Paraneoplastic cerebellar degeneration. Summary. A clinical and CTstudy. Case 1

Transcription

1 J urnal f Neur-Onclgy 2: (1984) Martinus Nijhff Publishers, Bstn. Printed in the Netherlands. Paraneplastic cerebellar degeneratin A clinical and CTstudy Harry S Greenberg Department f Neurlgy, University f Michigan Medical Schl, USA Keywrds: paraneplastic cerebellar degeneratin, CT scanning Summary Six patients develped a pancerebellar syndrme with symptms preceding the diagnsis f neplasia in five (median 4 mnths) and fllwing in ne (2 years). In all patients, the initial cranial cmputed tmgraphic (CT) scans were nrmal. Five patients had repeat CTs and f these three were abnrmal; cerebellar atrphy appearing 7 t 25 mnths fllwing the initial CT. Median fllw-up was 31 mnths (range mnths) withut evidence f CNS metastatic disease. In five f six patients the neurlgic impairment did nt prgress. One patient's neurlgic signs imprved markedly with mantle radiatin therapy f her Hdgkin's disease. An initially negative CT des nt preclude the diagnsis f remte effect cerebellar atrphy. Paraneplastic cerebellar degeneratin is a self-limited nnprgressive prcess in the majrity f patients. Intrductin Neurlgic dysfunctin in patients suffering frm cancer can be caused by either metastases f the primary tumr t the nervus system r thrugh nn-metastatic tumr effects n the nervus system. Neurlgic remte effects f cancer are disrders, cause unknwn, ccurring with greater frequency in patients with cancer. The remte effect cerebellar syndrme is a rare entity where symptms ften precede the diagnsis f malignancy. In adults with an unexplained cerebellar syndrme a careful search fr primary malignancy with gd fllw-up is necessary. Presented in part at the 35th Annual Meeting f the American Academy f Neurlgy, San Dieg, CA, April 28 30, Methds This reprt reviews six cases f remte effect cerebellar degeneratin diagnsed during a fiveyear perid at fur institutins. A seventh case was excluded because the histry and clinical findings supprted a diagnsis f alchlic cerebellar degeneratin. The sixth case was published previusly and is included with permissin f the authrs (1). Tw representative cases are reprted. Case 1 A 57-year-ld female had the nset f diplpia and blurry visin n June 6, Nine days later, slurred speech ccurred and was fllwed by vertig, nausea, and vmiting. Nystagmus was bserved n exam and initial wrk-up including skull X-rays and CT was negative. In August 1979 she was examined at an utside hspital, fund t have a Address fr reprints: Harry S Greenberg, MD, Department f Neurlgy, B4913 CFOB, Bx M056, The University f Michigan Hspitals, Ann Arbr, MI 48109, USA

