom al dom in an t in h eritan ce, but occasion ally dem on strate a recessive pattern . On set usually after 40 years of age. Pat hology Etiology is n ot kn ow n w ith certain t y. Histology: degen eration of an terior h orn alph a-m oton euron s (in th e spinal cord a nd in brain stem m otor n uclei) (LMNs) an d cort icospin al t ract s (UMNs). Produces m ixed UMN & LMN fin din gs, w ith a great deal of variabilit y depen din g on w h ich predom in ates at any given tim e.

184 General and Neurology Clin ica l Ch aracterized by progressive m uscle w astin g, w eakn ess, an d fasciculation s. Involvem en t is of volun tar y m uscles, sparin g th e volun tar y eye m uscles an d urin ar y sph in cter. Classically, presen ts in itially w ith w eakn ess an d atrophy of th e h an ds (low er m otor n euron ) w ith spast icit y an d hyperreflexia of th e low er extrem ities (upper m otor n euron ). How ever, LEs m ay be hyporeflexic if the low er m otor neuron deficits predom inate. Dysarth ria an d dysph agia are caused by a com bin ation of upper an d low er m otor n euron path ol- ogy. Tongue atrophy an d fasciculat ion s m ay also occur. Although cognitive deficits are generally considered to be absent in ALS, in actuality 1–2%of cases are associated w ith dem entia, and cognitive changes m ay occasionally predate the usual features of ALS.50 Di erent ial diagnosis At tim es, it m ay be ver y di cult to distin guish ALS from cer vical spon dylotic m yelopathy; see dis- cussion of di eren tiating features (p.1086). Diagnostic st udies EMG Not absolutely n ecessary to m ake diagn osis in m ost cases. Fibrillation s an d positive sh arp w aves are foun d in advan ced cases (m ay be absen t early, especially if upper m otor n euron path ology predom - in ates). LMN fin din gs in th e LE in th e absen ce of lum bar spin e disease, or fibrillation poten tials in th e tongue are suggestive of ALS. LP (CSF) May h ave sligh tly elevated protein . 10 Treatm ent Much of care is directed tow ards m inim izing disability: 1. risk of aspiration m ay be reduced w ith a) tracheostomy b) gastrostom y tube to allow con tin ued feeding c) vocal cord injection w ith Teflon 2. n on invasive ven tilation : e.g. BiPAP spast icit y th at occurs w h en upper m otor n euron deficits pre- dom in ate m ay be treated (usually w ith sh ort-lived respon se) w ith : a) baclofen (p. 1530): also m ay relieve th e com m on ly occurrin g cram ps b) diazepam 3. riluzole (Rilutek®): in h ibits presyn aptic release of glutam ate. Doses of 50-200 m g/d in creases t ra- ch eostom y-free sur vival at 9 & 12 m on th s, but th e im provem en t is m ore m odest or m ay be n on - existen t by ≈ 18 m on th s 51,52 Pr o g n o s is Most patien ts die w ith in 5 years of on set (m edian sur vival: 3–4 yrs). Th ose w ith prom in en t oroph ar- yn geal sym ptom s m ay h ave a sh orter life-span usually due to com plication s of aspiration . 10.7 Guillain -Barré syndrom e 10.7.1 General Key concept s ● acute onset of peripheral neuropathy with progressive muscle weakness (more severe proximally) with areflexia, reaches maximum over 3 days to 3 weeks ● cranial neuropathy: also common, m ay include facial diplegia, ophthalmoplegia ● little or no sensory involvem ent (paresthesias are not uncomm on) ● onset often 3 days-5 weeks following viral URI, immunization, Campylobacter jejuni enteritis, or surgery ● pathology: focal segmental demyelination with endoneurial m onocytic infiltrate ● elevated CSF protein without pleocytosis (albuminocytologic dissociation)

Neurology for Neurosurgeons 185 Guillain -Barré syn drom e (GBS) AKA acute polyradiculon eurit is, am ong oth ers, is actually a collect ion of syn drom es h avin g in flam m ator y polyradiculon europathy in com m on . Its m ost frequen t form is acute in flam m atory dem yelin atin g polyradiculon europathy (AIDP). First described as an ascendin g paralysis, m ost form s are ch aracterized by symmetr ic w eakn ess an d areflexia. Mild cases m ay presen t on ly w ith ataxia, w h ereas fulm in an t cases m ay ascen d to com plete tet raplegia w ith paralysis of respirator y m uscles an d cran ial n er ves. Th ere are also a n um ber of varian ts (p. 186). GBS is th e m ost com m on acquired dem yelin atin g n europathy. In ciden ce is ≈ 1–3/100,000. Th e lifetim e risk for any on e in dividual get ting GBS is ≈ 1/1,000. GBS is triggered by both hum oral and cell m ediated autoim m une response to an im m une sensitiz- ing event. Frequent (but not essen tial) an teceden ts: viral infection, surgery, im m unization, mycoplas- m a infection, enteral infection w ith Cam pylobacter jejuni (≈ 4 days of intense diarrhea). Higher frequency in th e follow ing conditions than in general population: Hodgkin’s disease, lymphom a, lupus. Most cases involve an tibodies to gan gliosides an d glycolipids in periph eral m yelin (axon an tibod- ies occur in som e form s). For un kn ow n reason s serum creatin e kin ase can be m ildly elevated, an d m ay correlate w ith m uscle t ype pain .53 10.7.2 Diagnost ic crit eria See referen ce.54 features required for diagn osis: ● progressive m otor w eakn ess of m ore th an 1 lim b (from m in im al w eakn ess ± ataxia to paralysis, m ay in clude bulbar or facial or EOM palsy). Un like m ost n europath ies, proxim al m uscles are a ected m ore than distal ● areflexia (usually un iversal, but distal areflexia w ith defin ite hyporeflexia of biceps an d kn ee jerks su ces if oth er features con sisten t) features st ron gly support ive of diagn osis: 10 ● clin ical features (in order