18010ournal ofNeurology, Neurosurgery, and Psychiatry 1995;58:180-183 Progressive spinocerebellar degeneration "plus" associated with Langerhans cell : a new paraneoplastic syndrome?

H Goldberg-Stem, R Weitz, R Zaizov, M Gomish, N Gadoth

Abstract enabling the study of long term sequelae of Langerhans cell histiocytosis (LCH), LCH. formerly known as histiocytosis-X, mani- Ranson et al5 reported that about half of his fests by granulomatous lesions consisting patients with generalised LCH had "neu- of mixed histiocytic and eosinophilic ropsychiatric disability", and the Southwest cells. The hallmark of LCH invasion into Oncology Group reported on 17 out of 56 the CNS is , reflecting long term survivors who had a variety of neu- local infiltration of Langerhans cells into rological disabilities including cerebellar the posterior pituitary or hypothalumus. ataxia in two of them; details of neurological In five patients who had early onset state or neuroimaging studies were not LCH with no evidence of direct invasion noted.6 into the CNS, slowly progressive spino- The present report describes five patients cerebellar degeneration accompanied in who had extraneural LCH, in whom progres- some by pseudobulbar palsy and sive spinocerebellar syndrome appeared sev- intellectual decline was seen. Neuro- eral years after the initial diagnosis. logical impairment started 2-5 to seven In all cases the family history was negative years after the detection of LCH. No cor- and the initial neurological examination, CSF relation was found between the clinical content, and brain imaging at the time of syndrome and location of LCH or its LCH detection were normal. Diabetes mode of treatment. insipidus was looked for but never found, nei- An extensive search for metabolic, ther initially nor during the long term follow toxic, neoplastic, and hereditary aetiolo- up. A meticulous search for known causes of gies for progressive cerebellar degenera- progressive spinocerebellar impairment of tion was negative. It seems that the young onset was negative in all cases. clinical entity described here may be con- sidered a new paraneoplastic syndrome related to LCH. It may be induced by the Case reports eosinophil derived neurotoxin, which was PATIENT NO 1 shown to cause damage to Purkinje cells In a previously healthy child, LCH, in the and pyramidal neurons. form of of the left mastoid, was excised at the age of 18 months. ( Neurol Neurosurg Psychiatry 1995;58:180-183) There were no symptoms or signs of invasion of the CNS. After operation he was irradiated The Felsenstein locally and subsequently developed postradia- Research Center, Keywords: Langerhans cell histiocytosis; central tion necrosis of the left side of his face and Beilinson Medical nervous system; cerebellum. stemocleidomastoid muscle resulting in fixed Center, Petah Tiqva, left torticollis and left nerve deafness. His and Sackler Faculty of , Tel Aviv It is almost 40 years since Lichtenstein' linked condition remained stable until the age of 4 University, Tel Aviv, eosinophilic granuloma of bone, Letterer- years, when gradual gait instability appeared. Israel Siwe and Hand-Schuller Christian Subsequently, progressive dysarthria devel- Department of disease, Neurology syndrome under the term "histiocytosis-X". It oped. Severe motor dysfunction confined him H Goldberg-Stem seems that the presently used term to a wheelchair at the age of 30 years. N Gadoth Langerhans cell histiocytosis (LCH) is more Recurrent grand mal seizures occurred at the Department of appropriate as the pathological proliferation of age of 37 years and have been successfully Pediatric Neurology At the last clinic R Weitz Langerhans cells, with the typical Birkbeck controlled with phenytoin. is the uniform microscopic finding visit after 36 years of continuous follow up, Department of granules, Pediatric Hematology for all forms of histiocytosis-X.2 3 the cardinal neurological abnormalities - Oncolocy Complications of the CNS as a result of included emotional lability with uncontrolled R Zaizov LCH, manifested mainly by diabetes crying, severe dysarthria, gaze directed hori- Department of insipidus or cerebellar dysfunction, are tradi- zontal nystagmus, abnormal ocular smooth Radiology M Gornish tionally believed to result from (a) CNS pursuit, slow saccades, generalised hypotonia, extension from bones; (b) dural symmetric hyperreflexia, mild ankle clonus, Correspondence to: neighbouring Dr Goldberg-Stern, and leptomeningeal spread; (c) primary intra- bilateral extensor plantar response, severe dis- Department of Neurology, side effects of and limb and Beilinson Medical Center, parenchymatous lesions; (d) equilibrium ataxia, prominent Petah Tiqva, 49100, Israel. chemotherapy and radiotherapy; (e) a combi- dysmetria. Received 2 February 1994 nation of these.4 and in revised form recent and PATIENT NO 2 17 June 1994. In years, improved diagnosis Accepted 10 August 1994 treatment has resulted in prolonged survival, A girl was healthy until 3 months of age when Progressive spinocerebellar degeneration "plus" associated with Langerhans cell histiocytosis 181