2 378 'stiff-legged', ataxic gait and rtary nystagmus n hrizntal gaze bilaterally. There was vertical nystagmus in the directin f gaze. Deep tendn reflexes were brisk with a 2+ jaw jerk and flexr plantar respnses. CT with psterir fssa views (Fig. 1 tp) was negative. SMA 12, CBC, TSH, T4, ESR, ANA, rheumatid factr and CPK were negative. In Octber 1979 she was admitted t anther hspital with incmplete partial bwel bstructin and an explratry lapartmy and left salpingphrectmy shwed a prly differentiated varian serus adencarcinma. In December 1979 she underwent right salping-phrectmy, hysterectmy, and mentectmy. Fllwing peratin, cerebellar symptms were wrse. She was begun n alkeran 4 mg rally three times a day fr five days mnthly in March Between January 1980 and August 1981 n change was nted in crdinatin, speech r strength. In August 1981 general physical exam revealed a mderately bese female and was therwise unremarkable. Cranial nerve exam shwed hrizntal and vertical nystagmus in the directin f gaze. Gait was ataxic, requiring assistance with supprt t bear weight. Fig, 1. (Tp): Nrmal CT at nset f illness. (Bttm): Tw years later with patient stabilizatin CT shws marked lateral cerebellar hemisphere and vermian atrphy. Finger-nse-finger and heel-knee-shin testing shwed symmetric dysmetria. Tne was increased in all fur extremities with nrmal strength. Reflexes were unchanged frm the initial examinatin. Sensry exam was nrmal. Labratry data: Hgb 12.4, Hct36.8, WBCS,100, PLT440,000, TP 8.7, albumin 3.7, alkaline phsphatase 143, with the rest f the SMA nrmal. B12 and flate were nrmal. Repeat CT f the psterir fssa shwed marked cerebellar atrphy (Fig. 1 bttm). Abdminal CT shwed massive periartic tumr. Adriamycin and cisplatinum chemtherapy were begun. The patient was alive n August 1, 1982 withut change in her neurlgic deficit frm March Case 2 A 20-year-ld healthy rthdx seminary student develped headache, neck pain, drwsiness and vertig accmpanied by shaking chills, diaphresis, nausea, vmiting and a temperature t 102 F. She was admitted t an utside hspital and cervical lymph nde hyperplasia was nted. On neurlgic exam she was fund t have a labile affect and generalized ataxia. A cervical lymph nde bipsy and lumbar puncture were perfrmed and she was transferred t the University f Michigan Hspital n September 8, Lumbar puncture prtein was 56, glucse 53, 2 RBC, 2 WBC (100% lymphcytes), negative cultures and cytlgy. On admissin her bld pressure was 120/80, pulse 80, respiratin 16, and temperature 98.6 F. Her general physical exam was nrmal except fr a surgical scar in the right anterir neck regin and guarding in the left upper quadrant f the abdmen n deep palpatin. On mental status exam she was riented and had slurred speech. Her affect was impulsive, childlike and inapprpriate. She denied gait difficulty. She remembered 3 ut f 3 bjects at five minutes and ne hur. Serial sevens were perfrmed well and prverb interpretatin was abstract. Cranial nerves were nrmal except fr gaze induced hrizntal nystagmus. Her supprted gait was wide-based and ataxie. Severe dysmetria and dystaxia was present in all fur extremities. Her strength was nrmal. Reflexes were 2+ bilaterally with flexr plantar respnses. Sensry exam was nrmal.

3 379 Initial labratry data: Hct 38.6, Hgb 11.9, platelet 621,000, WBC 24,000 with a differential f 62% segs, 27% bands, 1% myelcytes, 9% lymphcytes and 1% esinphils. Chemistries were: sdium 141, ptassium 4.3, chlride 98, CO2 23, BUN 14, creatinine 0.8, glucse 101, calcium 10.3, phsphrus 4.2, prtein 8.5, albumin 4.0, ttal bilirubin 0.3, SGOT 35, SGPT 39, LDH 770, alkaline phsphatase 74, and magnesium 2.0. Chest X-ray shwed mderate sclisis and right hilar mass. Lymph nde bipsy was reprted as ndular sclersing Hdgkin's disease. EEG n September 11, 1980 shwed diffuse slwing f the backgrund t 7 1/2 Hz. N labratry tests were btained between September 12-16, 1980 because f religius reasns. CT with and withut cntrast n September 17, 1980 was nrmal (Fig. 2A). Repeat lumbar puncture revealed a prtein f 36, glucse 52, 13 RBC, 13 WBC (98% lymphcytes and 2% histi- Fig. 2. (A) CT shws nrmal cerebellum and furth ventricle when patient has maximal neurlgic deficit. (B) Nine mnths later CT shws marked enlargement f furth ventricle at time when patient dramatically clinically imprved. cytes). The IgG/albumin rati was 21% with negative VDRL, cultures and cytlgy. There were n ligclnal bands. Visual and brainstem auditry evked respnses were nrmal. Bne marrw bipsy and abdminal CT were nrmal. Gallium scan shwed increased uptake in the right supraclavicular regin, liver and spleen. Staging lapartmy n September 29, 1980 was negative fr disease in the abdmen. The patient was treated with mantle raditherapy. Her mental status prgressively became nrmal during hspitalizatin. Eight mnths fllwing discharge her nly neurlgic abnrmality was a minimally wide-based stance and mild finger-nse-finger and heel-knee-shin dysmetria bilaterally. There was n evidence f active Hdgkin's disease. CT n June 15, 1981 shwed marked enlargement f the furth ventricle (Fig. 2B). Results Six cases f remte effect cerebellar degeneratin are reprted. In five f the six cases (83%) the cerebellar symptms preceded the diagnsis f neplasia by a median f fur mnths (range 0 56 mnths). Gait difficulty was the initial symptm in fur, diplpia and vertig in ne each (Table 1). At neurlgic exam at the time f diagnsis all six were dysarthric with gait ataxia and limb dysmetria. Fur patients had hrizntal nystagmus and tw f these vertical nystagmus. Seven primary tumrs were diagnsed in six patients. Tw patients had ndular sclersing Hgdkin's disease, and ne patient each had acute myelmncytic leukemia, varian carcinma, lung carcinma, with the sixth having bth cln and uterine carcinma. The fur patients with Hdgkin's disease r gyneclgic malignancy had pure cerebellar syndrmes except fr a transiently inapprpriate affect in ne (Table 1). In additin t their cerebellar syndrme, tw patients had neurpathy, ne with myasthenic syndrme and the ther with bilateral extensr plantar respnses. These tw patients had an increased cerebrspinal fluid prtein (Table 1). In all six patients the initial CTs were nrmal. Repeat CTs were btained in five patients and were abnrmal in three shwing cerebellar atrphy, 7 t 25 mnths after the initial CT. Clinical fllw-up was btained in all six patients fr a median f 31 mnths. Fur patients are alive

