Listerial brainstem encephalitis--treatable, but easily missed.
Listerial brainstem meningitis (LBE), however, is an uncommon, sporadically occurring form of listerial infection that progresses rapidly and is invariably fatal unless treated early. [3-5] Cases are often undetected.  It is characterised by a prodromal febrile illness followed within 4-10 days by the abrupt onset of cranial nerve deficits associated with encephalopathy, hemiparesis, hemisensory loss and/ or cerebellar signs. [3-5] Unlike the other forms of central nervous system (CNS) listeriosis, LBE is striking in respect of the stepwise development of brainstem signs in the absence of meningism. This presentation is probably accounted for by a novel route of infection that exploits retrograde axonal transport to the brainstem along the cranial nerves that supply the oropharynx. [2, 6]
We report on six patients with LBE, of whom five were managed or co-managed by the neurology unit at Tygerberg Hospital, Western Cape, South Africa, during the period January-June 2012. Definite cases were defined as cases with a compatible clinical syndrome (prodrome followed by stepwise neurological deficits due to brainstem disease) and microbiological demonstration of L. monocytogenes in blood, cerebrospinal fluid (CSF) or brain tissue. Probable cases were defined as cases with a compatible clinical syndrome with ancillary tests (brain imaging and CSF analysis) supporting the diagnosis and evidence of improvement after commencement of antilisterial therapy.
The Stellenbosch University Human Research Ethics Committee approved the reporting of clinical material (S13/10/223).
The index case (patient 1) was a 59-year-old woman who presented with a 1-week flu-like illness followed by ataxia and sensory loss involving the face. Thereafter she developed a deteriorating level of consciousness and died within 3 weeks.
At onset she complained of fever, dizziness and unremitting frontal headache, and she was treated with telithromycin followed by moxifloxacin for suspected sinusitis. One week later, she developed hoarseness, numbness of the left cheek and ataxia of the left arm. A chest radiograph was normal. Magnetic resonance imaging (MRI) of the brain showed signal abnormalities in the pons and left middle cerebellar peduncle on fluid-attenuated inversion recovery (FLAIR) sequences, with subtle contrast enhancement on T1-weighted images. Intravenous (IV) methylprednisolone was given for 3 days for a presumptive diagnosis of acute disseminated encephalomyelitis (ADEM), during which her condition remained stable and she was apyrexial. However, a day later, she developed a fever and became comatose, and was found to have bilateral papilloedema. CSF protein and glucose levels were normal, and there were 4 polymorphonuclear cells per high-power field on microscopy. A CSF Gram stain was negative, and neither the CSF nor initial blood cultures yielded growth after 5 days of incubation. Repeat MRI of the brain showed extension of signal abnormalities into both cerebellar peduncles, the cerebellum and rostrally into the basal ganglia. There was no clinical response to treatment with IV corticosteroids and acyclovir. Subsequent MRI brain imaging revealed progression of disease to involve the upper cervical cord, brainstem, cerebellum, bilateral basal ganglia and rostral left cerebral hemisphere. A repeat CSF sample was acellular with normal chemistry and microscopy. The patient died after 17 days of illness. Blood cultures taken on day 15 as well as CSF cultures taken on day 17 cultured L. monocytogenes, and at autopsy L. monocytogenes microabscesses were confirmed (Fig. 1).
We report two definite (patients 1 and 4) and four probable cases of LBE. The clinical data and ancillary tests are summarised in Tables 1 and 2, respectively. LBE typically begins with a prodrome of up to 16 days (median 4 days), [3-4] with isolated cases reported to have prodromes of more than a month.  In our series, the median time before the onset of neurological signs was 5.5 days. Headache (73%), fever (85%) and nausea or vomiting (64%) are the most commonly reported early features, [3, 4] but these were absent in a third of our patients. Mental state at admission is often preserved (59%).  The prodrome is followed by the onset of focal signs of lower brainstem and cerebellar involvement. Patients frequently present with asymmetrical cranial nerve dysfunction (VII, VI, IX, X and V, in order of descending frequency). [3, 5] Untreated patients deteriorate over days with new cranial nerve deficits and the emergence of crossed' or bilateral long-tract signs (hemiparesis more often than hemisensory loss), cerebellar signs and/or encephalopathy. At maximal evolution, most patients have combined cranial nerve deficits and long-tract signs (81%), and more than half have cerebellar signs. [3, 5] Cranial nerve involvement is seen in all patients at the nadir of the illness. Frequently, noncontiguous cranial nerve nuclei will be affected during the course of the illness; for instance, patient 6 had left trigeminal sensory involvement, right abducens palsy and lower motor neuron facial weakness, as well as a left palatal palsy (cranial nerve X), indicating multifocal brainstem involvement. Respiratory failure due to involvement of the medulla may occur early and necessitate ventilatory support. [3, 5] A reduced level of consciousness was present in four of the six patients.
