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Epilepsy Research 17 (1994) 175-181

Limbic encephalitis: a case report

Nadia Khan, Heinz Gregor Wieser*

Neurologische Klinik, Abteilung ftir Electroencephalographie und Epileptologie, UniversitZtsspital, CH-8091 Zrich, Switzerland

(Received 1 I August 1993; revision received 28 October 1993; accepted 28 October 1993)

Abstract

We report a case of a 24 year old patient, who presented with simple and complex partial epileptic seizures, progressive changes in behaviour and affect including marked aggression, and a decline in memory to the point of inability to learn. Extensive work-up resulted in a final diagnosis of limbie en~phalitis. This diagnosis was supported by a number of investigations performed during the follow-up of 6 years and ranging from the basic EEG to the more sophisticated investigations of magnetic resonance tomography, magnetoencephalography and positron emission tomography.

Key word: Limbic encephalitis

1. Introduction

Limbic encephalitis (LE) is a distinct clinico- pathological entity, localised to the limbic part of the temporal lobes. In 1960 Brierley et al. [4] de- scribed three cases of subacute encephalitis asso- ciated with oat cell carcinoma of the bronchus. Corsellis et al. [5] reported a further three patients with LE and carcinoma. These authors first recog- nised LE as a nonmetastatic manifestation of ma- lignant tumours. The association of a malignant process is commonly seen [9,&l 11, although pre- vious literature [2] supports the existence of LE also in the absence of a neoplasm.

Since its initial recognition and documentation in 1960 by Brierley et al. [4], we have found 45

* Corresponding author. Tel.: 41/l-255 55 31; Fax: 41/l-255 44 29.

reported cases with (36 cases) or without (9 cases) a primary neoplastic process.

Patients with LE usually suffer from marked impai~ent of recent memory, behavioural ab- normalities and epileptic seizures [ 1,2,8,12].

The serum and CSF investigations show neuro- nal antinuclear antibodies [3]. MRI studies have indicated an abnormal high signal intensity on T2 weighted images in one or both hippocampal for- mations (7,101.

We report the case of a 24 year old patient whose clinical presentation and work-up resulted in the diagnosis of limbic encephalitis.

2. Clinical history

A 24 year old female presented for the first time with a history of episodes of forgetfulness and

092s1211/94/~7.~ 0 1994 Elsevier Science B.V. AH rights reserved SSDI 0920-121 1(93)E0084-U

memory loss at the age of 17 years, leading to a decline in school performance. There was a ten- dency towards increased aggressive behaviour, which was out of character for the patient herself. She herself declared that she ‘felt unwell’ during such episodes. Within a short period of 5 months her memory declined, while the aggressiveness in- creased, to the degree that she had to leave school.

Deterioration of her general condition fol- lowed. Within a span of a few months attacks of feelings of ‘cramps’ occurred and the patient ex- perienced an odd epigastric sensation that gradu- ally rose to her head, ending in paraesthesias in the fingertips.

The attacks would last for less than 30 s, and occur up to 20 times a day, with a clustering of 2 weeks before her monthly menstruation. During these episodes the patient appeared to be con- scious but did not speak.

The perinatal period of the patient was unre- markable. At the age of 2 years, while living in Nairobi, Africa, she suffered from an episode of fever of unknown origin with leukocytosis and icterus.

Family history was positive for epilepsy: the grandfather had suffered from focal epilepsy.

3. Investigations

Clinical findings and course of illness are sum- marised in Fig. 1.

On admission, the general and a detailed neuro- logical examination were normal.

Baseline haematology showed a microcytic anaemia, with a decreased level of vitamin B12 and folic acid. Biochemistry was normal. Heavy metals analysis indicated a slight decrease of mag- nesium and zinc.

Serum protein electrophoresis indicated a slightly decreased ctl and p globulin, with the pre- sence of cryoglobin. There was a normal IgG con- centration. Complement factors C3, C4 were slightly decreased. No autoantibodies were de- tected.

The serology was negative for herpes, cytome- galovirus, varicella and toxoplasma fractions, po-

antigen. Titres for venereal diseases were negative. CSF examination: the initial CSF examination

revealed 11 WBCs, with 99% lymphocytes and 1% monocytes, proteins 405 mgjl (normal albu- min; but increased levels of IgG, showing an oli- goclonal band).

Cultures were negative for any organismal growth. Cytology was negative for the presence of any atypical cells.

EEG: Interictal standard routine scalp EEG, recorded on several occasions, revealed bitempor- al and occasionally frontal ‘irritative’, i.e., steeper waveforms (so called alpha-theta dysrhythmias).

Ictal EEG recording revealed a focal right tem- poral rhythmic epileptifo~ discharge (4/s slow theta), appearing 2.5 min after a standard 3 min hyperventilation (Fig. 2). The seizure was asso- ciated with the habitual epigastric aura, par/dys- aesthesias in the left hand, and an eyelid tremor.