of im portan ce) ○ progression : m otor w eakn ess peaks at 2 w ks in 50%, by 3 w ks in 80%, an d by 4 w ks in > 90% ○ relative sym m etry ○ m ild sen sor y sym ptom s/sign s (e.g. m ild paresth esias in h an ds or feet) ○ cra nia l ner ve involvem en t: fa cia l wea kness in 50%, usually bila tera l. GBS presen ts in itially in EOMs or oth er Cr. N. in < 5%of cases. Oroph ar yn geal m uscles m ay be a ected ○ recover y usually by 2–4 w ks after progression stops, m ay be delayed by m on th s (m ost patien ts recover fun ction ally) ○ auton om ic dysfun ct ion (m ay fluct uate): tachycardia an d oth er arrhyth m ias, postural hypoten - sion , HTN, vasom otor sym ptom s ○ afebrile at on set of n euritic sym ptom s ○ varian ts (n ot ran ked): – fever at on set of n eurit ic sym ptom s – severe sen sory loss w ith pain – progression > 4 w ks – cessation of progression w ithout recovery – sph in cter dysfun ct ion (usually spared): e.g. bladder paralysis – CNS involvem en t (con troversial): e.g. ataxia, dysarth ria, Babin ski sign s ● CSF: album in ocytologic dissociation (↑ protein w ith out pleocytosis) ○ protein : elevated after 1 w k of sym ptom s, > 55 m g/dl ○ cells: 10 or few er m on on uclear leukocytes/m l ○ varian ts – n o CSF protein rise 1–10 w ks after on set (rare) – 11–50 m onocytes/m l – elect rodiagn ostics: 80%h ave NCV slow in g or block at som e t im e (m ay take several w eeks in som e). NCV usually < 60%of n orm al, but n ot in all n er ves features casting doubt on diagn osis: ● m arked, persistent, asym m etry of weakness ● persisten t bow el or bladder dysfun ct ion ● > 50 m on ocytes/m l CSF ● PMNs in CSF ● sh arp sen sory level features of con dition s in th e di eren tial diagn osis (see below )

186 General and Neurology 10.7.3 Guillain-Barré variant s General inform at ion A n um ber of varian ts h ave been described (som e m ay sim ply be in com plete form s of typical Guil- lain -Berré). Auton om ic dysfun ct ion m ay occur in som e. Miller-Fisher variant of GBS Ataxia, areflexia an d oph th alm oplegia. May also h ave ptosis. 5%of cases of GBS. Serum m arker: an ti- GQ1b an t ibodies. Acut e m ot or axonal neuropat hy (AMAN) Th is varian t an d AIDP are th e m ost com m on to follow Cam pylobacter jejun i en teritis. Pharyngeal-cervical-brachial variant Facial, oroph ar yn geal, cer vical, an d UE w eakn ess, sparin g th e LEs. Pure sensory variant Sen sor y loss accom pan ied by areflexia. At ypical GBS May be accom pan ied by rh abdom yolysis.55 10 10.7.4 Di erent ial diagnosis Also see con dition s in th e di eren tial diagnosis un der Myelopathy (p. 1407) 1. Guillain -Barré syn drom e (in cludin g on e of its varian ts) 2. crit ical illn ess polyn europathy (p. 542): EMG: ↓ CMAP & SNAP 3. curren t h exacarbon abuse: volatile solven ts (n -h exan e, m eth yl n -but yl keton e), glue sn i n g 4. acute in term itten t porphyria (AIP): a disorder of porphyrin m etabolism . CSF protein is n ot ele- vated in AIP. Recurren t pain ful abdom in al crises are com m on . Ch eck urin e delta-am in olevulin ic acid or porphobilinogen 5. recen t diph th erit ic in fect ion : diph th erit ic polyn europathy h as a lon ger laten cy an d a slow er cre- scendo of sym ptom s 6. lead n europathy: UE w eakn ess w ith w rist drop. May be asym m etrical 7. poliom yelitis: usually a symmetr ic, has m en ingeal irritation 8. hypoph osph atem ia (m ay occur in ch ron ic IV hyperalim en tat ion ) 9. botulism : di cult to distin guish clin ically from GBS. Norm al NCV an d a facilitating respon se to repetitive n er ve stim ulat ion on elect rodiagn ostics 10. toxic n europathy (e.g. from n it rofuran toin , dapson e, th allium or arsen ic) 11. t ick paralysis: m ay cause an ascen din g m otor n europathy w ith out sen sor y im pairm en t. Careful exam in at ion of th e scalp for t ick(s) 12. ch ronic im m un e dem yelin atin g polyradiculon europathy (CIDP) AKA ch ron ic relapsin g GBS, ch ronic relapsin g polyn euritis.56 ICD9: 357.81 ch ron ic in flam m ator y dem yelin atin g polyn euri- t is. Sim ilar to GBS, but lon g t im e course (sym ptom s m ust be presen t > 2 m os). CIDP produces progressive, sym m etrical, proxim al & distal w eakn ess, depression of m uscle stretch reflexes, an d variable sen sor y loss. Cran ial n er ves are usually spared (facial m uscles m ay be involved). Balan ce di culties are com m on . Need for respirator y support is rare. Peak in ciden ce: age 40–60 yrs. Elect rodiagn ost ics an d n er ve biopsy fin din gs are in dicat ive of dem yelin ation . CSF fin dings are sim ilar to GBS (see above). Most respon d to im m un osuppressive th erapy (especially predn i- solon e & plasm aph eresis) but relapses are com m on . Refractor y cases m ay be treated w ith IV gam m a-globulin , cyclosporin -A,57 total body lym ph oid irradiation or in terferon -α 58 13. crit ical illn ess m yopathy: ICD9: 359.81 ch ron ic illn ess m yopathy. Muscles n ot excitable w ith direct st im ulation . EMG: low or n orm al CMAP w ith n orm al SNAP. Muscle biopsy: abn orm alit ies m ay ran ge from Type II fiber atrophy to n ecrosis (severe n ecrosis m ay n ot recover) 14. m otor n euron disease (p. 182): AKA ALS. Hyperreflexia in LEs 15. m yasth en ia gravis: w eakn ess w orsen s tow ards th e en d of th e day an d w ith repeat e orts. Posi- t ive assay for circulat in g an ti-acet ylch olin e receptor an tibodies 16. spinal cord injury

