Chorea Resulting from Paraneoplastic Striatal Encephalitis

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J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.4.512 on 1 October 2000. Downloaded from 512 J Neurol Neurosurg Psychiatry 2000;69:512–515

SHORT REPORT

Chorea resulting from paraneoplastic striatal encephalitis

T Tani, Y-S Piao, S Mori, N Ishihara, K Tanaka, K Wakabayashi, H Takahashi

Abstract the Romberg test gave a negative result. The A 73 year old man presented with progres- patient walked unsteadily, displaying chorea. sive choreic movement and dementia. An The laboratory tests showed no significant antineuronal antibody that recognised a findings except a slight increase in concentra- 68 kDa band on a western blot was found tions of C-reactive protein, creatine kinase, and in the patient’s serum; this antibody lactate dehydrogenase; thyroid function was immunolabelled neuronal somata in rat normal. A chest radiograph showed swelling of brain. Postmortem examination showed a the left hilar lymph nodes. Magnetic resonance small cell lung cancer and severe neuronal imaging of the brain demonstrated low signal loss with lymphocytic infiltration in the intensity on T1 weighted images and high sig- striatum that was more severe in the cau- nal intensity on T2 weighted images of the date head. This is thought to be the first bilateral caudate nucleus (fig 1). pathologically proved case of paraneo- The patient was treated with lithium carbon- plastic chorea with striatal encephalitis. ate and clonazepam, which was not beneficial. (J Neurol Neurosurg Psychiatry 2000;69:512–515) His choreic movements became generalised and worsened. The purposeless involuntary Keywords: paraneoplastic syndrome; chorea; striatal encephalitis movements, which were less rapid than myo- clonus in character, involved the arms, legs, trunk, and neck, and were present all day and The discovery of antibodies against onconeu- absent during sleep. They were identical with ronal proteins in the serum and CSF of the eyes closed or open. On 12 June, the patients with malignancy and paraneoplastic patient’s verbal intelligence quotient (IQ) score syndromes has shown the existence of immune was 76 (a performance IQ test was not Department of responses against the tumour and the nervous performed). His mental function deteriorated Neurology, Saiseikai and the choreic movements progressed rapidly;

system. Some syndromes have been accepted http://jnnp.bmj.com/ Niigata 2nd Hospital, he fell often and bruised his head. On 20 June, Niigata, Japan as paraneoplastic disorders because of their T Tani frequent association with a specific tumour he became unable to walk, and could not S Mori type, and selective involvement of the nervous understand complicated orders. An EEG system with corresponding major symptoms showed diVuse slowing without any diVerence Department of and signs.1 However, chorea as a remote eVect between the right and left hemispheres. No Pathology of malignancy is exceedingly rare, and the periodic synchronous discharges were seen. A N Ishihara lesions that cause chorea have yet to be estab- chest radiograph disclosed a small mass lesion on his left bronchus. Somatosensory evoked Department of lished. We have recently encountered a patient on September 25, 2021 by guest. Protected copyright. Pathology, Brain who manifested chorea as an initial and cardi- potentials were not examined, nor was a nerve Research Institute, nal symptom, and in whom postmortem exam- conduction study performed. On 6 August, his Niigata University, 1 ination showed small cell lung cancer and CSF showed normal glucose and protein con- Asahimachi, Niigata inflammatory lesions that were almost re- tent with 1.3 lymphocytes/mm3 and negative 951–8585, Japan Y-S Piao stricted to the basal ganglia of the brain. To our cytology. H Takahashi knowledge, this is the first postmortem estab- For screening for antineuronal antibody, lished case of chorea resulting from paraneo- western blot analysis was performed, using the Department of plastic striatal encephalitis. cerebral grey and white matter, sciatic nerve, Neurology liver, and kidney obtained from a man who K Tanaka Case report died of a non-neurological disorder, as well as Brain Disease CLINICAL COURSE the cerebrum, cerebellum, liver, and kidney Research Center A 73 year old Japanese man was admitted to dissected from a mouse killed under anesthetic. K Wakabayashi our hospital on 2 June 1997 complaining of Each sample was homogenised in Tris buVered restlessness. He was not demented at the time saline (TBS) containing 1 mM EDTA, 1 mM Correspondence to: of the initial examination, but his mood was phenyl methyl sulfonyl fluoride, and 0.32 M Dr Hitoshi Takahashi [email protected] manic. On neurological examination, he sucrose. It was then centrifuged, and the showed choreic movement in his limbs. No supernatants were boiled in modified Lae- Received 12 October 1999 cranial nerve signs were evident. All deep ten- mmli’s sample buVer. Fifty micrograms of each and in final form 21 May 2000 don reflexes were diminished. Neither muscle preparation were loaded for electrophoresis on Accepted 2 June 2000 weakness nor sensory disturbance was seen and 10% SDS-polyacrylamide slab gel, and trans-

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.4.512 on 1 October 2000. Downloaded from Chorea resulting from paraneoplastic striatal encephalitis 513