Visual evoked potentials (VEP) were within the normal range.

Interestingly enough the patient experienced an aura during the examination. The potential re- corded at that point in time had an increased PlOO latency.

Neuropsychological examination of this right-

Clinlcai findings 1966 - 1992

a) Simple and Complex padial seizures zok!ay. < 30 98*)

7-l 1 WBC - 5WEC - PWBC - 2wBc with increased IgG oiigcdonal

f@G +VB

Ittt t t, “ff,l986 fw88 Yd96 XIM6 I, 1967 fff-w ,988 1989 - 90 ff-“ffl 1992

Fig. 1. Graphic representation of the clinical course of the pa-

tient from the beginning of signs and symptoms in 1986 to the recent follow-up in 1992. The x-axis represents the time scale

from 1986 to 1992, the y-axis gives the respective signs/symp-

toms, results of investigations (interictal and ictal EEG, CSF

lindinrs) and the antiepileptic treatments. sitive for IgG against Epstein-Barr virus capsid _ .

N. Khan, H.G. WieserjEpilepsy Research 17 (1994) 175-181 177

Fig. 2. Six sections from an ictal taiemetric scalp EEG recording (date of recording: 29.7.86), showing the build-up and the full-blown, long lasting (87.5 s) seizure dischaPge (rhythmic 4/s slow theta), with a regional maximum right temporal, starting 2.5 min after hyperventilation. Black vertical bars represent ommitted EEG sections (from left to right: 2.5 s, 6 s, 6 s, 37 s and 21 s). Ag/AgCI cup electrodes were used. Electrode positions and the montage (with longitudinal chains) are according to the HESS system, as indicated. To the interrogating EEG technician the patient reported at the end of the discharge that she had experienced an odd gastric sensation, such as ‘blurring and flickering of vision’, followed by prickling dysaesthesias of the left hand.

handed patient, capable of conversing in five dif- ferent languages, revealed a specific short-term

memory weakness for both verbal and figurative material, with frequent incongruencies (repetition,

Fig. 3. Transverse, sagittal and coronal T2 weighted MRI sections (date of examination: 25.6.91), showing a structural lesion in the right temporal mesial region This lesion represents a probable regressive structural change.

178 N. Khan. H.G. WieseriEpilepsy Research 17 (1994) 17%IN1

Table I Asymmetry indices [(left -right)/(left + right)] x 200 of glucose uptake in the different cortical and subcortical regions of interest (ROI).

as measured by ‘sF-FDG PET

ROI Asymmetry index

(L-R/L+R)x200

ROI Asymmetry index

(LRiL+R)x200 ~~~~__ _____ ~.

Frontomedial 5.9

Frontolateral -1.1

Frontal average 1.1

lnsula -3.8

Temporal basal 15.5

Temporal lateral 0

Temporal pole 1.7

Temporal average 4.2

Occipital medial 9.9

Occipital lateral

Occipital average

Parietdl

Striatum

Caudate Putamen

Thalamus

Cerebellum

White matter

-9.1

2.1

-5.4

8.3

3.3 -0.1

--- 1.7

-0.7

-1.1

The values printed in bold typeface lie outside the normal range. There is a significant asymmetry of 15.5% between the right and left

temporal mesial ROI, the glucose uptake in the right temporal mesial region is diminished compared to that in the left,temporal mesial

region.

Fig. 4. Transverse (labelled white), sagittal (labelled yellow) and coronal (labelled green) planes of an ‘*F-FDG PET scan (date of

examination: 23.4.92) representing a focal glucose hypometabolism in the right temporal mesial region (the right cerebral hemisphere

is to the reader’s left). A colour scale on the right side of the image provides information on the extent of hypometabolism (scale:

minimum (black) to maximum (white) glucose uptake).

N. Khan, H.G. WieserlEpilepsy Research 17 (1994) 175-181 179

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Fig. 5. Magnetoencephalogram (MEG) representing a cluster of dipoles of spikes (crosses) in the right temporal mesial region (the

right cerebral hemisphere is to the reader’s right, date of examination: 22.6.92); courtesy of E. Hellstrand, M.D., Ph.D.

180 N. Khan, H.G. Wieser/Epilepsy Research 17 (1994) 175-181

confabulation and figurative rotation). Initial MRI of the head (May 9, 1989) showed

no clear-cut pathology, i.e., no structural abnorm- ality could be observed on T2 weighted images. The MRI repeated 3 years later (June 25, 1991) showed, however, a distinct structural lesion in the right rostra1 parahippocampal gyrus on the T2 weighted images (Fig. 3).

Radiology: chest X-ray and CT were unre- markable. The abdomen ultrasound was negative for a neoplastic process.

SPECT: a HMPAO SPECT scan performed at the time of onset of symptoms did not show any abnormality of perfusion.