Neurology for Neurosurgeons 187 10.7.5 Im aging No characteristic finding, however, di use enhancem ent of cauda equina and nerve roots occurs in up to 95%of cases.59 Thought to be due to disruption of the blood-nerve barrier from inflam m ation. Conspicu- ous nerve root enhancem ent correlates w ith pain, GBS disability grade, and duration of recovery.59 10.7.6 Treat m ent Im m un oglobulin s m ay be h elpfu l. In severe cases, early plasm aph eresis h asten s th e recover y an d reduces th e residual deficit . Its role in m ild cases is un certain . Steroids are n ot h elpful.60 Mech an ical ven tilation an d m easures to preven t aspiration are used as appropriate. In cases of facial diplegia, th e eyes m ust be protected from exposure (n europaralyt ic) keratit is. 10.7.7 Out com e Recover y m ay n ot be com plete for several m on th s. 35%of un treated patien ts h ave residual w eakn ess an d atrophy. Recurren ce of GBS after ach ieving m axim al recover y occurs in ≈ 2%. 10.8 Myelit is 10 10.8.1 General inform at ion AKA acute tran sverse m yelitis (ATM). The term in ology is con fusing: m yelitis overlaps w ith “m yelop- athy.” Both are pathologic conditions of th e spinal cord. Myelitis indicates inflam m ation , and etiolo- gies include: infectious/post-infectious, autoim m un e, and idiopath ic. Myelopathy is gen erally reser ved for com pressive, toxic, or m etabolic etiologies61; see also di eren tial diagn osis (p.1407). 10.8.2 Et iology Many so-called “causes” rem ain un proven . Im m un ologic respon se again st th e CNS (m ost likely via cell m ediated com pon en t) is th e probable com m on m ech an ism . An im al m odel: experim en tal aller- gic en ceph alom yelitis (requires m yelin basic protein of CNS, n ot periph eral). Gen erally accepted etiologies in clude (item s w ith an asterisk * m ay be m ore properly associated w ith m yelopathy rather th an m yelitis): 1. in fect ious an d post-in fect ious a) prim ar y in fect ious m yelit is ● viral: poliom yelitis, m yelitis w ith viral encephalom yelitis, herpes zoster, rabies ● bacterial: in cluding tuberculom a of spin al cord ● spiroch etal: AKA syph ilitic m yelitis. Causes syph ilitic en darteritis ● fun gal (aspergillosis, blastom ycosis, cr yptococcosis) ● parasitic (Ech in ococcus, cysticercosis, paragon im iasis, sch istosom iasis) b) post-in fect ious: in cluding post-exan th em atous, in fluen za 2. post-traum atic 3. physical agents a) decom pression sickness (dysbarism ) b) elect rical injury* c) post-irradiation 4. paraneoplastic syndrom e (rem ote e ect of cancer): m ost com m on prim ary is lung, but prostate, ovary and rectum h ave also been described62 5. m etabolic a) diabetes m ellitus* b) pern icious an em ia* c) chronic liver disease* 6. toxins a) cresyl phosphates* b) in tra-ar terial con trast agen ts* c) spinal anesth etics d) m yelographic contrast agents e) follow in g ch em on ucleolysis63 7. arach n oidit is 8. autoim m une a) m ultiple sclerosis (MS), especially Devic syn drom e (p. 1409) b) follow in g vaccin at ion (sm allpox, rabies)

188 General and Neurology 9. collagen vascular disease a) system ic lupus erythem atosus b) m ixed con n ective tissue disease 10.8.3 Clinical Present at ion 34 pat ien ts w ith ATM64: age of on set ran ged 15–55 yrs, w ith 66% occurrin g in 3rd an d 4th decade. 12 patien ts (35%) h ad a viral-like prodrom e. Presen ting sym ptom s are sh ow n in Table 10.5, w ith oth er presen t in g sym ptom s of un specified frequen cy in cludin g65: fever an d rash . Present ing level Th e levels at presen tat ion in 62 patien ts w ith ATM are sh ow n in Table 10.6.65 Th e th oracic level is th e m ost com m on sen sor y level. In frequen tly, ATM is th e presen ting sym ptom of MS (≈ 3–6% of patien ts w ith ATM develop MS). Pr o g r e s s io n Progression is usually rapid, w ith 66% reach in g m axim al deficit by 24 h rs, h ow ever th e in terval betw een first sym ptom an d m axim al deficit varies from 2 h rs-14 days.65 Fin din gs at th e t im e of m axim al deficit are sh ow n in Table 10.7. 10.8.4 Evaluat ion 1 0 Im aging sh ould be don e to rule-out a com pressive lesion . Myelogram , CT & MRI: n o ch aracteristic fin din g. On e paper repor ts 2 patien ts w ith fusiform cord en largem en t .67 MRI m ay be able to dem on - st rate th e area of involvem en t w ith in th e cord. MRI m ay sh ow th e “cen tral dot sign ”,68 an area of h igh sign al on axial T2WI usually cen trally located w ith a sm all dot of isoin ten se sign al in th e core of th e hyperintensit y. CSF: n orm al durin g acute ph ase in 38%of LPs. Rem ain der (62%) h ad elevated protein (usually > 40 m g%) or pleocytosis (lym ph ocytes, PMNs, or both) or both . Table 10.5 Presenting symptom s in m yelitis Series Aa Series Bb Sym pt om 35% 35% pain (back or radicular) 32% 13% m uscle weakness 26% 46% sensory deficit or paresthesias 12% 6% sphincter disturbance aseries A: 34 patients with ATM64 bseries B: 52 patients with acute or subacute transverse m yelitis66 Table 10.6 Level of sensory deficit % Le ve l 8% cervical 36% high thoracic 32% low thoracic 8% lu m b a r 16% unknown