4 380 =~ < 2 2,= ~ E z Z Z Z Z e~ 0 8 Z,~- i e~ e- cq ~ ~.g "-d ~~ ~ ~ ~ ~ ~ ~'I = c~.= z < < < < <..= e~ -.~ ~ ~ ~ ~ -s "~ ~ "= ~ ~ ~,~.,~ 2 E N

5 381 at a median f 30 mnths (range mnths fllwing diagnsis). N patient has develped evidence f CNS psterir fssa metastatic disease. One patient imprved markedly fllwing mantle radiatin therapy and is nw ambulatry with a minimally wide-based stance and nly mild appendicular ataxia (Case 2). Fur patients' neurlgic impairment stabilized withut further prgressin and ne prgressed slwly. Discussin The six patients reprted here and the previus 60 cases in the literature describe a unique pancerebellar syndrme (1 12). The illness is characterized by the subacute nset f prgressive, painless gait ataxia, dysmetria f the limbs, and dysarthria. In 83% f ur cases the cerebellar symptms and signs preceded the diagnsis f malignancy, which is slightly higher than the 63% reprted in the literature by Brain et al. (2). In Hensn and Urich's (3) experience apprximately ne-half f patients with late nset nn-familial, crtical cerebellar degeneratin will eventually develp a malignancy. Nne f ur patients had antecedent cyttxic chemtherapy r radiatin directed t r verlapping the neuraxis (Table 1). The etilgy f paraneplastic cerebellar degeneratin is unknwn but in five patients, three secndary t varian carcinma and ne each secndary t Hdgkin's disease and breast carcinma, circulating anti-purkinje cell antibdies have been fund, suggesting an immune-mediated disrder (9, 10, 1 l, 12). The antibdy was an immunglbulin G with cytplasmic flurescent clumping t Purkinje cell cytplasm withut clumping t ther neuraxis sites r rat cerebellum (11). Nne f the patients with anti-purkinje cell antibdies have had pathlgic cnfirmatin f diagnsis. One antibdy psitive and three antibdy negative patients did nt respnd t plasmapheresis (1 l). All patients had grss cerebellar abnrmalities n initial exam (invlving bth the upper and lwer limbs), althugh all CTs were initially nrmal. In the series f Brain et al. (2) 18 f 19 patients had upper and lwer extremity cerebellar abnrmalities. On repeat CT three f five cases develped abnrmalities 7 t 25 mnths fllwing initial CT with cerebellar atrphy and enlargement f the furth ventricle. Hensn and Urich (3) divided 43 pathlgically prven cases int a pure crtical cerebellar degeneratin [24] r with an inflammatry cmpnent in the meninges and perivascularly in the cerebellum [19]. In bth types there is usually a severe r ttal lss f Purkinje cells. The granule cell layer may be invlved but less than Purkinje cell layer, while the mlecular layer is spared (2, 3). Degeneratin f the lng tracts f the spinal crd has been seen and may explain the extensr plantar respnses in ne patient (2). The delayed cerebellar atrphy seen n CT is cnsistent with autpsy pathlgy. Prlnged fllw-up in ur six cases revealed that in five f the six patients this was a nn-prgressive syndrme. In fur patients neurlgic impairment stabilized and nly ne prgressed during the curse f their malignancy. One patient imprved markedly after mantle radiatin therapy f her Hdgkin's disease. Furth ventricular enlargement appeared n her CT after dramatic clinical imprvement. Three reprts in the medical literature dcument significant imprvement in the cerebellar dysfunctin, ne withut treatment and tw fllwing treatment. In the first patient with cln carcinma gait and appendicular ataxia remitted ne mnth after nset befre any treatment was given, while in the secnd imprvement fllwed pneumnectmy fr brnchgenic carcinma (5, 6). In the secnd case the remissin f symptms began immediately after surgery and by seven days the patient was able t ambulate with a cane. At eleven mnths there was n signs f cerebellar disease (5). In the third patient with brnchgenic carcinma and remte effect sensry plyneurpathy, cerebellar syndrme, and lng tract signs, there was imprvement frm pr antigravity functin being unable t keep his shin n the ppsite heel t walking with a walker fllwing 4 1/2mnths f therapy (7). Jaeckle et al. (11) fund that the antibdy psitive patients (2/6) had a steady prgressin f neurlgic dysfunctin whereas antibdy negative patients had intervening perids f remissin. Hwever, f three antibdy psitive patients reprted by Trtter (9) and Greenlee (12) nly ne had prgressive disease ver ne year, the ther tw were stable. Althugh the paraneplastic cerebellar syndrme caused majr neurlgic disability it was a self-limited nn-prgressive prcess in the majrity f ur patients. An