The differential diagnosis of brainstem encephalitis varies depending on population and geographical region.  Broadly, this presentation may be due to demyelination (e.g. multiple sclerosis, ADEM) or autoimmune/inflammatory (e.g. Behcet's disease, paraneoplastic), infectious and very rarely neoplastic diseases (e.g. lymphoma). [7, 8] Infectious causes in adults include viruses, such as entero- and herpesviruses. Surprisingly, however, a bacterial infection such as listeria is one of the most common infectious causes of brainstem encephalitis. In an SA setting, tuberculosis and progressive multifocal leucoencephalopathy due to JC virus infection are also important considerations in the setting of progressive brainstem disease.
With CNS invasion, listeriosis may target the meninges resulting in the typical clinical picture of acute/subacute bacterial meningitis,  but unlike other bacteria may also target the brain parenchyma and specifically the rhombencephalon (pons, medulla, cerebellum). In humans, brainstem infection occurs in up to 11-24% of patients with CNS listeriosis. [3, 5] In LBE, it appears that food-borne bacteria invade the brainstem by retrograde axonal migration along the oropharyngeal cranial nerves.  A postmortem study of nine human cases of LBE revealed brainstem microabscesses that were prominently distributed within the nuclei, tracts and intraparenchymal portions of the cranial nerves innervating the oropharynx (V, VII, IX, X and XII).  Injection of listerial bacteria into the facial nerves of mice was followed 5-10 days later by ipsilateral CNS deficits that were prevented by section of the nerve proximal to the inoculation site.  Similarly, injection of listerial bacteria into the sciatic nerves of mice resulted in a flaccid paraparesis that was prevented by sectioning the sciatic nerve proximal to the inoculation site.  Actin-dependent locomotion of L. monocytogenes along microtubules has been demonstrated in other eukaryote cells and remains the most plausible explanation for bacterial propagation along axons. 
Factors predisposing to LBE in humans have not been identified. Unlike listerial meningitis, where two-thirds of patients are immunosuppressed by medication, advanced age or comorbid disease, LBE has been reported to occur mainly in immunocompetent adults.  Of our patients, three had comorbid conditions such as immunosuppressant therapy, diabetes, alcoholism and HIV infection.
Of importance, CSF abnormalities in LBE are not typical of bacterial infections of the CNS, and one in five patients may have normal CSF on initial sampling.  A relatively normal CSF glucose level, moderate lymphocytic pleocytosis and a moderately increased CSF protein level may mistakenly be attributed to viral or mycobacterial infection, or, as in one of our patients, to inflammatory demyelination. [3-5] The CSF was normal in one of our patients, and patient 3 had a neutrophil-predominant mild pleocytosis.
In a review of patients with LBE by Armstrong and Fung,  CSF Gram stains were positive in only 10% of cases, with CSF cultures positive in 33-41% and blood cultures in 61%. Positive cultures were obtained in two of our six patients (two on blood, one on CSF).
MRI is the radiological investigation of choice in the diagnosis of brainstem disease. In our series, findings on MRI were abnormal in all patients studied (five scanned, see example in Fig. 2), and showed T2 signal change in the brainstem, cerebellar peduncles and cerebellum associated with variable enhancement on contrasted T1-weighted images. Computed tomography (CT) is less sensitive than MRI in LBE; [3-5] two of five patients in this study had abnormal findings. Striking cranial nerve enhancement may be seen on MRI,  or, less often, on CT, and was present in three of our six patients (two MRI, one CT). Radiological appearances are nonspecific, however, and in a region of high tuberculosis prevalence listerial brainstem abscesses may be radiologically indistinguishable from tuberculomas. In the absence of microbiological or histopathological confirmation, empiric treatment for both L. monocytogenes and Mycobacterium tuberculosis may have to be considered. Rapid radiological and clinical improvement would favour listeriosis over tuberculosis as the likely cause.
Supratentorial abscess formation may occur in conjunction with LBE and was present in patients 1 and 6 in our series. [3, 13] Following the prodrome and initial neurological deficit, patient 6 received high-dose corticosteroids for a presumed diagnosis of ADEM, after which disease progression appeared stable until abrupt deterioration on day 35. MRI showed left thalamic and parietal lobe abscess formation. A biopsy specimen of brain tissue for culture, obtained 5 days after starting intravenous ampicillin, was negative. The patient made a remarkable recovery.
