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Home , Encephalitis, Limbic encephalitis

80888ournal ofNeurology, Neurosurgery, and Psychiatry 1993;56:808-81 1 Limbic occurring in association with Alzheimer's disease J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.808 on 1 July 1993. Downloaded from

R C Sutton, M H Lipper, H R Brashear

Abstract revealed hilar adenopathy, but bronchoscopy Paraneoplastic is a was again negative. In June 1989, she was rare cause of subacute . A evaluated for unsteady gait and numbness in patient with limbic encephalitis and her hands. A CT scan of the chest showed small-cell lung- carcinoma is reported in improvement. CSF was normal except for a whom the onset of subacute cognitive protein of 122 mg/dl. CT and MRI scans of impairment was-obscured by concurrent the head were unremarkable except for mild Alzheimer's disease. MRI revealed cortical atrophy. She became confused and increased T2 signal in medial temporal incontinent and was transferred to the lobes which corresponded to inflam- University of Virginia Health Sciences matory pathology demonstrated at Centre. necropsy. High titres of antineuronal On admission the patient was alert but (type II, anti-Hu) were present confused, oriented only to person. She had at death. Direct immunofluorescent severe memory and cognitive impairment. staining of necropsy tissue revealed IgG Cranial nerve examination was normal. bound to most remaining neurons in the Strength was 4/5 in all muscle groups with temporal lobe. Antineuronal antibody mild . There was marked dys- screening and MRI are important in metria. Sensory examination was incon- detecting limbic encephalitis. sistent. Deep tendon reflexes were absent with bilateral Babinski responses. Chest x ray (7 .VNurol Ncurosurg PR vchiarrv 1 993;56:808-8 11) showed no masses. CSF was sterile with pro- tein 70 mg/dl and 6 WBCs. EEG revealed bihemispheric slowing. An MRI scan of the Limbic encephalitis was first described as a head (fig 1) showed increased signal intensity unique clinical and pathological by involving the medial temporal lobes on T2- Brierly in 1960.1 Its association with carcino- weighted images. The patient was treated ma was elucidated by Corsellis in 1968.2 Subsequent reports have established limbic encephalitis as one of several classic clinico- pathological presentations of paraneoplastic disorders.3 Limbic encephalitis is charac- http://jnnp.bmj.com/ terised clinically by subacute cognitive deteri- oration with variable degrees of anxiety, Departnents of and and memory impairment which Behavioral Medicine may be difficult to differentiate from other and Psychiatry causes of dementia. Laboratory and radio- University ofVirginia School ofMedicine graphic findings are usually non-specific. An

Charlottesville, exception is the finding of circulating anti- on September 29, 2021 by guest. Protected copyright. Virginia, USA neuronal which point strongly to Department of an underlying neoplasm.45 Since paraneoplas- Pathology, Division of limbic encephalitis and the associated Neuropathology R C Sutton malignancy are potentially treatable, it is Department of important to differentiate this syndrome from Radiology other causes of cognitive impairment. We M H Lipper report the clinical, immunological, radio- Department of graphic and pathological features of a case of Neurology, and limbic encephalitis occurring in association Department of Behavioral Medicine with Alzheimer's disease. and Psychiatry H R Brashear Correspondence to: Case report Dr Brashear, Department of Neurology, Box 394, A 78 year old white woman began to have University of Virginia Health subtle memory and personality changes in Sciences Center, Charlottesville, VA, 22908, 1987. She complained of dyspnoea in USA December 1987, and x ray and CT scan of Received 11 March 1992 the chest at another suggested two and in revised form hospital Figure 1 Axial T2-weighted (2500190) MRI 19 October 1992. left lobe nodules. Bronchoscopy and biopsy demonstrating diffuse increased signal intensity in the Accepted 10 November 1992 were negative. In April 1989, repeat CT scan medialportions of both temporal lobes (arrows). Limbic encephalitis occurring in association with Alzheimer's disease 809 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.808 on 1 July 1993. Downloaded from

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Figure 2 Section ofthe amygdala demonstrating perivascular lymphocytic infiltrate within the (hematoxylin and eosin, x 250).

empirically with acyclovir. A brain biopsy of the right temporal lobe showed perivascular Figure 3 Indirect immunofluorescence ofnormal human lymphocytic infiltrates in the leptomeninges. cerebellum incubated with 1:80 dilution ofpatient serum She deteriorated rapidly, became comatose followed by FITC-conjugated anti-human IgG. There is 22 1989. intense, granular labelling ofnuclei and cytoplasm ofall and died on August neurons typical of type II (anti-Hu) staining (x 475). PATHOLOGY Necropsy revealed pulmonary emphysema serum controls produced no staining. with recent pulmonary emboli. A 2 x 2-5 cm Direct immunofluorescence was performed small-cell carcinoma of the lung was present on frozen sections of the patient's necropsy in the left hilum. A 5 x 9 cm adenocarcin- tissue as described previously.9 Immuno- oma of the colon was found. staining produced moderate to intense cyto- The brain weighed 1290 grams and plasmic and nuclear labelling of most appeared grossly normal except for post remaining neurons in temporal cortex indi- surgical changes over the right temporal lobe. cating bound IgG (fig 4). Neurons in the Microscopic examination revealed chronic cerebellum, brainstem and dorsal root ganglia perivascular inflammatory changes in the meninges (fig 2) and encephalitis with lym- http://jnnp.bmj.com/ phocytic infiltrates of the medial temporal lobes. There was neuronal loss and gliosis in the olivary complex and ganglioradiculitis at multiple levels. There were recent small infarcts in the right amygdala, pontine tegmentum and left lateral basis pontis and