Neurology for Neurosurgeons 189 Table 10.7 Symptoms at tim e of maximal deficit (62 patients with ATM65) % Sym pt om 100% sensory deficit or paresthesias 97% m uscle weakness 94% sphincter disturbance (hesitancy, retention, overflow incontinence) 34% pain in back, abdomen, or lim bs 27% fever 13% nuchal rigidit y Evaluat ion schem e 10 In a pat ien t developin g acute m yelopathy/paraplegia, especially w h en ATM is con sidered likely, th e first test of ch oice is an em ergen cy MRI. If n ot readily available, a m yelogram (w ith CT to follow ) directed at th e region of th e sen sor y level is perform ed (CSF m ay be sen t in th is circum stan ce on ce block is ruled out). 10.8.5 Treat m ent No t reatm en t h as been st udied in a ran dom ized con trolled t rial. 1. steroids: n ot ben eficial for all causes of m yelitis,69 especially w ith ASIA A (com plete loss of spin al cord fun ct ion ).70 Rx: h igh -dose IV m ethylpredn isolon e 3-5 days (doses quoted in clude 500 m g/d, an d 1000 m g/d71). Th e decision to in troduce addit ion al t reat m en t m easures is based on th e res- pon se to steroids an d th e MRI appearan ce after ≈ 5 days of steroids 2. plasm a exch ange (PLEX) for patien ts th at do n ot respon d to steroids w ith in 3-5 days 3. oth er form s of im m un e suppression m ay be attem pted for failure of above th erapies, in cluding: cycloph osph am ide (usually un der th e direct ion of an on cologist) 4. in cases of focal spin al cord en largem en t, surgical decom pression m ay be con sidered in cases th at fail to respon d to th e above 10.8.6 Prognosis In a series of 34 ATM patien ts w ith ≥ 5 yrs follow -up (F/U)64: 9 pat ien ts (26%) h ad good recover y (am bulate w ell, m ild urin ar y sym ptom s, m in im al sen sor y an d UMN sign s); 9 (26%) h ad fair recover y (fun ct ion al gait w ith som e degree of spast icit y, urin ar y urgen cy, obvious sen sor y sign s, paraparesis); 11 (32%) poor (paraplegic, absen t sph incter con trol); 5 (15%) died w ith in 4 m os of illn ess. 18 patien ts (62%of sur vivors) becam e am bulator y (in th ese cases, all could w alk w ith support by 3–6 m os). In a series of 59 patien ts65 (F/U period un specified): 22 (37%) h ad good recover y; 14 (24%) poor; 3 died in acute stage (respirator y in su cien cy in 2, sepsis in 1). Recover y occurred betw een 4 w eeks an d 3 m os after on set (n o im provem en t occurred after 3 m os). 10.9 Neurosarcoidosis 10.9.1 General Key concept s ● neurologic involvement of sarcoidosis (a system ic granulomatous disease) ● m ay produce multiple cranial nerve palsies ● the most comm on neurologic manifestation is diabetes insipidus ● corticosteroids are beneficial for systemic as well as neurologic involvement Sarcoidosis is a gran ulom atous disease th at is usually system ic, an d m ay in clude th e CNS (so-called n eurosarcoidosis AKA n eurosarcoid). On ly 1–3% of cases h ave CNS fin dings w ith out system ic m an i- festation s.72 Th e cause of th e disease is un kn ow n . An exaggerated cellular im m un e respon se for

190 General and Neurology un kn ow n reason s is th e curren tly favored hypoth esis. Organ s com m on ly involved in clude lun gs, skin , lym ph n odes, bon es, eyes, m uscles, an d parotid glan ds.30 10.9.2 Pat hology CNS sarcoidosis prim arily involves th e leptom en in ges, h ow ever paren chym al invasion often occurs. Adh esive arachn oiditis w ith n odule form ation m ay also occur (n odules h ave a predilect ion for th e posterior fossa). Di use m en in git is or m en ingoen ceph alitis m ay occur, an d m ay be m ost pron oun ced at th e base of th e brain (basal m en ingit is) an d in th e subepen dym al region of th e th ird ven tricle (in cludin g th e hypothalam us). Con stan t m icroscopic features of n eurosarcoidosis in clude n on caseating gran ulom as w ith lym - ph ocyt ic in filt rates. Lan gh an s gian t cells m ay or m ay n ot be presen t . 10.9.3 Epidem iology Incidence of sarcoidosis is ≈ 3–50 cases/100,000 population ; n eurosarcoidosis occurs in ≈ 5% of cases (reported range: 1–27%). In one series, the m edian age of onset of neurologic sym ptom s was 44 years. 10.9.4 Clinical findings Clin ical fin din gs in clude m ultiple cran ial n er ve palsies in 50–70% (particularly facial n ., in cludin g diplegia), periph eral n europathy, an d m yopathy.73 Occasion ally th e lesion s m ay produce m ass e ect ,74 an d hydroceph alus m ay result from adh esive basal arachn oiditis. Patien ts m ay h ave low grade fever. In t racran ial hyper ten sion is com m on an d m ay be dangerous. Hypoth alam ic involvem en t m ay produce disorders of ADH (diabetes in sipidus, disordered th irst). Rare involvem en t of th e pit ui- tar y m ay produce pit uitary in su cien cy. Seizures occur in 15%. 1 0 0.4%of patien ts w ith sarcoidosis develop spinal cord involvem en t,75 an d in 16%of th ese, th e spi- n al cord w as th e on ly iden tifiable site of involvem en t. 10.9.5 Laborat ory CBC: m ild leukocytosis an d eosin oph ilia m ay occur. Serum an giotensin -convert in g en zym e (ACE): abn orm ally elevated in 83%of patien ts w ith act ive pulm on ar y sarcoidosis, but in on ly 11% w ith in active disease.76 False positive rate: 2–3%; m ay also be elevated in prim ar y biliar y cirrh osis. CSF: sim ilar to any subacute m en in gitis: elevated pressure, m ild pleocytosis (10–200 cells/m m 3) m ostly lym ph ocytes, elevated protein (up to 2,000 m g/dl), m ild hypoglycorrh ach ia (15–40 m g/dl), CSF ACE is elevated in ≈ 55%of cases w ith n eurosarcoidosis (n orm al in pat ien ts w ith sarcoidosis n ot involving th e CNS).77 No organ ism s are recovered on culture or gram stain . 10.9.6 Im aging CXR Usually dem on strates ch aracteristic fin dings of sarcoidosis (hilar aden opathy, m ediast in al lym ph n o d e s…). MRI Gadolin ium en h an cem en t of th e leptom en in ges an d/or optic n er ve m ay be th e on ly abn orm al fin d- in g(s). Men in geal en h an cem en t w as seen in 38%of n eurosarcoidosis pat ien ts.78 Leson s m ay be soli- tar y or m ultiple, an d m ay be located intra- or extraparenchym al, periventricular, and/or in basal cistern s. Lesion s m ay be seen on FLAIR th at w ould oth erw ise h ave been m issed. Hydroceph alus m ay occur. Gallium scan Nuclear m edicin e scan w ith 67Ga cit rate (p. 236). Described fin din gs in clude: 1. Pan da sign 79: uptake in lacrim al glan ds, parotid glan ds & n asoph ar yn x (n orm al). Not specific for s a r co id o s is 2. lam bda distribution 80: uptake in hilar lym ph nodes 3. leopard m an sign81: di use dappled pattern due to uptake in soft t issues, skin , m uscles, m ediasti- num , and lacrim al glands