Patient No 3, a 27year and gaze directed horizontal nystagmus were old man. (A) Tl weighted (TRITE 440127) sagittal; found. Progressive intellectual deterioration, and (B) coronal (TRITE confirmed by appropriate psychometric tests, 350112) 05 TMR resulted in his transfer to a special education images. Note pronounced institution. His latest neurological evaluation atrophy ofvermis, cerebellar hemispheres, and was performed at the age of 27. At that time pons with mildly prominent an examination of eye movement showed cerebral sulcifor age. abnormal pursuit with sluggish saccades, inability to maintain lateral gaze, rebound nystagmus, and lack of optokinetic nystag- mus. Brisk deep tendon reflexes with muscle hypotonia in the upper limbs and severe spas- tic weakness with hyperreflexia in the lower limbs, bilateral ankle clonus, and extensor plantar responses were also present; severe ataxia, dysmetria, cognitive deterioration, and frequent outbursts of uncontrolled laughter were also noted.

PATIENT NO 4 A right handed man had a normal neonatal and early childhood history. A routine exami- nation before army enlistment showed an osteolytic lesion in the right 9th rib. This was excised and proved to be LCH, eosinophilic granuloma type. Afterwards he completed an uneventful army service. At the age of 21 he noticed gradual onset of disequilibrium with intentional tremor. Neurological examination showed a nasal voice, dysarthria, muscle hypotonia, brisk deep tendon reflexes, bilat- eral extensor plantar response, and bilateral ankle clonus. The finger to nose, heel-knee- shin, and Romberg tests were greatly impaired. His condition continued to deterio- rate very slowly and at the present time he can walk only with canes.

PATIENT NO 5 erythematous seborrheic skin rash and puru- A 19 year old woman was healthy until the lent otitis were noted. An osteolytic lesion of age of 2 years when she had a mild head the left mastoid was seen on skull radi- trauma and was found to have a soft swelling at ographs. Skin biopsy disclosed typical LCH. the right side of her scalp. Skull radiographs The neurodevelopmental state, routine labo- and a radiological skeletal survey disclosed ratory tests, spinal fluid, skeletal radiological multiple lytic bone lesions (biparietal, right survey, and cerebral CT were normal. The proximal femur, and right iliac bone). The family history was negative. She was treated diagnosis of LCH, eosinophilic granuloma with sulphate, cyclosphos- type was confirmed histologically. No treat- phamide, and prednisone divided into 17 sin- ment was offered, and she led a normal life gle doses during the first year of life. At the until the age of 9 when progressive ataxia with age of 3 years and 10 months she started drag- frequent falls was first noted. During the sub- ging her right leg. A year later she was seen for sequent years mental deterioration, severe dis- frequent falls. During the subsequent months, equilibrium and limb ataxia, dysarthria, mental deterioration, severe progressive abnormally brisk deep tendon reflexes, ankle ataxia, limb dysmetria, muscle hypotonia, clonus, and bilateral extensor plantar brisk deep tendon reflexes, and bilateral response were noted. During the 10 years of extensor plantar response were noted. follow up, slow deterioration with no evidence of relapse of disease was documented. PATIENT NO 3 A boy was healthy until 2 years of age when a ANCILLARY TESTS painful swelling was noted below his right In all five cases routine laboratory tests, auricle. Skull radiographs disclosed a round including a screen for metabolic errors of osteolytic lesion of the right mastoid, which childhood, heavy metal storage, CSF composi- was excised and found to be LCH, tion, EEG, nerve conduction studies, and eosinophilic granuloma type. He received a EMG were normal. In all cases brain CT dis- total dose of 750 rads to the affected area and closed mild to moderate cerebellar and pon- was well until the age of 4 years and 8 months tine atrophy, symmetric dilatation of the when unsteadiness and a wide based gait were ventricular system, and mild cerebral cortical noted. Six months later, pronounced ataxia atrophy. Similar findings were obtained in 182 Goldberg-Stern, Weitz, Zaizov, Gornish, Gadoth