old lacunar infarcts in the right globus pal- on September 29, 2021 by guest. Protected copyright. lidus. On Bielschowsky silver staining there were moderate numbers of neuritic plaques, greater than 15 per mm2 in all areas of the neocortex, amygdaloid bodies and hippo- campal formations, meeting neuropathologi- cal criteria for Alzheimer's disease.6 There were numerous neurofibrillary tangles and granulovacuolar degeneration in the hippo- campi and modest numbers of cortical neuro- fibrillary tangles.

IMMUNOFLUORESCENCE Indirect immunofluorescence was carried out with the patient's serum as described previ- ously.7 Serum was titrated against normal human cerebellum using FITC-conjugated goat anti-human IgG as secondary. Screening produced intense, finely granular nuclear and cytoplasmic staining of all neurons (fig 3) and Figure 4 Direct immunofluorescence ofpatient's temporal no other cells in a type II pattern8 (anti-Hu4). cortex indicating bound IgG in most but not all neurons The endpoint titration was 1:1,280. Normal and no other cells ( x 320). 810 Sutton, Lipper, Brashear

were also labelled but non-neuronal cell types Direct immunostaining of neuron-bound

were not stained. Direct immunofluorescence antibodies in affected areas of the CNS sug- J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.808 on 1 July 1993. Downloaded from of normal brain produced no staining. gests a direct role for antineuronal antibody in the pathogenesis of paraneoplastic limbic encephalitis, but few such clear associations Discussion have been reported in the literature. Several Limbic encephalitis is a rare of authors4 14-18 have described neuronal cancer, most often small-cell lung carcinoma, immunostaining in patients with paraneoplas- but occasionally other lung tumours, tic disorders, but without precise correlation Hodgkin's lymphoma, and other malignan- with clinical symptoms and pathology. cies.' Limbic encephalitis is one manifestation Brashear et a15 demonstrated direct immuno- of a spectrum of paraneoplastic , staining of neurons in multiple regions, including and sensory including temporal lobe structures in a neuronopathy, associated with small-cell car- patient with paraneoplastic encephalomyelo- cinoma. This group of paraneoplastic neuro- neuritis and prominent limbic encephalitis. logical syndromes is distinguished by the Dalmau et al'8 eluted antineuronal antibody occurrence of circulating antineuronal anti- with anti-Hu reactivity from post mortem bodies which label nuclei and cytoplasm in a brain tissue of five patients with paraneoplas- pan-neuronal (type II) pattern8 and are tic encephalomyelitis and limbic involvement. directed against neuronal antigens of 35-40 Our case confirms that antibody can be Kd molecular weight (anti-Hu).5 detected on target neurons in active limbic Paraneoplastic limbic encephalitis is usual- encephalitis and shows the utility of obtaining ly characterised by subacute dementia. frozen tissue. Alzheimer's disease, the most common cause This report shows the extent to which cog- of dementia, also has a predilection for limbic nitive impairment due to a progressive neuro- structures and usually presents with the insid- degenerative disorder, such as Alzheimer's ious onset of similar symptoms. As illustrated disease, can obscure the onset of a subacute by this patient, the gradual progression of a dementia, in this case due to limbic degenerative dementia can obscure the onset encephalitis. Most laboratory tests do not of limbic encephalitis. Subacute behavioural narrow the differential diagnosis, however, changes are not uncommon in patients with MRI may demonstrate typical involvement of Alzheimer's disease, frequently due to medi- limbic structures. Antineuronal antibody cation effects, systemic illnesses or changes in screening can be diagnostic, indicating the environment. Memory impairment in both presence of occult carcinoma responsible for disorders compromises the patient's ability to the paraneoplastic disorder. give an accurate history. Routine laboratory This work was supported in part by NIH grants AG 00407 and radiographic features usually show little and T32NS7236. We thank Dr P Colopy for referring the patient, Ms P Keeney for excellent technical assistance, and or no abnormalities. Thus the initial clinical Ms R Powell for help in preparing the manuscript. features of the onset of limbic encephalitis may be ignored or attributed to other causes. Most