J Neurol (1994) 241:401-403 © Springer-Verlag 1994

J. Duarte J. A r g e n t e E Gutierrez M. J. Catalan A. C a b e l l o L. E. C l a v e r i a

Received: 13 May 1993 Received in revised form: 5 October 1993 Accepted: 16 October 1993 J. Dnarte (N~) • J. Argente • P. Gutierrez M. J. Catalan • L. E. Claverfa Clinical Neurology Hospital General of Segovia, E-40002 Segovia, Spain A. Cabello Neuropathology Unit, C.S. 12 de Octubre, E-28041 Madrid, Spain

Herpes simplex brainstem encephalitis with a relapsing course

Abstract W e report a patient with a r e l a p s i n g f o r m o f acute b r a i n s t e m encephalitis. P a t h o l o g i c a l e x a m i n a tion d e m o n s t r a t e d necrotizing encephalitis in the cerebral cortex and, m o r e p r o n o u n c e d , t h r o u g h o u t the d i e n c e p h a l o n , as well as in the pes pontis. N e u r o n s and glial cells in the cerebral cortex and b r a i n s t e m contained herpesvirus antigens. The

Introduction H e r p e s s i m p l e x has been w e l l d o c u m e n t e d as one o f the m a i n causes o f acute b r a i n s t e m encephalitis [5-7, 10, 12], with a classical m o n o p h a s i c course. A l t h o u g h an apparently u n c o m m o n disease, the similarity o f acute herpetic b r a i n s t e m encephalitis and the b r a i n s t e m encephalitis described b y B i c k e r s t a f f has b e e n p o i n t e d out [6]. B i c k e r staff's b r a i n s t e m encephalitis has been r e g a r d e d as a f o r m o f M i l l e r F i s h e r s y n d r o m e ( M F S ) [ 1]. A p o s s i b l e relationship b e t w e e n M F S and L a n d r y - G u i l l a i n - B a r r 6 s y n d r o m e has also b e e n the subject o f debate [1, 11]. W e r e p o r t a patient in w h o m the clinical features and c o m p l e m e n t a r y data were consistent with r e l a p s i n g b r a i n s t e m areflexia in the context o f b r a i n s t e m encephalitis with high titres to herpes s i m p l e x d e m o n s t r a t e d at necropsy.

Case report An 18-year-old boy presented with fever (38.6°C), chills, sore throat, bifrontal headache, vomiting and photophobia. He had had a mild upper respiratory illness that resolved spontaneously a week before admission. On admission, the patient had a temperature of 39°C and pulse of 75 beats/min; blood pressure was 120/80 mmHg, and respiratory rate 22 breaths/rain. He was alert and orientated. Meningeal signs were absent. Fundi and pupils were normal. There was impairment of upward and downward gaze, with spontaneous conjugate down-

clinical interrelationship o f b r a i n s t e m encephalitis, M i l l e r F i s h e r s y n d r o m e and L a n d r y - G u i l l a i n - B a r r 6 s y n d r o m e is discussed. Key words Herpes simplex B r a i n s t e m encephalitis - R e l a p s i n g course - M i l l e r F i s h e r s y n d r o m e L a n d r y - G u i l l a i n - B arr6 s y n d r o m e