patients 1-4 by MRI. Neither masses, nor EMG, and nerve conduction studies together hyperintense signals on T2 weighted images with the negative family history helped in were detected. No gadolinium enhanced excluding the hereditary progressive cerebellar images were obtained. During the long follow atrophies of young age. up, additional CT and MRI were almost iden- Diabetes insipidus and other endocrine tical to the initial studies in case 1. In patients abnormalities resulting from hypothalamic or 2-4, slow progression of imaging abnormali- pituitary invasion of tumour cells are the most ties was evident. The most striking changes common neurological manifestations of were seen in patient No 2. Initial studies were LCH.48 Among the extradiencephalic sites of almost normal, but the typical radiological this disease, the cerebellum seems to be the picture evolved during the next five to six most vulnerable.4 Recently, a diffuse infiltra- years. tion of the CNS by Langerhans cells was The serum samples and CSF of patients reported.9 Nos 1, 3, and 4 did not contain antibodies to Grois et al summarised 72 cases with LCH Purkinje cells. and CNS complications reported since 1924.'° In 72% those symptoms started a few years after the onset of LCH. The most fre- Discussion quent presentation was spinocerebellar In 1985 we first reported four cases with late impairment, as in our cases. In all patients neurological deterioration associated with there was evidence of invasion of the CNS LCH with no evidence of disease invasion manifested by diabetes insipidus or intra- into the nervous system.7 In the present report parencyhmatous infiltration into the cere- we have completed a follow up period ranging brum, cerebellum, etc, detected by from 10 to 36 years and have added an addi- neuroimaging or necropsy. l 14 tional patient. Our cases are unique in that they lacked Of the five patients described, four had the evidence of cranial or brain parenchymatous localised form of LCH, eosinophilic granu- spread at the time of initial diagnosis or dur- loma type and one had the diffuse type with ing the long term follow up. Rosenfeld et al mastoid lesions and skin involvement. The described the neuroimaging features of eight diagnosis in each case was confirmed histolog- patients with LCH who had neurological ically. The bony lesions were excised in four manifestations. Their case No 4 showed clini- patients (with addition of local irradiation in cal and radiological signs of progressive cere- two). Patient No 2, with the generalised form bellar degeneration without evidence of of the disease, was the only one who received invasion of the CNS.'5 We believe that this chemotherapy. All patients developed signs of case resembles our patients. Kepes4 stated progressive spinocerebellar impairment 2-5 to that a possible mechanism for neurological seven years after the initial diagnosis. dysfunction without direct spread of Neurological findings consisted of severe Histiocytosis-X into the CNS may be sec- cerebellar ataxia, brisk deep tendon reflexes, ondary demyelination. The absence of hyper- and bilateral extensor plantar responses. In intense signals on the T2 weighted MRI in three patients intellectual deterioration and in our patients, however, excludes this assump- two pseudobulbar signs subsequently tion. As patients with skull lesions have occa- appeared (table). The neuroradiological find- sionally received radiotherapy, the possibility ings in all cases were similar and showed cere- that cerebellar degeneration is a delayed effect bellar and pontine atrophy with no signs of of radiation was considered.'0 The presence of demyelination on MRI and no evidence of clinical and radiological cerebellar degenera- disease invasion. tion in cases that were never irradiated An extensive search for hereditary, meta- exclude this possibility. bolic, neoplastic, immunological, and toxic Considering that progressive spinocerebel- aetiologies was negative. No correlation was lar dysfunction in our patients could not be found between the clinical syndrome and the attributed to currently known aetiologies and location of the lesion or its mode of treatment. that it is not caused by tumour invasion, the The normal CSF protein, metabolic screen, possibility that a remote effect of LCH caused

Clinical manifestations ofpatients Age at Age at onset of LCH neurological Duration of Patient diagnosis Location of impairment neurological Neurological No Sex (y) granulomas Treatment (y) disease signs 1 M 18/12 Left mastoid Excision and local 4 36 SCD irradiation Seizures PBP 2 F 3/12 Skin, left mastoid Chemotherapy 3 10/12 10 SCD MD 3 M 2 Right mastoid Excision and local 4 8/12 22 SCD irradiation MD PBP 4 M 18 Right 9th rib Excision 21 20 SCD PBP 5 F 2 Biparietal Excision of 9 10 SCD Right proximal femur skull lesion MD Right iliac bone SCD = Spinocerebellar degeneration; MD = mental deterioration; PBP = pseudobulbar palsy. Progressive spinocerebellar degeneration "plus" associated with Langerhans cell histiocytosis 183