Neurology for Neurosurgeons 191 Table 10.8 Di erential diagnosis of neurosarcoidosis 1. Hodgkin’s disease 2. chronic granulomatous m eningitis: a) Hansen’s disease (leprosy) b) syphilis c) cryptococcosis d) tuberculosis 3. m ultiple sclerosis 4. CNS lym phom a 5. pseudotumor cerebri 6. granulom atous angiitis 10.9.7 Di erent ial diagnosis Di eren tiatin g gran ulom atous an giitis (GA) from n eurosarcoidosis th at involves on ly th e CNS can be don e on h istologic criteria: th e in flam m ator y react ion in sarcoidosis is n ot lim ited to th e region im m ediately surroun din g blood vessels as it is in GA, w h ere exten sive disruption of th e vessel w all m ay occur. 10.9.8 Diagnosis 10 Makin g th e diagn osis is relatively easy w h en system ic involvem en t occurs: ch aracteristic fin dings on CXR, biopsy of skin or liver n odules, m uscle biopsy, serum ACE assay. Isolated n eurosarcoidosis m ay be m ore di cult to diagn ose, an d m ay require biopsy (see below ). 10.9.9 Biopsy In un cert ain cases, biopsy m ay be in dicated. W h en ever possible, MRI sh ould be used to localize a supraten torial region of involvem en t. If a m ass lesion can n ot be biopsied, a m en ingeal biopsy m ay be don e an d sh ould in clude all layers of m en in ges an d cerebral cortex. Cult ures an d stain s for fun gus an d acid-fast bacteria (TB) sh ould be perform ed in addit ion to m icroscopic exam in at ion . 10.9.10 Treat m ent An tibiotics h ave n ot been proven to be of ben efit. Im m un osuppression prim arily w ith cort icostero- ids are ben eficial for system ic as w ell as n eurologic involvem en t. Th erapy m ay be in itiated w ith pre- dn ison e 60 m g PO qd in adults, an d tapered based on respon se. Th erapy w ith cyclosporin e m ay allow a reduct ion in steroid dosage in refractor y cases.82 Treatm en t for un respon sive cases in clude: m eth ot rexate, cytoxan , cycloph osph am ide, azath ioprin e, low dose XRT. CSF sh un tin g is in dicated if hydrocephalus develops. 10.9.11 Prognosis Usually a ben ign disease. Periph eral an d cran ial n er ve palsies recover slow ly. Re fe r e n ce s [8] Groves R, Moller J. Th e Value of th e Cerebral Cor tical Biop sy. Acta Neurol Scan d . 1966; 42:477–482 [1] Con sen su s Con feren ce. Di erential Diagn osis of Dem en t in g Diseases. JAMA. 1987; 258:3411–3416 [9] Forsyth PA, Posn er JB. Head ach es in Patien ts w ith Brain Tu m ors: A Study of 111 Patien ts. Neurology. [2] Flem in g KC, Adam s AC, Petersen RC. Dem en tia: Diagn osis an d Evaluation . Mayo Clin Proc. 1995; 1993; 43:1678–1683 70:1093–1107 [10] Welch KMA, Levin e SR. Migrain e-related st roke in [3] Lipow ski ZJ. Deleriu m (Acu te Con fu sion al States). th e con text of th e In tern ation al Head ach e Society JAMA. 1987; 258:1789–1792 Classification of h ead pain . Arch Neurol. 1990; 47:458–462 [4] Pom pei P, Forem an M, Ru d berg MA, et al. Deleriu m [11] Lan ce JW . Treatm ent of Migrain e. Lan cet. 1992; in Hosp italized Old er Person s: Ou tcom es an d Pre- 339:1207–1209 dictors. J Am Geriat r Soc. 1994; 42:809–815 [12] Kit trelle JP, Grouse DS, Seybold ME. Cluster Head- ach e: Local An esth etic Abor t ive Agen ts. Arch Neu - [5] Petersen RC. Acu te Con fusion al State: Don 't Mistake rol. 1985; 42:496–498 it for Dem en t ia. Postgrad Med . 1992; 92:141–148 [13] San ders M, Zuurm on d W W A. E cacy of Sph en op a- latin e Gan glion Blockad e in 66 Patien ts Su erin g [6] Hu lette CM, Earl NL, Crain BJ. Evaluation of Cerebral Biopsies for th e Diagn osis of Dem en tia. Arch Neurol. from Cluster Headach e: A 12- to 70-Mon th Follow - 1992; 49:28–31 Up Evalu ation . J Neurosurg. 1997; 87:876–880 [7] Javedan SP, Tam argo RJ. Diagn ostic Yield of Brain Biopsy in Neurodegen erative Disord ers. Neu rosu r- ger y. 1997; 41:823–830

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194 General and Neurology 11 Neurovascular Disorders and Neurot oxicology 11.1 Post erior reversible encephalopat hy syndrom e (PRES) 11.1.1 General inform at ion AKA reversible posterior leukoen ceph alopathy syn drom e (RPLS). A group of en ceph alopath ies w ith ch aracteristic pattern of w idespread vasogen ic brain edem a seen on CT or MRI w ith som e predom i- n an ce in th e parietal an d occipital region s.1 Th e m ost com m on PRES pat tern involves w atersh ed zon es w ith involvem en t of th e cortex, subcort ical an d deep w h ite m atter to a variable exten t.1 A sm all n um ber of pat ien ts w ith PRES w ill go on to in farct ion . Pat ien ts m ay presen t w ith h eadach e, seizures, m en tal status ch anges an d focal n eurologic deficit . In tracerebral h em orrh age (ICH) an d SAH m ay occur in up to 15%.1 11.1.2 Associat ed findings and condit ions In cludes: 1. hypertensive encephalopathy: com m only seen in the setting of subacute blood pressure eleva- tion s (as m ay occur w ith m align an t hyperten sion ). Im aging st udies sh ow sym m etric con fluen t lesions w ith m ild m ass e ect an d patchy en hancem ent prim arily in th e subcort ical w hite m atter of th e occipita l lobes2 w h ich m ay produce cort