Brainstem encephalitis: an unusual presentation of herpes simplex virus infection

Herpes simplex virus (HSV) encephalitis has a predilection for the temporal and frontal lobes but occasionally affects the brainstem. We describe a patient who developed HSV brainstem encephalitis that progressed to quadriplegia. Using MEDLINE, we conducted a comprehensive review of other published cases of HSV brainstem encephalitis. Twenty-four published cases of HSV brainstem encephalitis met our inclusion criteria. The mean age was 41.4 years (range 18–71). HSV-1 was the etiologic agent in 79% of reported HSV brainstem encephalitis cases, and HSV-2 accounted for 21% of cases. Infection was limited to the brainstem in 29% of cases and multi-focal, including the brainstem, in 71%. Common manifestations of HSV brainstem encephalitis included neuro-ophthalmologic findings (81%), cranial nerve deficits (69%), and fever (69%). Quadriplegia, as occurred in our patient, was an unusual finding (19%). The mortality rate of HSV brainstem encephalitis was 41%. Intravenous acyclovir showed a beneficial effect on mortality (75% vs. 22%, p = 0.06). HSV brainstem encephalitis is a distinct type of HSV encephalitis. With the increasing use of HSV-PCR, more cases of HSV brainstem encephalitis may be identified. A greater recognition of this syndrome will help better define its optimal treatment and prognosis.     

Vessel wall enhancement in herpes simplex virus central nervous system vasculitis

Infection is a well-known cause of cerebral vasculopathy and vasculitis. We report a 36-year-old woman with cerebral vasculitis and ischemic stroke secondary to herpes simplex virus (HSV). MRI studies revealed a pontine stroke with basilar artery stenosis and vessel wall gadolinium enhancement. This case demonstrates the ability of HSV to cause a focal brainstem vasculitis and the utility of enhanced MRI in the diagnosis of stroke related to HSV central nervous system vasculitis.     

Herpes simplex virus (HSV) DNA in microglial nodular brainstem encephalitis

Thirty-four brains with microglial nodular brain stem encephalitis were retrospectively investigated for herpes simplex virus (HSV) and cytomegalovirus (CMV) by in situ hybridization (ISH) with biotinylated cDNA probes, and by immunocytochemistry with polyclonal and monoclonal antibodies on formalin fixed paraffin embedded serial tissue sections. In 16 cases (47%), HSV DNA was found by ISH in the nuclei of neurons in microglial nodules or in the adjacent parenchyma of the brainstem, and more rarely at various cerebellar and telencephalic sites. None of the 34 cases was labeled for CMV DNA and none revealed HSV or CMV antigens. Ten control brains without microglial nodules were not labeled. This study suggests an HSV etiology for many cases with microglial nodular brainstem encephalitis.     

Herpes-simplex-related antigen in human demyelinative disease and encephalitis

Summary Using immunohistochemical methods optimized to detect herpes simplex virus type 2 (HSV-2) antigen, paraffin sections from human central nervous system tissues from 31 cases pathologically diagnosed as multiple sclerosis (MS), 34 cases of other neurological diseases, 4 adult cases of HSV encephalitis, and mouse brains infected with various HSV strains were examined. Two distinct patterns of immunoreactivity with HSV antisera were seen. In typical acute human and experimental encephalitis, antigen was readily detected using high dilutions of antisera to both HSV types –1 and –2, and was found nonselectiviely in both neurons and glia. Lesions were destructive, with necrosis of all neural cell types, and inflammation was a mixture of polymorphonuclear and mononuclear cells. By contrast, immunoreactivity in lesions in each of three MS cases and in one case of brain stem encephalitis was found only with HSV-2 antisera, and relatively high antiserum concentrations were required to detect it. Reactivity appeared to be largely restricted to glial cell nuclei within and near lesions that were selectively demyelinated. Only mononuclear inflammation was present. These experiments suggest that HSV-related antigen may be found in a broader spectrum of human CNS lesions than has previously been recognized, and that HSV or a related agent may be associated with a selective infection of glial cells and with CNS demyelination.     