High-dose ampicillin is the drug of choice. The recommended treatment is ampicillin 2 g IV 4-hourly for 21 days,  although some authors suggest longer treatment periods and the addition of an aminoglycoside.  Gentamicin acts synergistically with ampicillin and may be added in patients with immune impairment.!3! Co-trimoxazole is an acceptable alternative in penicillinallergic patients.  It is important to note that third-generation cephalosporins, commonly recommended as first-line therapy for bacterial meningitis of unknown cause, have no activity against Listeria species.
Untreated patients invariably die, [3-5] usually within 5-18 days after symptom onset.  Treated survival rates of 49-64% have been reported. [3, 4] Early treatment with ampicillin is associated with improved survival (76%) compared with delayed treatment or initial treatment with inappropriate antibiotics such as cephalosporins.  Neurological dysfunction improves within 2-7 days of drug initiation.  In our series, no patient suffered disabling sequelae.
Small epidemics of listeriosis from contaminated food sources are frequently reported in countries where the infection is notifiable, and the source of the contaminated food has often been identified. Given the high fatality rate of listeriosis, contaminated food is an important public health hazard. In SA, however, the disease is not notifiable at present. It is of interest that, as three patients in this series presented within 6 months of each other and came from geographically closely related areas, the infection may have been caused by a common contaminated food source.
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Accepted 1 August 2014.
Pearl Fredericks and Jonathan Carr are affiliated to the Division of Neurology, Department of Internal Medicine, Tygerberg Hospital and Faculty of Medicine and Health Sciences, Stellenbosch University, Tygerberg, Cape Town, South Africa. Marcell Britz is a specialist neurologist in private practice in Port Elizabeth, Eastern Cape, South Africa. Roland Eastman and Kathleen Bateman are affiliated to the Division of Neurology, Department of Medicine, Groote Schuur Hospital
and Faculty of Health Sciences, University of Cape Town, South Africa.
Corresponding author: K Bateman (email@example.com)
Table 1. Clinical presentation, course and outcomes Patient 1 2 Geographical PE, E Cape Caledon, location W Cape Age 59 37 (years) Gender F M Comorbid Recent Hpt, DM disease sinusitis Length of 6 3 prodrome (days) Symptoms HA, dizziness, Fever, (in order facial numbness, dizziness, of onset) hoarseness ataxia Signs (in Fever, L CN V2 Fever, nystag, order of (S), CN X, L arm L dysmetria, onset) dysmetria, coma gait ataxia (d3); drowsiness, apnoea (d6); bilat CN IV, L CN VII (LMN), nystag, CN X, mild quadriparesis (d8) Antibiotics TEL, MXF AMX (d2), CRO (d3) prior to cultures Treatment MP (dll) AMP (d8); ACV (d5); RHZE (d8-d22) Nadir d10 Outcome Death (dl7) Alive, no focal signs (d41) Patient 3 4 Geographical Paarl, Kleinmond, location W Cape W Cape Age 51 36 (years) Gender M F Comorbid HIV *, ethanol RA on disease abuse immuno- suppressants Length of 5 1 prodrome (days) Symptoms Unilat HA; fever, dysarthria, (in order N&V, gait ataxia, dysphagia, of onset) dysphonia (d5); L numb L arm facial numbness, D/V (d6) Signs (in R Horner's, Fever, coma, order of bilat CN VI, nystag, bilat ptosis, bilat onset) L CN V (S), L gaze palsies, skew CN X, worsening deviation, R CN VII L dysmetria, (LMN), quadriparesis, gait ataxia (dll) hyperreflexia (dll) Antibiotics RHZE (d5) prior to cultures Treatment AMP (dll) ACV, CRO, DXM (dll); AMP (dl2); GEN (dl4) Nadir dl3 Outcome Alive, residual Death (d!8) facial numbness, mild gait ataxia (d33) Patient 5 6 Geographical Villiersdorp, Atlantis, location W Cape W Cape Age 25 32 (years) Gender M F Comorbid None None disease Length of 7 7 prodrome (days) Symptoms HA, dizziness; HA; dizziness, (in order R facial palsy, gait ataxia (d7); of onset) N&V (d7) L facial numbness, R facial palsy (dl5); D/V, N&V Signs (in Fever, meningism, R R CN VI, R CN VII, order of CN VII (LMN) (d7); L CN X, L hemisensory, onset) drowsiness, vertigo, bilat leg dysmetria hiccups, L gaze palsy, R (dl5), R hemiplegia hemisensory (dl7) (d35) Antibiotics prior to cultures Treatment CRO (dl4); DXM (dl7); MP (d 15); CRO, AMP (d20) TMP/SXT, MTZ, AMP (d35) Nadir d20 d35 Outcome Alive, residual mild Alive, no focal R facial palsy, L gaze signs (d72) palsy (d60) PE = Port Elizabeth; E Cape = Eastern Cape Province, South Africa; W Cape = Western Cape Province; F = female; M = male; Hpt = hypertension; DM = diabetes mellitus; RA = rheumatoid arthritis; CN = cranial nerve; S = sensory; L = left; R = right; bilat = bilateral; unilat = unilateral; LMN = lower motor neuron; nystag = nystagmus; HA = headache; N&V = nausea and vomiting D/V = double vision; d = days since illness onset; TEL = telithromycin; MXF = moxifloxacin; AMX = amoxicillin; CRO = ceftriaxone; RHZE = rifampicin, isoniazid, pyrazinamide, ethambutol; MP = methylprednisolone; AMP = ampiciUin; ACV = acyclovir; DXM = dexamethasone; GEN = gentamycin; TMP/SXT = trimethoprim/sulfamethoxazole; MTZ = metronidazole. * Not on combination antiretroviral therapy. Table 2. Laboratory, pathology and radiological investigations Patient 1 2 Inflammatory markers WCC 13 13.07 CRP ND 97 CSF Cells (PMN, Ly, E) 4, 0, 0 11, 484, 5 Protein (g/L) 0.3 0.8 Glucose (mmol/L) 6.3 6 L. monocytogenes culture Blood Pos(d15) Neg (x 2) CSF Pos(d17) Neg Brain biopsy Pos ND CT ND N MRI Distribution L Po, MCP, L cerebral ped, of high and Cb L MCP, L Cb signal on T2WI & FLAIR sequences Enhancement Subtle, Complete ring pattern on T1WI incomplete pre-/post ring dorsal Po gadolinium CN enhancement N Y present Radiological Demyelination Abscess differential (BS/ADEM), reported glioma Patient 3 4 Inflammatory markers WCC 6.52 12.17 CRP 86 85 CSF Cells (PMN, Ly, E) 66, 21, 6 12, 68, 9 Protein (g/L) 0.69 0.5 Glucose (mmol/L) 3.2 2.8 L. monocytogenes culture Blood Neg (x 2) Pos (x 2) CSF Neg ND Brain biopsy ND ND CT Well-defined Poorly defined ring lesions lesions dorsal Po, R Po, R MCP; L MCP3 incomplete ring enhancement MRI Distribution ND R cerebral ped, of high R MCP, Me, signal on upper cord T2WI & FLAIR sequences Enhancement ND Incomplete pattern on T1WI ring pre-/post gadolinium CN enhancement Y Y present Radiological Tuberculoma, Demyelination differential listerial (ADEM) reported abscess Patient 5 6 Inflammatory markers WCC 15.31 9.57 CRP ND ND CSF Cells (PMN, Ly, E) 4, 375, 0 0, 60, 0 Protein (g/L) 0.59 0.63 Glucose (mmol/L) 3.3 3.3 L. monocytogenes culture Blood Neg (x 2) Neg (x 2) CSF Neg Neg Brain biopsy ND ND CT N N MRI Distribution R cerebral ped, Mb, dorsal Po, of high R MCP, dorsal Cb vermis, signal on Po, Me, upper Me; after 9 d T2WI & FLAIR cord interval: sequences new lesions L thalamic, L parietal Enhancement Patchy, Patchy, pattern on T1WI nodular nodular; pre-/post complete ring gadolinium CN enhancement N N present Radiological Demyelination Abscess, differential (ADEM) demyelination reported WCC = white cell count; CRP = C-reactive protein; CSF = cerebrospinal fluid; PMN = polymorphonuclear cell; Ly = lymphocyte; E = erythrocyte; CT = computed tomography; MRI = magnetic resonance imaging; T2WI = T2-weighted imaging; FLAIR = fluid attenuated inversion recovery; Pos = positive; Neg = negative; d = days since symptom onset; ND = not done; N = normal; L = left; R = right; Mb = midbrain; Po = pons; MCP = middle cerebellar peduncle; Cb = cerebellum; Me = medulla; ped = peduncle; CN = cranial nerve; N = no; Y = yes; BS = Bickerstaff encephalitis; ADEM = acute disseminated encephalomyelitis.
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|Title Annotation:||CLINICAL ALERT|
|Author:||Fredericks, P.; Britz, M.; Eastman, R.; Carr, J.A.; Bateman, K.J.|
|Publication:||South African Medical Journal|
|Date:||Jan 1, 2015|
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