PET: An 18F-FDG PET scan was carried out 6 years (April 23, 1992) after the initiation of symp- toms in the light of persistence of seizures. This revealed a discrete hypometabolism in the right temporomesial and temporopolar regions (Table

1). Magnetoencephalographic examination (MEG)

done in January 1993 in the Karolinska Hospital by Dr. E. Hellstrand revealed a well defined clus- ter of dipoles of spikes located in the right tempor- al lobe, deep mesially (Fig. 5). Similar, but less convincing spike dipole clusters were, however, also found in the left temporal region.

4. Clinical course and follow-up

Since the initial onset of symptoms in 1986 and the investigations that followed, the presence of an infectious cerebral process was assumed although a definitive diagnosis was not reached until later when other possible diseases such as systemic lu- pus erythematosus and sarcoidosis were definitely ruled out.

Treatment was symptomatic and aimed at ame- lioration of the two major problems of the patient, i.e., weak memory and persistent complex partial seizures. She was initially started on carbamaze- pine for a period of 4 months when due to the continuing increase in seizure frequency the antie- pileptic treatment was changed to phenytoin. Over the next few months this change resulted in im- provement in terms of reduced seizure frequency and some improvement in memory.

However, after withdrawal of this antiepileptic medication due to unwanted side effects the sei- zures reappeared. Phenobarbital along with clona- zepam was the new antiepileptic regimen, which however proved its effectiveness only for a very short period of 1 month, during which no seizure occurred and the patient felt better. At this time after a long pause, the patient once again was ac- tively taking part in sporting activities. From No- vember 1988 until now, the patient has been tak- ing carbamazepine and sodium valproate. This has resulted in some decrease of seizure occur- rences and some neuropsychological improve- ment.

5. Discussion

The case of a 24 year old patient with progres- sive short-term memory disturbances, accompa- nied by bouts of aggressive behaviour, episodes of simple and complex partial seizures, all in the pre- sence of an initial CSF leukocytosis with increased oligoclonal y-globulins, but in the absence of spe- cific neuronal antibodies, presented some diagnos- tic difficulties.

Following an initial relatively rapid decline of memory, associated with the appearance of a marked ‘personality and behavioural syndrome’ [13], over a time course of in total 6 years, some improvement of memory functions took place along with improvement of seizure frequency (last follow-up indicates no seizure occurrence over a period of 6 months), under antiepileptic therapy. This improvement was accompanied by a contin- uous decrease of CSF leukocytosis and hence of the initially present central inflammatory process.

Since its first description by Brierley et al. [4], the majority of the described patients with limbic encephalitis have presented with a clinical semeiol- ogy of marked changes of affect, anxiety or de- pression, epilepsy, memory disturbances and de- mentia, similar to what our patient presented with. The age at presentation as reported in the literature has been older than our patient’s age. Patients usually present with tumours, and defini- tive diagnosis is only attainable on post-mortem brain studies. All these factors made the possible

N. Khan, H.G. WieserlEpilepsy Research 17 (1994) 175-181 181

diagnosis difficult. PET investigation, early ictal and interictal

EEG recordings were in accordance with neuro- psychological as well as late MRI and MEG data, and suggested that a chronic circumscribed LE was responsible for the late structural and functional changes within the temporal lobes, with a clear predominance on the right side.

In spite of these common clinical, anatomical and pathophysiological presentations of the dis- ease, the exact aetiology of LE remains unclear.

Direct viral infection due to previous evidence of inclusion bodies, in the absence of actual viral particles, has been suggested [12]. Involvement of an immunological process by the presence of anti- neuronal antibodies has also been entertained in the past [3]. The frequent association with a neo- plastic process has led to the hypothesis of the production of a neurotoxic factor by the tumour

u21. Histological changes seen in post-mortem brain

studies show extensive neuronal loss with reactive gliosis, perivascular monocytic infiltrates and mi- croglial nodules, all localised to the limbic areas [12]. The limbic region has been shown to have specific metabolic needs due to its overall high

rate of cellular activity [S]. The rate of protein synthesis in the hippocampal region is increased in comparison to other brain regions, and hence its demand for glucose and oxygen is high. This may render the hippocampus susceptible to any slight change in the normal milieu.

Our reported case of limbic encephalitis is rather unusual, because of the patient’s age, the unknown cause, and a rather mild outcome. Lim- bit encephalitis usually represents remote effects of a neoplasm. This was not the case in our pa- tient and therefore the diagnosis became difficult and could only be corroborated after years of fol- low-up and by exclusion. A variety of diagnostic tests, including serial CSF examinations, interictal and ictal EEG, MEG, MRI, SPECT and PET, support this diagnosis, which is usually suspected but not made in life. under such circumstances.

Improved imaging techniques now allow this diagnosis to be made with a greater degree of con- fidence than in the past and hopefully will permit research into the aetiology in patients like the one reported, who do not have obvious neoplasms.

6. References

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