Brainstem auditory evoked potential abnormalities and magnetic resonance imaging in posterior fossa lesions

Brainstem auditory evoked potentials (BAEPs) were evaluated in a series of 15 patients with extra-axial cerebello-pontine angle tumors (3 cases), demyelinating plaques (11 cases), and intra-axial tumor (1 case), verified by magnetic resonance imaging (MRI). A satisfactory correlation between the location of the lesions and the type of BAEP abnormalities was found in 11 cases. In 2 other cases, definite MRI brainstem lesions located outside the acoustic pathways were associated with normal BAEPs. In the opposite situation (2 cases of BAEP abnormalities with normal MRI), the inability of MRI to detect demyelinating lesions may be due to the temporal evolution of the lesions themselves. The results of this BAEP-MRI comparative study confirm that BAEP is a sensitive diagnostic tool in revealing brainstem dysfunction, although its localizing power appears to be debatable. The most satisfactory MRI/BAEP topodiagnostic correlation was found with lesions involving the acoustic nerve in its intracranial tract or the caudal pons and bulbopontine junctions.     

Neuroimaging-evident lesional pathology associated with REM sleep behavior disorder

Background/RationaleRapid eye movement (REM) sleep behavior disorder (RBD) is a potentially injurious parasomnia characterized by dream enactment behavior and polysomnographic REM sleep without atonia (RSWA). Recently, RBD not only has been shown to be strongly associated with synucleinopathy neurodegeneration but has also been rarely reported to be associated with structural lesions involving the brainstem or limbic system. The aim of this study was to describe the clinical, neuroimaging, and outcome characteristics in a case series of patients with lesional RBD.MethodsThis is a retrospective case series from a tertiary care referral center.ResultsA total of 10 patients with lesional RBD were identified. Seven (70%) were men, with an average age of sleep symptom onset of 53.7 ± 17.0 years. Structural pathology evident on neuroimaging included four extraaxial (three meningiomas and one basilar fusiform aneurysm with brainstem compression) and six intraaxial (encephalomalacia, multiple sclerosis, vasculitis, autoimmune limbic encephalitis, and leukodystrophy) lesions. No patient developed parkinsonian features or cognitive impairment suggestive of synucleinopathy over an average of 45.4 ± 35.2 months of follow-up.ConclusionsRBD is rarely associated with non-synuclein structural lesions affecting the pons, medulla, or limbic system. The spectrum of lesional RBD comprises tumors, aneurysms, leukodystrophy, and autoimmune/inflammatory/demyelinating brain lesions.     

Overlapping Guillain–Barré syndrome and Bickerstaff's brainstem encephalitis associated with anti-GQ1b IgG antibody after herpes simplex virus infection

Herpes simplex virus (HSV) is a rare, antecedent infectious agent in Guillain-Barré syndrome (GBS). We report a patient with overlapping GBS and Bickerstaff's brainstem encephalitis (BBE). The patient had a vesicular lesion on her nose. Antecedent HSV type 1 (HSV-1) infection was confirmed by isolation of the virus and detection of the presence of serum anti-HSV-1 IgM antibody during the acute phase. Her serum IgG had high anti-GQ1b antibody titer. External ophthalmoplegia has been noted in 2 of 4 reported cases of HSV-associated GBS. Herpetic brainstem encephalitis cases of poor prognosis are known, but only 2 cases of benign brainstem encephalitis secondary to HSV infection, in which there was acute ophthalmoplegia and clinical features consistent with those of BBE have been reported.     

Herpes simplex virus type I (HSV I)-induced multifocal central nervous system (CNS) demyelination in mice.

Multifocal central nervous system (CNS) demyelination develops in the brains of SJL/J, PL/J, and A/J mice following lip inoculation with a specific strain of herpes simplex virus I (HSV I). The lesions in all three inbred strains of mice share similar characteristics including demyelination, relative preservation of axons, and a mononuclear cell (MNC) infiltrate. The lesions, developing during the early phase of demyelination, also appear sequentially in the CNS (trigeminal root entry zone of the brainstem greater than cerebellum greater than cerebral hemispheres) of all three strains of mice but differ in the time of their initial appearance following infection as well as their morphology. In SJL/J mice, new areas of demyelination are observed for only 24 days following lip inoculation with virus. Late stage multifocal CNS demyelination persists throughout 28 weeks postinoculation (pi) in PL/J mice while in A/J mice the development of new areas of demyelination are restricted to 8 weeks pi. Although mononuclear inflammatory cells are present in the new areas of demyelination in either PL/J or A/J mice, viral antigens are not detected in the CNS beyond 12 days pi. In contrast, in situ hybridization studies using 35S-cDNA HSV probes and performed beyond day 12 pi identify probe-positive cells central to a number of the multifocal CNS demyelinating lesions in A/J mice. Results from studies with inbred and congenic strains of mice indicate that the major histocompatibility complex (H-2) does not determine the development of multifocal CNS demyelination following lip inoculation with HSV I but does influence the morphological appearance of the lesions that do develop.     