Figure 1 Magnetic resonance image through the basal ganglia. Reduced intensity is evident in the T1 weighted image of the bilateral caudate head (A), and markedly increased intensity is evident in the T2 weighted image (B).

ferred to nitrocellulose paper electrophoreti- cally. The blotted papers were incubated at room temperature first with TBS containing 3% skimmed milk (TBSM), and then, in the 68 kDa following sequence, with a particular patient’s serum diluted at 1:200 in TBSM, biotinylated anti-human IgG (ã-chain specific; Vector, Bur- lingame, CA, USA; diluted 1:1000), then avidin-biotin peroxidase complex (ABC rea- gent; Vector).Each incubation required 1 hour, which was followed by rinsing with TBS. The blots were finally incubated with 4-chloro-1- naphthol (Sigma, St Louis, MO, USA) and hydrogen peroxide for the colour development. The results showed that the serum of this patient contained an antibody that recognised KiLiCbr PCC YoHu http://jnnp.bmj.com/ a 68 kDa band only on a western blot of the homogenates of human cerebral grey and white Figure 2 Western blot with the patient’s serum (diluted matter, and murine cerebrum and cerebellum 1:200), using murine cerebrum (Cbr), liver (Li), and kidney (Ki) homogenates, shows a 68 kDa band only on (fig 2). Anti-Hu, anti-Yo, and anti-Ri antibod- the cerebrum homogenate. In addition to serum (diluted ies were not detected in the serum by enzyme 1:200) from the present patient (P), serum (diluted 1:200) linked immunosorbent assay. Cryostat sections from two healthy controls (C), an anti-Yo positive patient of the rat brain, liver, and kidney after fixing in (Yo) and an anti-Hu positive patient (Hu) were also blotted as negative and positive controls (P and C, murine on September 25, 2021 by guest. Protected copyright. 4% paraformaldehyde were submitted for cerebrum homogenates; Yo and Hu, murine cerebellum immunohistochemical examination using the homogenates). patient’s serum (diluted 1:1600) and CSF (diluted 1:5). Positive staining was found in POSTMORTEM EXAMINATION neuronal cell bodies and proximal dendrites, At necropsy, small cell carcinoma in the upper being more pronounced in the thalamus and lobe of the left lung was confirmed. Metastasis hippocampus (data not shown), but not in the was found only in the left hilar lymph nodes. liver or kidney. The control serum from 20 The above mentioned serum and CSF of this healthy volunteers, 35 patients with various patient did not react with the tumour. The types of spinocerebellar degeneration, and two brain weighed 1200 g. Coronal sections of the patients with Huntington’s disease did not cerebrum were examined; marked atrophy with react with any tissue samples. brownish discoloration of the bilateral caudate As paraneoplastic encephalitis was strongly nucleus was evident (fig 3 A). Histologically, suspected, the patient was treated with intra- the caudate nucleus exhibited severe neuronal muscular injections of dexamethasone for 77 loss with perivascular lymphocytic cuYng and days. Dexamethasone (initial dose 16 mg/day) proliferation of astrocytes (fig 3 B). The was tapered; this improved his mental status inflammatory reaction consisted of both B and only slightly. He died of bacterial colitis and T cells. Similar, but mild changes were seen in pneumonia on 22 September, 3 months after the anterodorsal portion of the putamen and the onset of his condition. the globus pallidus. The thalamus and subtha-

www.jnnp.com J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.69.4.512 on 1 October 2000. Downloaded from 514 Tani,Piao, Mori, et al

Figure 3 (A) Severe atrophy of the caudate nucleus is evident, mimicking Huntington’s disease. (B) The caudate head exhibits marked neuronal loss, perivascular lymphocytic cuYng, and proliferation of astrocytes. Haematoxylin and eosin. Bar=30 µm.

lamic nucleus were well preserved. In the posterior column, but not in the basal ganglia. cerebellum, mild loss of granule cells was Heckmann et al3 reported on a patient with noted, but the Purkinje cells were preserved. chorea, ataxia, and sensory neuropathy in The midbrain, pons, and medulla oblongata association with small cell lung cancer and showed no obvious abnormalities. In the spinal anti-Hu antibody. Batchelor et al4 reported on a cord, posterior fascicles showed only slight patient presenting with chorea and cerebellar myelin pallor with a few macrophages. The ataxia as a remote eVect of Hodgkin’s disease, dorsal root ganglia showed mild neuronal in whom anti-Hu and anti-Yo antibodies were degeneration with slight inflammatory infil- negative, but immunohistochemistry using the trates and several Nageotte nodules. The patient’s serum showed positive staining in the cerebral cortex showed no remarkable changes, molecular layer of the cerebellum. Brain MRI apart from some senile plaques. of the patients demonstrated atrophy of the caudate nucleus on the T1 weighted image3 Discussion and increased signal intensity in the caudate The presence of a small cell carcinoma of the head and anterior putamen on the proton 4 lung, the detection of an antineuronal antibody weighted image. Unfortunately no postmor- in the serum and CSF, and the neuropathology tem findings were included in these two reports. Postmortem examination in our pa-