ward spasmodic movements of the eyes with added vertical nystagmus in neutral gaze. He moved all limbs spontaneously but had myoclonic jerks in the right arm. There was generalized hyperreflexia, but plantar responses were both flexor. The rest of his physical and neurological examination was normal. Laboratory tests included a complete blood count with 12,000 leucocytes/mm3 with a shift to the left, normal haemoglobin and haematocrit, and normal blood chemistry. Cerebrospinal fluid (CSF) was clear and colourless with 80 nucleated cells/gl, with 90% polymorphs and 10% lymphocytes. CSF glucose was 61 mg/dl (3.4 mmol/1) for a blood sugar of 85 mg/dl and proteins 40 mg/dl. CSF Gram stain, Indian ink, syphilis serology, cryptococcal antigen and latex agglutination test for encapsulated bacteria were all negative. Computed tomography of the brain was unremarkable. The following day the patient developed ptosis, fixed mydriasis, and a medial rectus palsy in the left eye. A right hemiparesis and hemisensory deficit was noted. On the 3rd day in hospital the patient developed bilateral incoordination of all four limbs and an ataxic gait. He gradually deteriorated over the next 5 days and became progressively drowsy. Repeated CT of the brain (Fig. 1) showed an enhancing low-density abnormality in the midbrain, extending into the thalamus on the left as well as into the posterior area of the left temporal lobe. EEG was normal. On the 7th day, because of progressive deterioration, prednisone 80 rag/day i.v. was started and continued in decreasing dosage for 20 days. On the 10th day the patient's condition began to improve. A week after treatment with prednisone had been stopped he was discharged and was able to walk unaided, the only sequelae being vertical nystagmus on neutral gaze and persisting right facial weakness of upper motor neuron type. CSF before discharge was normal. A week later he insidiously developed, over the course of 48 h, general malaise, fever and occipital headache and became drowsy. On examination he was pyrexic (39°C) and responsive only to forceful stimulation. There was no signs of meningeal irritation. Paralysis of upward gaze and bilateral facial weakness of lower motor neuron

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No serological evidence of Treponema pallidum, Toxoplasma gondii, Epstein-Barr virus, cytomegalovirus, Coxiella burnetti or herpes simplex infection in blood or CSF was found. At necropsy there was extensive patchy haemorrhagic infarction of both temporal lobes, and small haemorrhagic softenings were scattered throughout the thalamus, subthalamus, mesencephalon and pons. Microscopic examination showed necrotizing encephalitis in the cerebral cortex, more severe and diffuse throughout the tegmentum, pes pontis, and floor of the fourth ventricle (Fig. 2). Inclusion bodies were not seen. Sections from many areas of the brain were examined by the indirect immunofluorescence technique. Neurons and glial cells in the cerebral cortex and brainstem contained herpes virus antigen.

Discussion

Fig. 1 CT scan of the brain showing an enhancing low-density lesion in the midbrain, extending into the thalamus on the left as well as into the posterior area of the left temporal lobe

type were noted. All four limbs were globally weak, and tendon reflexes were all absent. CT of the brain showed no further changes compared with the previous scan (Fig. 1). CSF demonstrated xanthochromia; 106/mm s lymphocytes; protein 60 mg/dl; glucose 46 mg/dl. EEG showed only marked slowing of background activity. Acyclovir 30 mg/kg/day was initiated immediately and continued for 10 days. Over the next 40 days the patient remained stuporous and gradually developed trismus and masticatory and facial spasms. On the 40th day, as his consciousness began to improve, he had marked bulbar palsy and flaccid tetraplegia, though he was able to communicate by blinking. On the 60th day he developed a partial right abducens palsy with horizontal nystagmus on right lateral gaze. On the 70th day of hospitalization he developed fever (39°C) and died after sudden respiratory arrest.

Fig.2 a Left subthalamus. Parenchymal necrosis with cavitation; perivascular molecular infiltration (PAS × 50). b Same area. Abundant macrophages, inflammatory cells and reactive astrogliosis (PAS x 160)