Herpes simplex brainstem encephalitis presenting high intensity area on MRI--a case report

A case of herpes simplex encephalitis with high signal intensity area in brainstem on MRI was presented. A 44 year-old woman suffered from oral aphthous ulcerations in the end of 1988, and then it improved naturally. Oral aphtha appeared again on February 1988 followed by resistant fever to antibiotics and right hemiparesis. She was admitted to our hospital on 25 February 1988. Neurological examination revealed mild consciousness disturbance, neck stiffness, right-side deviation of tongue with dysarthria and right hemiparesis with bilateral plantar extensor reflex. Right hemisensory deficit in all modalities and truncal ataxia was also detected. Some aphthous ulcerations were revealed in oral cavity, but there were no ulcers on genitalia nor uveitis. CSF showed 32 mononuclear cells/mm3, protein 52 mg/dl and glucose 97 mg/dl. CSF culture and india ink stain, and serum autoantibodies were all negative. EEG and CT scan with contrast enhancement showed no significant abnormalities. T2-weighted brain MRI revealed high intensity area in the center of the pons. Anti-herpes simplex virus (HSV) type I antibody titer (FA method) in both serum and CSF were highly positive. Neurological symptoms gradually improved on the therapy of aciclovir and adrenal cortico-steroid. High intensity area in the pons on MRI was also gradually reduced. In this case, complete diagnostic differentiation from neuro-Beh?et disease was difficult, but this case did not meet its diagnostic criteria. From the change of anti-HSV antibody titer both in serum and CSF, we diagnosed this case HSV brainstem encephalitis presenting high intensity area in the pons on MRI which has never been reported.     

Clinico-pathological comparative study between brainstem encephalitis of Iizuka type and neuro-Beh?et's disease

We experienced one necropsy case of brainstem encephalitis of Iizuka type (BSE) and one necropsy case of the brain-stem syndrome (BSS) of typical neuro-Beh?et's disease, and compared them clinically and neuropathologically. Clinically both of these cases showed chronic progressive mental disturbance, pseudobulbar paresis, spastic tetraparesis, cerebrospinal fluid pleocytosis, increased protein, and brainstem atrophy observed by X-CT. Neuropathologically, irregular, boundary-indistinct demyelinating lesions and obsolete softening lesions were sporadically found, associated with perivascular lymphocytic infiltration and gliosis centering on the brainstem. In this way, both cases were similar in many points except for the presence or absence of cutaneo-muco-ocular signs specific for Beh?et's disease. Also BSE and BSS reports in the literature showed that both diseases were similar not only in clinical findings consisting of mental disturbance and brainstem signs but also in neuropathological findings with similar topographical distribution of the same histopathological changes, including the variations and diversity of these characteristics. Especially of much interest is their similarity in characteristic mental disturbance. In discriminating BSE from multiple sclerosis and other diseases with exclusive involvement of the brainstem, it is important to understand their clinical characteristics. The characteristic mental disturbance includes damage to memory and sentiment, a change in personality, and lowering in spontaneity, but calculation ability and orientation are comparatively preserved. Of course the similarity in clinical and neuropathological findings does not necessarily mean the identical etiopathogenesis. However, it is possible to consider that neuro-Beh?et's disease (syndrome) may form a wide spectrum with BSE and typical neuro-Beh?et's disease at the both ends, regarding the time and spatial diversity of the appearance of cutaneo-muco-ocular signs.     

A case of brainstem encephalitis caused by herpes simplex virus type 1 with possible infection via trigeminal nerve]

A 24-year-old man was admitted to our hospital because of consciousness disturbance, a stiff neck and various brainstem symptoms including a right one-and-a-half syndrome and right peripheral facial palsy a week after an episode of pharyngitis and right facial herpes simplex. Magnetic resonance imaging of the brain on admission showed high-signal intensities in the right pontine tegmentum, right cerebellar peduncle and vermis on fluid-attenuated inversion recovery imaging. Examination of cerebrospinal fluid yielded mononuclear pleocytosis, elevated protein and increased IgM antibodies to herpes simplex virus (HSV) by enzyme immunoassay. HSV-1 specific antibodies also were detected in serum by neutralization test. We gave a diagnosis of brainstem encephalitis caused by HSV-1. The patient was successfully treated with high dose of acyclovir, steroid and intravenous immunoglobulin. He was discharged without any neurologic sequelae. We herein presented a case of atypical encephalitis due to HSV-1 involving mainly the brainstem with possible infection via right trigeminal nerve and summarized recent 35 cases with herpetic brainstem encephalitis since 1990.     