the late neurological impairment should be bellar degeneration may be considered a entertained. remote effect on the nervous system, by a The lesions of LCH consist of mixed histio- mechanism as yet unknown. cytic and eosinophilic infiltrates with varying multinucleated giant cells. It has been sug- gested that LCH may represent an uncon- 1 Lichtenstein L. Histiocytosis X. Integration of eosinophilic granuloma of bone, "Letterer-Siwe disease" and trolled immunological reaction to an "Schuller-Christian syndrome" as related manifestations unknown antigen. 16 In 1932, Gordon of a single nosologic entity. Arch Pathol 1953;56:84-102. 2 Broadbent V, Gadner H, Komp DM, Ladisch S. reported that injecting rabbits intracerebrally Histiocytosis syndromes in children. II: Approach to the with suspension obtained from clinical and laboratory evaluation of children with Langerhans cell histiocytosis. Med Pediatr Oncol 1989; patients with Hodgkin's disease caused ataxia 17:492-5. and muscle paralysis after two to 20 days. The 3 Yarbro JW. The histiocytic syndromes. Semin Oncol 1991; 18:1. histopathological findings consisted mainly of 4 Kepes JJ. Histiocytosis-X. In: Vinken JH, Bruyn GW, eds. damage to Purkinje cells, with a lesser hip- Handbook of clinical neurology. Vol 38, Part 1, Amsterdam: Elsevier, 1979:93-117. pocampal and pyramidal neuronal involve- 5 Ranson U, Powazek M, GoffJR, et al. Neuropsychological ment. 17 late sequelae of histiocytosis-X [abstract]. Pediatr Res 1978;12:472. Further information on the potential tissue 6 Komp DM, El Mahdi A, Starling KA, et al. Quality of sur- damaging effects of eosinophils has emerged vival in histiocytosis-X: a Southwest Oncology Group study. Med Pediatr Oncol 1980;8:35-40. from precise delineation of the unique intra- 7 Gadoth N, Weitz R, Zaizov R, Vogel R, Bechar M. Long cytoplasmic content of the eosinophilic gran- term neurological sequelae of localized eosinophilic granuloma [abstract]. J Neurol 1 985;232(suppl 1):21. ules. 8 Beard W, Foster DB, Kepes JJ, Guillan RA. It was shown that intracerebral injection of Xanthomatosis of the central nervous system. Clinical and pathological observations of a case with a posterior eosinophil derived neurotoxin, a glycosylated fossa syndrome. Neurology 1970;20:305-14. protein with ribonuclease like activity can 9 Hasegawa K, Mitomi T, Kowa TP, Mootoori T, Yagisita S. A clinico-pathological study of adult histiocytosis-x cause ataxia and limb paralysis in experimental involving the brain. J Neurol Neurosurg Psychiatry animals probably by inactivation of protein 1993;56: 1008-12. 10 Grois N, Barkovich J, Rosenau W, Ablin AR. Central ner- synthesis.'8 Necropsy studies show that the vous system disease associated with Langerhans' cell his- neurotoxin damages mainly Purkinje cells, tiocytosis. Am J Pediatr Hematol Oncol 1993;15:245-54. 11 Braunstein GD, Whitaker JN, Kohler PO. Cerebellar dys- pyramidal neurons, and myelin. function in Hand-Schuller-Christian disease. Arch Intern The fact that the median time of onset of Med 1973;132:387-90. 12 Adornato BT, Eil C, Head GL, Loridux LD. Cerebellar neurological findings after the detection of involvement in multifocal eosinophilic granuloma: LCH in our patients was 3-5 (range 2 5-7) demonstration by computerized tomography scanning. Ann Neurol 1980;7:125-9. years is compatible with the concept of para- 13 Amirdjazil Z, Serban-Aurel E, Konard K. Histiocytosis-X in neoplastic syndromes according to Posner,'9 an adult with skin and uncommon central nervous sys- tem involvement. Dermatologica 1977;155:283-91. who stated that a remote effect of cancer 14 Burn DJ, Waston JDG, Roddie M, Chu AC, Legg NJ, implies any nervous system dysfunction that is Frackowiak RSJ. Langerhan's cell histiocytosis and the nervous system. J Neurol 1992;239:345-50. not caused by direct invasion or metastases. 15 Rosenfield J, Komp AJ. Brain MRI in patients with There is no limitation of time between the Langerhans cell histiocytosis: findings and enhancement with Gd-DTPA. Pediatr Radiol 1990;20:433-6. appearance of the neurological deficit and the 16 Ladisch S, Jaffe ES. The histiocytoses. In: Pizzo PA, neoplastic process or vice versa. Although no Poplack DG, eds. Principles and practice of pediatric Oncology, 2nd ed. Philadelphia: Lippincot, 1993: antibodies against Purkinje cells or other neu- 491-505. ronal elements were found in our cases and 17 Fredens K, Dahl R, Venge P. The Gordon phenomenon induced by the eosinophil cationic protein and others'0 the possibility that the damage is eosinophil protein X. 7 Allergy Clin Immunol 1982;70: mediated by an autoimmune mechanism was 361-6. 18 Durack DT, Sumi SM, Klebanoff JS. Neurotoxicity of not excluded. human eosinophils. 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