cases of paraneoplastic limbic encephalitis were recorded before the advent of CT and MRI. The few reported cases indi- 1 Brierly JB, Corsellis JAN, Hierons R, Nevin S. Subacute http://jnnp.bmj.com/ cate CT is insensitive in this condition as it is encephalitis of late adult life mainly affecting the limbic areas. Brain 1960;83:357-68. unremarkable or may show atrophy,'0 11 2 Corsellis JA, Goldberg GJ, Norton AR. Limbic although contrast enhancement may be encephalitis and its association with carcinoma. Brain 2 1968;91:481-96. seen. MRI may show increased signal 3 Henson RA, Urich H. Cancer and the : the intensity on T2-weighted images in affected neurological manifestations of systemic malignant disease. Boston:Blackwell, 1982. portions of the temporal lobes'01113 (fig 1). 4 Graus F, Elkon KB, Lloberes P, et al. Neuronal anti- nuclear in paraneoplastic Our report correlates these MRI findings in antibody (anti-Hu) on September 29, 2021 by guest. Protected copyright. encephalomyelitis simulating acute polyneuritis. Acta necropsy confirmed limbic encephalitis with Neurol Scand 1987;75:249-52. demonstrated antineuronal antibodies. Late 5 Anderson MB, Rosenblum MK, Graus F, Wiley RG, Posner JB. in paraneoplastic syndromes in the course of limbic encephalitis MRI associated with small-cell lung cancer. Neurology 1988; scans may show evidence of temporal lobe 38:1391-8. 6 Khachaturian Z. Diagnosis of Alzheimer's disease. Arch atrophy, such as parenchymal volume loss Neurol 1985;42:1097-1105. and dilatation of the temporal horns.'0 12 7 Greenlee JE, Brashear HR. Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar Routine laboratory studies are usually of degeneration and ovarian carcinoma. Ann Neurol little help in the diagnosis of limbic 1983;14:609-13. 8 Jaeckle KA, Greenlee JE. Immunohistochemical patterns encephalitis.' CSF protein may be elevated of antibody response in paraneoplastic neurological syn- with occasional white cells. In contrast, the dromes correlate with specific syndromes and with tumor types (abstract). Ann Neurol 1988;24:121. detection of anti-neuronal antibodies is highly 9 Brashear HR, Caccamo DV, Heck A, Keeney PM. specific for a paraneoplastic neurological dis- Localization of antibody in the nervous system of a patient with paraneoplastic encephalomyelitis. Neurology order.5 Indirect immunofluorescence demon- 1991;41:1583-7. strated high serum titres of antineuronal 10 Dirr LY, Elster AD, Donofrio PD, Smith M. Evolution of brain MRI abnormalities in limbic encephalitis. antibody in a type II pattern typical for both Neurology 1990;40: 1304-6. encephalomyelitis and ganglioradiculitis asso- 11 Lacomis D, Koshbin S, Schick RM. MR imaging of para- neoplastic limbic encephalitis. J Comput Assist Tomogr ciated with small-cell carcinoma of the lung. 1990;14:¶115-7. The specificity and noninvasiveness of in- 12 Burton GV, Bullard W, Walther PJ, Burger PC. Paraneoplastic limbic with testicular direct immunostaining emphasise the impor- carcinoma. A reversible neurologic syndrome. Cancer tance ofearly consideration oflimbic encephalitis. 1988;62:2248-51. Limbic encephalitis occuming in association with Alzheimer's disease 811

13 Kohler J, Hufschmidt A, Hermle L, Volk B, Lucking CH. Rozman C. Immunohistochemical analysis of the Limbic encephalitis: two cases. Jf Neuroimmunol immune reaction in the nervous system in paraneoplas- 1988;20: 177-8. tic encephalomyelitis. Neurology 1990;40:219-22. J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.56.7.808 on 1 July 1993. Downloaded from 14 Graus F, Elkon KB, Cordon-Cardo C, Posner JB. 17 Grisold W, Drlicek M, Popp W, Jellinger K. Antineuronal Sensory neuropathy and small-cell lung cancer: anti- antibodies in small-cell lung carcinoma: a significance neuronal antibody that also reacts with the tumor. Am for paraneoplastic syndromes? Acta Neuropath Med 1986;80:45-52. 1987;75: 199-202. 15 Anderson NE, Budde-Steffen C, Wiley RG, et al. A vari- 18 Dalmau J, Furneaux HM, Rosenblum MK, Graus F, ant of the anti-Purkinje cell antibody in a patient with Posner JB. Detection of the anti-Hu antibody in specific paraneoplastic cerebellar degeneration. Neurology regions of the nervous system and tumor from patients 1988;38:1018-26. with paraneoplastic encephalomyelitis/sensory neuro- 16 Graus F, Ribalta T, Campo E, Monforte R, Urbano A, nopathy. Neurology 1991;41:1757-64. http://jnnp.bmj.com/ on September 29, 2021 by guest. Protected copyright.