ical blin dn ess a) m oderate to severe hyper ten sion is seen in ≈ 75%of patien ts w ith PRES1 alth ough th e upper lim its of autoregulat ion are often n ot reach ed b) in addition to h em isph eric patterns of edem a isolated brain stem and cerebellar edem a h ave been described. Posterior fossa edem a h as been reported to cause obstruct ive hydroceph alus in a severe case3 2. preeclam psia/eclam psia associated w ith cerebral edem a.4 Th e con dition is often tem porar y, but 1 1 (perm an en t) in farction s also occur. Restricted di usion on MR im agin g is seen in 11–26%of cases. Abn orm al DW I areas on MRI m ay be associated w ith a w orse progn osis5 a) m ay presen t (e.g. w ith blin dn ess) durin g pregn an cy com plicated by preeclam psia or eclam psia6 b) m ay develop 4–9 days post-part um an d m ay be associated w ith vasospasm 7 even in patien ts n ot m eetin g clin ical criteria for th e diagn osis of eclam psia c) toxem ia is attributed to the placenta. Delivery and rem oval of the placenta is felt to be curative8 3. in fect ion , sepsis an d sh ock: blood pressure w as n orm al in 40%(edem a w as greater in th e n orm o- ten sive pat ien ts). Gram positive organ ism s predom in ate9 4. autoim m un e disease: PRES h as been described in patien ts w ith lupus, scleroderm a, Wegen er’s gran ulom atosis an d polyarteritis n odosa.1 Th ese patien ts often receive regim en s of im m un osup- pressive m edicat ion s (tacrolim us, cyclosporin e), w h ich h ave also been lin ked to cases of PRES 5. can cer ch em oth erapy: PRES occurs in patien ts receiving m ulti-drug h igh dose ch em oth erapy m ost com m on ly for h em atopoietic m align an cies 6. tran splan tation : PRES h as been reported both w ith bon e m arrow an d solid organ tran splan tat ion a) inciden ce: 3–16%w ith bon e m arrow transplantation depen ding on the preconditioning regi- m en and w h ether or n ot it is m yeloablative1 b) h igh est in ciden ce in th e first m on th follow in g allogen eic bon e m arrow tran splan t1 c) low er in ciden ce follow in g solid organ tran splan ts. Occurs earlier follow in g liver tran splan ta- t ion , usually w ith in 2 m on th s. Occurs later in ren al tran splan ts1 7. cyclosporine post-transplant neurotoxicity9 11.1.3 Treat m ent Disordered autoregulat ion m an dates tigh t con trol of blood pressure to reduce th e risk of ICH. Th e un derlying cause n eeds to be addressed (i.e. con trol HTN, h old im m un osuppressives or ch em oth era- peutics, deliver y of th e placen ta, etc.). 11.2 Crossed cerebellar diaschisis Hypom etabolism of cerebellar cortex con tralateral to a cerebral h em isph eric lesion (lesion s in clude: st roke, brain tum or…). Lesion s in th e m otor cortex, an terior coron a radiata, an d th alam us produce th e m ost m arked suppression of m etabolism . Th eor y: hypom etabolism is due to discon n ection of

Neurovascular Disorders and Neurotoxicology 195 cerebro-pon to-cerebellar path w ays → decreased oxygen an d glucose con sum ption → decreased CO2 product ion → local arterial con striction (dow n -regulat ion of cerebellar blood flow ). 11.3 Vasculit is and vasculopat hy 11.3.1 General inform at ion Th e vasculitides are a group of disorders ch aracterized by in flam m at ion an d n ecrosis of blood ves- sels. Vasculit is m ay be prim ar y or secon dary. Th ose th at m ay a ect th e CNS are listed in Table 11.1, all of th ese cause tissue isch em ia (even after th e in flam m ation is quiescen t) th at m ay ran ge in e ect from n europraxia to in farct ion . 11.3.2 Giant cell art erit is (GCA) Key concept s ● formerly often referred to as temporal arteritis ● a chronic vasculitis of large and medium caliber vessels, prim arily involving cranial branches of the arteries arising from the aortic arch ● age > 50 years; a ects women t wice as often as men ● important possible late complications: blindness, stroke, thoracic aortic aneurysms and aortic d isse ct io n s ● tem poral artery biopsy is recom mended for all patients suspected of GCA ● corticosteroids are the drug of choice for treatment AKA tem poral ar teritis (TA), AKA cran ial arteritis. A ch ron ic gran ulom atous arteritis of un kn ow n eti- 11 ology involving prim arily th e cran ial bran ch es of th e aort ic arch (especially th e extern al carotid artery (ECA)),11 w h ich if un treated, m ay lead to blin dn ess. Takayasu’s arterit is is sim ilar to GCA, but ten ds to a ect large arteries in young wom en; it has 2 ph ases: inflam m atory (treated w ith cort ico- steroids) an d sten otic (treated w ith ar terial bypasses). Epidem iology Seen alm ost exclusively in Caucasian s > 50 yrs age (m ean age of on set is 70). In ciden ce: 17.8 per 100,000 people ≥ 50 years old 12 (ran ge: 0.49–23). Prevalen ce: ≈ 223 (autopsy in ciden ce m ay be m uch Table 11.1 Vasculitides that may a ect the CNS10 Vasculit is Frequency of Type of CNS involvem ent a neuro involvem ent Acut e ence- Seizure Cranial Spinal ICH or phalopat hy nerve cord SAH periarteritis nodosab (PAN)C 20–40% ++ ++ + + + hypersensitivit y vasculitisb 10% + +0 0 + giant cell (temporal) arteritisb 10% + 0 ++ 0 0 Takayasu’s arteritis 10–36% + ++ ++ + + Wegener’s granulom atosisb 23–50% + ++ ++ + + lym phom atoid granulom atosisb 20–30% ++ + ++ + 0 isolated angiitis of the CNSb 100% ++ + ++ ++ + Behçet’s diseaseb 10–29% ++ + ++ + + aKEY: 0 = uncom mon or unreported; + = not uncomm on; + + = comm on; ICH = intracerebral hemorrhage; SAH = subarachnoid hemorrhage bsee section that follows for these topics cPAN: a group of disorders, frequencies may vary by subgroup