Skew deviation with ocular torsion: A vestibular brainstem sign of topographic diagnostic value

Fifty-six patients with unilateral brainstem infarctions presenting with skew deviation of the eyes were analyzed for static vestibular function in the roll plane. Ischemic lesions were allocated to the level and side of the brainstem by the clinical syndrome and neuroimaging. Two findings of clinical relevance were obtained: (1) All skew deviations were ipsiversive (ipsilateral eye was undermost) with caudal pontomedullary lesions and contraversive (contralateral eye was lowermost) with rostral pontomesencephalic lesions. (2) All skew deviations were associated with concomitant ocular torsion and tilts of subjective visual vertical toward the undermost eye. Thus, skew deviation or more correctly, ocular skew torsion is a sensitive brainstem sign of localizing and lateralizing value. Evidence is presented that the ocular skew torsion sign indicates a vestibular tone imbalance in the roll plane secondary to graviceptive pathway lesions.     

Clinical correlates of abnormal P14 in median SEPs

Recording median somatosensory evoked potentials (SEPs) from scalp and neck in separate channels with the use of an ear reference, 52 patients had abnormal scalp-recorded P14 associated with normal cervical-recorded N13. The patients had multiple sclerosis or other brainstem or high cervical cord lesions. Evidence of brainstem lesions was found in 35 patients on clinical examination or by brainstem auditory evoked potentials or blink reflex. Abnormalities of P14 were correlated highly with brainstem dysfunction, but high cervical cord lesions could not be excluded by this finding. The localizing value of SEP is improved by measuring the N13 and P14 peaks separately and assessing the cervical cord-brainstem conduction time.     

Sleep disorders caused by brainstem tumor: case report.

Few studies concerning sleep disorders in brainstem lesions or tumors have been published. We report the case of a girl who was operated on for a brainstem tumor at the age of 4 years. In postsurgery, she had hemiparesis of the left side, swallowing difficulties, and severe apneas requiring a tracheotomy with nocturnal ventilation. The child's health improved progressively. Two sleep recordings were performed at 7 and 9 years without nocturnal ventilation. These recordings showed sleep disorders with a decrease in total sleep time and rapid eye movement (REM) sleep. Several central apneas were observed. The apneas were more frequent during REM sleep in the first recording and were associated with desaturation and microarousals.     

Brainstem representation of vestibular evoked myogenic potentials

ObjectiveVestibular evoked myogenic potentials (VEMPs) are caused by a short-latency reflex recorded from averaged electromyography from the sternocleidomastoid muscle evoked by intense auditory clicks. Besides peripheral vestibulopathy, abnormal VEMPs can be caused by lesions of the brainstem. The aim of this study was to analyze the topology of ischemic brain lesions generating pathological VEMPs.MethodsTwenty-nine patients with brainstem infarcts were prospectively studied using VEMPs and MR imaging to evaluate the brainstem representation of the VEMP reflex. Individual brainstem lesions were projected to a standard MR-dataset for normalization. Probabilistic lesion maps were calculated. A digital brainstem atlas was fitted to the lesion maps.ResultsTwelve patients showed unilaterally abnormal VEMPs, 10 patients had normal VEMPs. Seven patients with bilaterally absent VEMPs were not analyzed. Most lesions were located in the lateral medulla oblongata involving the spinal accessory nerve. Most lesions in the pons were associated to anterolateral parts of pyramidal tract fibers. In a few cases, lesions were located in the tegmental area of the pons, including the vestibular nuclei.ConclusionsAbnormal VEMPs may be produced not only by peripheral vestibulopathy but also by brainstem lesions. VEMPs may be influenced by effects caused by lesions located above the level of the vestibular nuclei.SignificanceThis study adds to the knowledge of anatomical brainstem representation of VEMP.     