6 382 initially negative CT scan des nt preclude the diagnsis f remte effect cerebellar degeneratin. References 1. Zweifel T J, Albers JW: Multiple neurlgic paraneplastic syndrmes. Reprt f a case. Arch Neur137: , Brain L, Wilkinsn M: Subacute cerebellar degeneratin assciated with neplasms. Brain 88: , Hensn RA, Urich H: Crtical cerebellar degeneratin. In: Cancer and the nervus system. Blackwell Scientific Publicatins, Oxfrd, England, 1982, pp Brazis PW, Biller J, Fine M, Palacis E, Pagan R J: Cerebellar degeneratin with Hdgkin's disease. Cmputed tmgraphic crrelatin and literature review. Arch Neurl 38: , Pane JF, Jeyasingham K: Remissin f cerebellar dysfunctin after pneumnectmy fr brnchgenic carcinma. New Eng J Med 302(3):156, Auth TL, Chd HP: Transient cerebellar syndrme frm extracerebral carcinma. Neurlgy 7: , Rberts HJV: A case f spincerebellar degeneratin assciated with carcinma f the prstate. Med J Austral 1: , Rewcastle NB: Subacute cerebellar degeneratin with Hdgkin's disease. Arch Neurl 9: , Trtter JL, Hendin BA, Osterland CK: Cerebellar degeneratin with Hdgkin's disease. An immunlgical study. Arch Neurl 33: , Greenlee JE: Is paraneplastic cerebellar degeneratin an immune-mediated cnditin? Detectin f circulating antibdies t Purkinje cells in a patient with the disrder. Ann Neurl 12:103, Jaeckle KA, Hughtn AN, Nielsen SL, Psner JB: Demnstratin f serum anti-purkinje antibdy in paraneplastic cerebellar degeneratin and preliminary antigenic determinatin. Ann Neurl 14:111, Greenlee JE, Brashear HR: Antibdies t cerebellar Purkinje cells in patients with paraneplastic cerebellar degeneratin and varian carcinma. Ann Neur114: , 1983.