of the inflammatory reaction in our patient led http://jnnp.bmj.com/ to the diagnosis of paraneoplastic encephalitis tient showed severe neuronal loss with lym- that had aVected primarily the basal ganglia. phocytic infiltration in the striatum that was Paraneoplastic encephalomyelitis is charac- more severe in the caudate head. It has been terised clinically by a subacute, progressive established that the choreoathetosis seen in course over weeks to months. The underlying Huntington’s disease is the result of a loss of malignancy is usually small cell lung cancer, the striatal neurons that project to the lateral and anti-Hu antibody is often detected. segment of the globus pallidus.5 The lesion responsible for the chorea in the paraneoplastic Although the distribution of the lesions on September 25, 2021 by guest. Protected copyright. throughout the central and peripheral nervous syndrome seen in our patient was considered to systems varies, so do the symptoms. The be in the basal ganglia or, more precisely, the predominant regions of pathology have led to caudate nucleus. the characterisation of the following clinico- The serum and CSF in our patient con- pathological entities: limbic encephalitis, brain- tained an antibody other than anti-Hu, anti-Yo, stem encephalitis, myelitis, ganglioradiculone- or others, as previously reported to occur in uritis, and autonomic neuropathy. However, relation to paraneoplastic neurological selective involvement of the basal ganglia in syndrome.1 Initially, paraneoplastic autoanti- paraneoplastic syndromes is exceedingly rare. bodies themselves were considered to be To our knowledge, only three patients pathogenic. However, treatments that reduce presenting with chorea as a paraneoplastic antibody titres proved to be ineVective.6 In ani- symptom have been reported previously.2–4. mal models, passive transfer of autoantibody or Albin et al2 reported the first case of chorea as a lymphocytes from patients with paraneoplastic remote eVect of small cell lung cancer. This disease, or passive transfer of lymphocytes sen- patient showed a progressive multifocal neuro- sitised to recombinant Yo protein antigen, has logical disorder with dystonia, ataxia, sensory failed to induce the disease.7 Although the sig- neuropathy, and cranial nerve palsies in nificance of the antibody found in our patient addition to chorea, and postmortem examina- remains unclear, the neuropathological fea- tion showed neuronal loss in the 10th and 12th tures of prominent lymphocytic infiltration cranial nerve nuclei, cerebellar cortex, and with neuronal loss suggests the presence of

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lymphocyte mediated neuronal cell death. 6 Furneaux HF, Reich L, Posner JB. Autoantibody synthesis in the central nervous system of patients with paraneoplas- Some recent studies have reported the possi- tic syndromes. Neurology 1990;40:1085–91. bility that cytotoxic T cells have roles in the 7 Tanaka M, Tanaka K, Onodera O, et al. Trial to establish an pathogenesis of paraneoplastic neurological animal model of paraneoplastic cerebellar degeneration 8–11 with anti-Yo antibody. 1. Mouse strains bearing diVerent syndromes. MHC molecules produce antibodies on immunization with recombinant Yo protein, but do not cause Purkinje cell loss. Clin Neurol Neurosurg 1995;97:95–100. 1 Dalmau J, Gultekin HS, Posner JB. Paraneoplastic neuro- 8 Albert ML, Darnell JC, Bender A, et al. Tumor-speciﬁc logic syndromes: pathogenesis and physiopathology. Brain killer cells in paraneoplastic cerebellar degeneration. Nat Pathol 1999;9:275–84. 1998;4:1321–4. 2 Albin RL, Bromberg MB, Penney JB, . Chorea and Med et al 9 Benyahia B, Liblau R, Merle-Béral H, . Cell-mediated dystonia: a remote eVect of carcinoma. Mov Disord 1988;3: et al 162–9. autoimmunity in paraneoplastic neurological syndromes 3 Heckmann JG, Lang CJG, Druschky A, et al. Chorea result- with anti-Hu antibodies. Ann Neurol 1999;45:162–7. ing from paraneoplastic encephalitis. Mov Disord 1997;12: 10 Tanaka K, Tanaka M, Inuzuka T, et al. Cytotoxic T 464–6. lymphocyte-mediated cell death in paraneoplastic sensory 4 Batchelor TT, Platten M, Palmer-Toy DE, et al. Chorea as a neuronopathy with anti-Hu antibody. J Neurol Sci 1999; paraneoplastic complication of Hodgkin’s disease. J 163:159–62. Neurooncol 1998;36:185–90. 11 Tanaka M, Tanaka K, Tokiguchi S, et al. Cytotoxic T cells 5 Reiner A, Albin RL, Anderson KD, et al.DiVerential loss of against a peptide from Yo protein in patients with paraneo- striatal projection neurons in Huntington disease. Proc Natl plastic cerebellar degeneration with anti-Yo antibody Acad Sci USA 1988;85:5733–7. [abstract]. J Neuroimmunol 1998;90:102. http://jnnp.bmj.com/ on September 25, 2021 by guest. Protected copyright.