Comparison of MRI and electrophysiological studies for detecting brainstem lesions in traumatic brain injury

The yield of magnetic resonance imaging (MRI) and electrophysiological studies in detecting brainstem lesions was assessed in 35 patients suffering from traumatic brain injury (Glasgow Coma Scale, 3-10). As an inclusion criterion, all patients had brainstem trauma as revealed by early MRI or electrophysiological studies. Of the 35 cases, 7 (20%) had brainstem lesions detected by MRI only, whereas in 10 patients (29%), electrophysiological examination disclosed impairment of brainstem function with normal MRI. In 18 (51%) subjects, both diagnostic techniques revealed brainstem lesions. The midbrain was the most common location of lesions. Masseter reflex recording had the highest yield (93%) of abnormal findings. No mismatch with respect to site and side of abnormality occurred between MRI and electrophysiological studies. Outcome analysis indicated an unfavorable course for the vast majority (83%) of patients, regardless of the diagnostic means disclosing traumatic brainstem injury. Therefore, both techniques are effective in disclosing traumatic brainstem injury, with diagnostic overlap in about 50% of cases. In contrast to MRI, electrophysiological investigation is easily performed and repeated at low cost in the setting of an intensive care unit, where such patients are typically hospitalized after trauma. In addition to electrophysiological assessment of brainstem function, MRI is recommended in each case having normal electrophysiological findings when brainstem injury is suspected.     

Leigh syndrome with spinal cord involvement due to a hemizygous NDUFA1 mutation

Leigh syndrome, which is a common phenotype of pediatric mitochondrial disease, is a progressive neurodegenerative disease. The typical neuroimaging findings of Leigh syndrome include bilateral symmetric lesions in the basal ganglia and/or the brainstem. However, there are a few reports on spinal cord involvement in patients with Leigh syndrome. In the present case, magnetic resonance imaging (MRI) obtained during infancy revealed symmetric lesions in the substantia nigra of a patient with Leigh syndrome with an NDUFA1 mutation; lesions of the bilateral putamen and brainstem were subsequently observed. Additionally, our patient presented large and extended spinal cord lesions. Therefore, this case is suggesting that we should consider the occurrence of spinal cord lesions as an atypical finding in Leigh syndrome.     

Herpes simplex encephalitis: Immunohistological demonstration of spread of virus via olfactory and trigeminal pathways after infection of facial skin in mice

An immunohistological study of viral antigen (VA) in the brain was carried out in mice which had been infected with herpes simplex type 1 virus (HSV) in the skin of the face. In 77% of the mice with VA in the brain the olfactory system as well as the trigeminal system/brainstem was affected. The remaining 23% had VA in the trigeminal system/brainstem only. Eye swab cultures yielded HSV from all mice with VA in the olfactory system. The ease of access of virus infecting the face to the olfactory system shown in this model may have implications for human infections.     

Latent herpes simplex virus trigeminal ganglionic infection in mice and demyelination in the central nervous system.

Mice were inoculated with herpes simplex virus (HSV) type 1 by gently scraping the skin of the nose with a fine needle. About 80% of the animals developed latent inapparent HSV infections in trigeminal ganglia. Virus was demonstrable for at least 6 months post inoculation (p.i.) by cocultivation of ganglionic tissue with GMK cells. Histologically, trigeminal ganglia revealed infiltrations of inflammatory cells even 6 months p.i. In addition, lesions occurred in the brainstem corresponding to the entry of trigeminal roots, trigeminal tracts and nuclei. Inflammatory cell infiltration, disruption of myelin sheaths and macrophages laden with myelin degradation products were observed 7 days p.i. Fourteen to 30 days p.i. electron microscopy demonstrated completely naked axons. In the transitional region of the trigeminal root denuded axons occurred in the central part of the region while the peripheral myelin, bordering the demyelinated central segments, was intact. Small areas of demyelination were still detectable 3 and 6 months p.i. but there were then also signs of remyelination. Possible mechanisms causing the demyelinations are discussed.     

Isoelectric focusing herpes simplex virus-gB overlay study in brainstem encephalitis

We report a case of herpetic brainstem encephalitis (HBE) retrospectively diagnosed in adult patient. Conventional immunovirological studies failed to disclose the etiology of this patient's affection. An isoelectric focusing-antigen overlay (IEF-O) technique showed that the target of one of the four cerebrospinal fluid oligoclonal bands was herpes simplex virus (HSV)-1 glycoprotein B, indicating a specific anti-HSV immunoresponse restricted to the CNS. IEF-O may represent a useful support for in vivo diagnosis of HBE.