196 General and Neurology h igh er).13 More com m on in n orth ern latitudes an d am ong in dividuals of Scan din avian descen t sug- gesting a gen et ic an d environ m en tal causes.11 Fem ale:m ale ratio is ≈ 2:1 (reported ran ge: 1.05– 7.4:1). 50%of GCA patien ts also h ave polym yalgia rh eum atica (PMR) (p. 198). Pat hology Discon tinuous (so-called “skip lesions”) inflam m atory reaction of lym phocytes, plasm a cells, m acro- phages, ± giant cells (if absent, intim al proliferation m ay be prom inent); predom inantly in m edia of involved arteries. Arteries preferentially involved include the ophthalm ic and posterior ciliary bran ches an d the entire distribution of the external carotid system (of w hich the STA is a term inal branch). Oth- er arteries in the body m ay be involved (reported involvem ent of abdom inal aorta, fem oral, brachial an d m esenteric arteries are rarely sym ptom atic). Unlike PAN, GCA generally spares the renal arteries. Clin ica l Various com bin ation s of sym ptom s of gian t cell ar teritis are listed in Table 11.2. On set is usually in sidious, alth ough occasion ally it m ay be abru pt.14 Details of som e fin din gs: 1. H/A: th e m ost com m on presen ting sym ptom . May be n on specific or located in on e or both tem - poral areas, foreh ead, or occiput. May be superficial or burn in g w ith paroxysm al lan cin atin g pain 2. sym ptom s relatin g to ECA blood supply (strongly suggestive of GCA, but n ot path ogn om on ic16): jaw claudication, tongue, or pharyngeal m uscles 3. oph th alm ologic sym ptom s: due to arterit is an d occlusion of bran ch es of oph th alm ic artery or posterior ciliary arteries a) sym ptom s in clude: am aurosis fugax (precedes perm an en t visual loss in 44%), blin dn ess, visu- al field cuts, diplopia, ptosis, ocular pain , corn eal edem a, ch em osis b) blin dn ess: in ciden ce is ≈ 7%, an d on ce it occurs, recover y of sigh t is un likely 4. system ic sym ptom s a) n on specific con stitut ion al sym ptom s: fever (m ay presen t as FUO in 15%of cases), an orexia, 11 w eight loss, fatigue, m alaise b) 30%h ave n eurologic m an ifestation s. 14%are n europath ies in cludin g m on on europath ies and periph eral polyneuropath ies of th e arm s or legs17 c) m usculoskeletal symptom s ● PMR (p. 198) is th e m ost com m on (occurs in 40%of patien ts): ● periph eral arth rit is, sw ellin g & pitting edem a of h an ds & feet in 25% ● arm claudication from sten osis of subclavian an d axillar y arteries d) th oracic aortic an eur ysm s: 17 t im es as likely in GCA. An n ual CXRs are adequate for screen ing 5. tem poral arteries on physical exam ination m ay exh ibit tenderness, sw elling, er ythem a, reduced pulsation s, or n odularit y. Norm al in 33% 6. th e presen ce of system ic sym ptom s correlates w ith a lower in ciden ce of blin dn ess or stroke Di erent ial diagnosis 1. periarteritis n odosa (PAN) (p. 199) 2. hypersensitivit y vasculitis 3. ath erosclerot ic occlusive disease 4. m align an cy: sh ares system ic also h as sym ptom s of low grade fever, m alaise an d w eigh t loss 5. in fect ion 6. trigem in al n euralgia (p.479) 7. oph th alm oplegic m igrain e 8. dental problem s Table 11.2 Signs and sym ptom s of GCA15,11 Fre q u e n t Occa sio n a l Rare (> 50% of cases) (10–50% of cases) (< 10% of cases) H/A: 66% visual sym ptoms blindness temporal artery tenderness weight loss extrem it y claudication fever (low grade) tongue claudication proximal myalgias ear pain jaw claudication syn o vit is facial pain st ro ke scalp tenderness a n g in a

Neurovascular Disorders and Neurotoxicology 197 Evaluat ion 11 Laboratory studies 1. ESR > 40 m m /h r (usually > 50) by Westergren m eth od (if > 80 m m /h r w ith above clin ical syn - drom es, h igh ly suggestive of GCA). ESR is n orm al in up to 22.5%18 2. C-react ive protein : an other acute ph ase reactan t th at is m ore sen sitive th an ESR. Has th e advan t- age th at it can be perform ed on frozen sera 3. CBC: m ay sh ow m ild n orm och rom ic an em ia19 4. rh eum atoid factor, ANA, an d serum com plem en t usually n orm al 5. LFTs abn orm al in 30%(usually elevated alkalin e ph osph atase) 6. tests for rh eum atoid factor an d ANA are usually n egative 7. tem poral ar ter y an giography n ot h elpfu l (an giography elsew h ere in dicated if suspicion of large artery involvem ent exists) 8. CT: usually n ot h elpfu l, on e report described calcified areas correspon ding to th e tem poral a r t e r ie s20 9. tem poral artery biopsy: see below Tem poral artery biopsy Sen sitivity an d specificit y are sh ow n in Table 11.3. Indicat ions and t im ing Curren t recom m en dation s: tem poral artery biopsy in all patien ts suspected of h avin g GCA.11 May be con troversial. Argum en ts for: toxicit y of a lon g course of steroids in an elderly patien t, an d a h igh rate of false in itial respon ses of oth er illn esses to steroids. Argum en ts again st: sin ce a n egative biop - sy can n ot exclude th e diagn osis, cases w ith a n egative biopsy but a st ron g clin ical suspicion are often t reated as th ough th ey h ave GCA.22 In gen eral, h ow ever, biopsy is con sidered pruden t before em barking on a lon g course of h igh -dose steroid th erapy.16 Com plication s of biopsy are rare an d in clude bleedin g, in fect ion , an d on ly in th e sett in g of active vasculit is h as scalp n ecrosis been reported (not lin ked to biopsy). In gen eral, perform biopsy before startin g steroids if biopsy can be don e im m ediately.11 Oth er- w ise, start steroids to preserve