This case is u n u s u a l b e c a u s e o f the fluctuations in the clinical course with two relapsing e p i s o d e s and a r e m i s sion o f short duration. Reports o f cases with relapse and r e m i s s i o n in the literature are few. T h e characteristic features o f b r a i n s t e m encephalitis are those d e s c r i b e d b y F i s h e r [9] and B i c k e r s t a f f [3] and include acute p r o g r e s s i v e o p h t h a l m o p l e g i a , ataxia and hyporreflexia. M F S and B i c k e r s t a f f ' s b r a i n s t e m encephalitis b e a r similarities, and s o m e authors have r e g a r d e d t h e m as the s a m e entity [3]. F i s h e r ' s s y n d r o m e was once thought to represent a variant o f L a n d r y - G u i l l a i n - B a r r 6 s y n d r o m e [9], since the neural inury, according to m o s t authors, has a p e r i p h e r a l origin. Nevertheless, r e c e n t l y a case has been r e p o r t e d with d e l a y e d central d e m y e l i n a t i o n [8]. B r a i n s t e m encephalitis is t y p i c a l l y a m o n o p h a s i c illness with p r o g r e s s i v e p a r a l y s i s o f cranial nerves o v e r 2 - 4 weeks. N o relapses were seen in any case over a p e r i o d o f 2 0 - 2 5 years [4]. T h e s e c o n d phase o f our p a t i e n t ' s illness

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had the typical neurological symptoms described in MFS, with an acute onset after an asymptomatic interval of several days; the recurrence raises the question of GuillainBarr6 syndrome or other multifocal CNS diseas. A biphasic illness with limited relapses after initial improvement is seen in 10% of patients with Guillain-Barr6 syndrome treated with steroids [8]. The aetiology of brainstem encephalitis has been confirmed in a few cases. Herpes simplex was reported as the main aetiological agent [5-7, 10, 12]. The diagnosis of MFS was considered in our patient during the relapse period, but acyclovir was administered to cover the possibility of herpes simplex, which was finally confirmed at necropsy. However, although the most commonly used criterion for exclusion of a viral aetiology is the absence of viral inclusions on light microscopy, well-documented cases of herpetic encephalitis have occurred without the demonstration of inclusions in biopsy tissue [2]. To our knowledge, our patient represents the first reported case of herpes simplex brainstem encephalitis

with a relapsing course, with a first relapse compatible with brainstem encephalitis and a second phase like a variant of MFS. This may exemplify the problems with the criteria that define both MFS and brainstem encephalitis and the interrelationship between MFS and Guillain-Barr6 syndrome. This case demonstrates an overlap between these syndromes occurring sequentially in the same patient and would thus suggest a similar pathogenesis underlying the wide spectrum of these disorders. Even accepting the postinfectious and inflammatory nature of these disorders, intriguing questions remain unanswered. What is the nature of the immunological target in MFS, and how does it differ from that in GuillainBarr6 syndrome? The answers might provide significant insight into the types of antigens expressed by different neuronal populations. An indirect effect through an immunological mechanism may also play a pathogenic role in these disorders, and it may represent part of the spectrum of the same pathological process.

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5. Dayan AD, Goody W, Harrison MJG, Rudge P (1972) Brain stem encephalitis caused by Herpesvirus hominis. BMJ 4 : 405-406 6. Ellison PH, Hanson PA (1977) Herpes simplex: a possible cause of brain-stem encephalitis. Pediatrics 59 : 240-243 7. Fenton TR, Marshall PC, Cavanagh N, Wilson J, Marshall WC (1977) Herpessimplex infection presenting as brainstem encephalitis. Lancet 2: 977-978 8. Ferrer X, Ellie E, Larrivi~re M, Deleplanque B, Lagueny A, Julien J (1993) Late central demyelination after Fisher's syndrome: MRI studies. J Neurol Neurosurg Psychiatry 56 : 698-699 9. Fisher M (1956) An unusual variant of acute idiopathic polyneuritis (syndrome of ophthalmoplegia, ataxia, areflexia). N Engl J Med 255 : 57-65

10. Kindley AD, Harris F, Bush GH (1978) Herpes-simplex infection presenting as brainstem encephalitis. Lancet 1:212-213 11, Petty RKH, Duncan R, Jamal GA, Hadley D, Kennedy PGE (1993) Brainstem encephalitis and Miller Fisher syndrome. J Neurol Neurosurg Psychiatry 546 : 201-203 12. Romfin-Campos G, Toro G (1980) Herpetic brainstem encephalitis. Neurology 30:981-985