vision an d perform biopsy usually w ith in 1 w eek (path ologic changes can be seen after m ore th an 2 w eeks of th erapy,23 th erefore do n ot w ith h old steroids to aw ait b io p sy). Technique of tem poral art ery biopsy Biopsy side of involvem en t if lateralit y exists. Th e yield is in creased by rem ovin g a port ion of arter y th at is involved clin ically (a ten der or in flam ed segm en t).24 Mark th e fron tal bran ch of th e STA w ith a skin m arker (spare th e m ain trun k an d parietal bran ch if possible). In filtrate local an esth etic. Th e in cision is m ade parallel to th e arter y an d if possible beh in d th e h airlin e. Th e in cision is taken dow n to th e fascia of th e tem poralis m uscle, to w h ich th e STA is superficial.25 Optim al len gth of STA biop - sy: 4–6 cm (if an abn orm al segm en t of STA can be palpated, som e say th at a sm aller biopsy to in clude th is area m ay be su cien t, but th is is probably un reliable as th e m uscle m ay be ten der, etc.). Step - sect ion in g by path ologist th rough th e en tire len gth of th e biopsy specim en also in creases th e yield. Frozen sect ion s can be perform ed. Biopsy of th e con tralateral side if th e first side is n egative in cases w h ere clin ical suspicion is h igh in creases th e yield on ly by 5–10%. Treat m ent No kn ow n cure. Steroids can produce sym ptom at ic relief an d usually preven t blin dn ess (progression of ocular problem s 24–48 h rs after in stitution of adequate steroids is rare). Totally blin d patien ts or those w ith longstandin g partial visual loss are unlikely to respond to any treatm ent. 1. for m ost cases: a) start w ith prednisone , 40–60 m g/d PO divided BID- QID (qod dosing is usually n ot e ect ive in in itial m an agem ent) b) if n o respon se after 72 h rs, an d diagn osis certain , ↑ to 10–25 m g QID Table 11.3 Temporal artery biopsy ≈ 90% (reported range15,21 is 9–97%) sensitivit y near 100% specificit y ≈ 94% predictive value

198 General and Neurology c) on ce respon se occurs (usually w ith in 3–7 days), give en tire dose as q AM dose for 3–6 w eeks un til sym ptom s resolved an d ESR n orm alizes (occurs in 87%of patien ts w ith in ≈ 4 w eeks) or stabilizes at < 40–50 m m /hr d) on ce quiescen t, a gradual taper is perform ed to preven t exacerbation s: reduce by 10 m g/d q 2–4 w eeks to 40 m g/d, th en by 5 m g/d q 2–4 w ks to 20 m g/d, th en by 2.5 m g/d q 2–4 w ks to 5–7.5 m g/d w h ich is m ain tain ed for several m on th s, follow ed by 1 m g/d decrem en ts q 1–3 m os (usual len gth of treatm en t is 6–24 m os; do not D/C steroids w h en ESR n orm alizes) e) if sym ptom s recur during treatm en t, predn isone dose is tem porarily increased until sym p- tom s resolve (isolated rise in ESR is n ot su cien t reason to in crease steroids11) f) patien ts sh ould be follow ed closely for ≈ 2 years 2. in severely ill patien ts: m ethylpredn isolon e, 15–20 m g IV QID 3. an ticoagulan t th erapy: con troversial 4. acute blin dn ess (on set w ith in 24–36 h rs) in a patien t w ith gian t cell arteritis: a) con sider up to 500 m g m ethylpredn isolon e IV over 30–60 m in s (n o con trolled studies sh ow reversal of blindness) b) som e have used interm itten t inhalation of 5%carbon dioxide and oxygen Out com e Com plication s of steroid th erapy occur in ≈ 50%of pat ien ts. Most are n ot life th reaten in g, an d in clude vertebral com pression fract ures in ≈ 36%, peptic ulcer disease in ≈ 12%, proxim al m yopathy, cata- ract s, exacerbation of diabetes; also see Possible deleterious side e ects of steroids (p. 146). 30–50% of patien ts w ill h ave spon tan eous exacerbation s of GCA (especially durin g th e first 2 years) regardless of th e cort icosteroid regim en .11 Sur vival parallels th at of th e gen eral population . On set of blin dn ess after in itiation of steroid th er- apy is rare. 11.3.3 Polym yalgia rheum at ica (PMR) 11 General inform at ion PMR an d gian t cell arterit is (GCA) (p.195) m ay be di eren t poin ts on a con tin uum of th e sam e dis- ease. Both h ave in in creased frequen cy of HLA-DR4 an d system ic m on ocyte activation . 15% of patien ts w ith PMR even tually develop GCA. Epidem iology See referen ce.11 Both GCA & PMR occur in people ≥ 50 years old. Th e in ciden ce in creases w ith age an d peaks betw een 70–80 years an d is h igh er at h igh er latitud es.11 PMR is m ore com m on th an GCA. Prevalen ce: 500/100,000).26 In ciden ce: 52.5 per 100,000 peo- ple ≥ age 50, h igh er in fem ales (61.7) th an m ales (39.9).27 Feat ures See referen ce.11 ● an in flam m ator y condition of unknow n etiology ● clinical ch aracteristics a) aching and m orning sti ness in the cer vical region an d shoulder & pelvic girdles lasting > 1 m on th . Th e pain usually in creases w ith m ovem en t ○ sh oulder pain : presen t in 70–95%of patien ts. Radiates tow ard elbow ○ h ip & n eck pain : 50–70%. Hip pain radiates tow ards kn ees b) age ≥ 50 years c) ESR ≥ 40 m m /h r (7–20%h ave n orm al ESR28) d) usually responds rapidly to low dose cort icosteroids (≤ 20 m g prednisone/day) see below e) system ic sym ptom s (presen t in ≈ 33%): fever, m alaise or fat igue, an orexia an d w eigh t loss ● favorable progn osis: usually rem its in 1–3 years Treat m ent PMR responds to either to low doses of steroids26 (10–20 m g prednisone/day) or som etim es to NSAIDs (respon se to steroids is m uch m ore rapid). Th e in itial dose of steroids is m ain tain ed for 2–4 w eeks, an d th en by ≤ 10%of th e daily dose ever y 1–2 w eeks11 w h ile obser vin g for sign s of GCA.