Infectious Mononucleosis

Also known as: Glandular fever, EBV infection

A clinical syndrome of fever, pharyngitis and lymphadenopathy caused predominantly by Epstein Barr virus, a gamma herpesvirus, with atypical lymphocytosis and heterophile antibodies.

Virology and pathogenesis

Epstein Barr virus is transmitted in saliva, which is why it is called glandular fever or the kissing disease, with an incubation period of 30 to 50 days. The virus infects oropharyngeal epithelium and then B lymphocytes through the CD21 receptor, driving polyclonal B cell proliferation. The clinical syndrome is largely produced by the vigorous CD8 positive cytotoxic T cell response to these infected B cells, which accounts for the atypical lymphocytes, that is Downey cells, the lymphadenopathy, the splenomegaly and the systemic symptoms. The virus then establishes lifelong latency in memory B cells with intermittent asymptomatic shedding in saliva for months and years afterwards.

Over 90 percent of adults worldwide are seropositive. Primary infection in early childhood is usually asymptomatic or mild, which is why the classical syndrome is a disease of adolescents and young adults in higher income settings where primary infection is delayed.

Other causes of a mononucleosis like syndrome, which are heterophile negative

Cytomegalovirus, which accounts for the majority of heterophile negative cases, with less prominent pharyngitis and lymphadenopathy and more prominent hepatitis.
Acute HIV seroconversion, which is the diagnosis that must not be missed, presenting with fever, pharyngitis, rash, generalised lymphadenopathy and mucocutaneous ulceration.
Toxoplasma gondii, with prominent cervical lymphadenopathy and little pharyngitis.
Human herpesvirus 6, adenovirus, hepatitis viruses, rubella.
Drug reactions, including DRESS syndrome.

Associated malignancies and conditions

Epstein Barr virus is associated with nasopharyngeal carcinoma, Burkitt lymphoma, Hodgkin lymphoma, post transplant lymphoproliferative disorder, gastric carcinoma and, in the immunocompromised, oral hairy leukoplakia and central nervous system lymphoma. X linked lymphoproliferative disease, that is Duncan syndrome, produces fulminant and often fatal primary Epstein Barr infection.

Prodrome of 3 to 5 days with malaise, fatigue, headache, myalgia and anorexia.
Fever, often prolonged for 1 to 2 weeks and occasionally longer.
Severe sore throat with marked odynophagia, which is the symptom that brings most patients to attention.
Profound fatigue, which is out of proportion to other findings and which is characteristically prolonged, persisting for weeks to months after the acute illness.
Anorexia and reduced oral intake.

Signs

Markedly enlarged tonsils, frequently kissing, with a thick grey white membranous exudate that is more confluent than the follicular exudate of streptococcal disease.
Palatal petechiae at the junction of the hard and soft palate, present in around a third and reasonably specific.
Generalised lymphadenopathy, characteristically involving the posterior cervical chain in addition to the anterior chain, which is a useful discriminator from streptococcal tonsillitis where adenopathy is anterior. Axillary, inguinal and epitrochlear nodes may be involved.
Splenomegaly in around 50 percent, maximal in the second and third weeks.
Hepatomegaly in 10 to 20 percent, with mild jaundice in around 5 percent.
Periorbital oedema, which is an early and characteristic sign.
A maculopapular rash in around 5 percent spontaneously, but in 70 to 90 percent of patients given amoxicillin or ampicillin. This rash is a virus induced immune phenomenon, not a penicillin allergy, and mislabelling it as such wrongly restricts antibiotic choice for the rest of the patient's life. This point must be explained clearly to the patient and recorded.

Red flags

Stridor, drooling, inability to swallow saliva or lie flat, indicating airway obstruction from tonsillar and pharyngeal oedema. Airway obstruction occurs in around 1 percent and is the commonest indication for admission.
Severe left upper quadrant or shoulder tip pain, hypotension and abdominal distension, indicating splenic rupture. This occurs in around 0.1 to 0.5 percent, usually in the second or third week, and in around half of cases without any preceding trauma.
Marked jaundice and coagulopathy, indicating severe hepatitis.
Pallor, jaundice and dark urine, indicating autoimmune haemolytic anaemia.
Petechiae and bleeding, indicating severe thrombocytopenia.
Neurological features: headache, neck stiffness, confusion, seizures, cranial nerve palsies, ascending weakness. Neurological complications occur in 1 to 5 percent and include meningoencephalitis, Guillain Barré syndrome, transverse myelitis, Bell palsy and Alice in Wonderland syndrome with distorted perception of size and shape.
Persistent fever beyond 3 weeks, weight loss and progressive lymphadenopathy, requiring exclusion of lymphoma.

Full blood count with differential and film: lymphocytosis above 50 percent of white cells, with atypical lymphocytes exceeding 10 percent. Atypical lymphocytes are large, with abundant basophilic cytoplasm indented by adjacent red cells. Mild thrombocytopenia and neutropenia are common.
Heterophile antibody test, that is the Monospot or Paul Bunnell test, which detects immunoglobulin M antibodies agglutinating horse or sheep erythrocytes. Specificity is high at around 95 to 99 percent, but sensitivity is limited: it is negative in the first week in around 25 percent, and it is unreliable in children under 4 years, in whom false negative rates approach 50 percent. A negative test early does not exclude the diagnosis and should be repeated at 1 week.
Epstein Barr virus specific serology, which is definitive:
Viral capsid antigen immunoglobulin M positive with viral capsid antigen immunoglobulin G positive and Epstein Barr nuclear antigen negative indicates acute primary infection.
Viral capsid antigen immunoglobulin G positive with Epstein Barr nuclear antigen positive and viral capsid antigen immunoglobulin M negative indicates past infection.
Epstein Barr nuclear antigen antibodies appear only 6 to 12 weeks after infection, which is what makes their absence useful for confirming acute disease.
Epstein Barr virus polymerase chain reaction for viral load, used in immunocompromised patients and in monitoring for post transplant lymphoproliferative disorder rather than in routine diagnosis.
Liver function tests, which are abnormal in 80 to 90 percent with a transaminitis, usually mild and self limiting.
HIV testing with a fourth generation antigen antibody assay or HIV RNA in every adult with a mononucleosis like illness, since acute retroviral syndrome is clinically indistinguishable and antibody testing alone may be negative during seroconversion. This test is omitted far too often.
Cytomegalovirus and Toxoplasma serology in heterophile negative cases.
Throat swab, remembering that streptococcal carriage occurs in 5 to 30 percent and that a positive swab does not exclude mononucleosis or justify amoxicillin.
Direct antiglobulin test where haemolysis is suspected.
Abdominal ultrasound where splenomegaly needs quantification or splenic rupture is suspected, and urgent contrast computed tomography for suspected rupture in a stable patient.
Lymph node biopsy where lymphadenopathy is progressive, persistent beyond 4 to 6 weeks, or associated with B symptoms, since Hodgkin lymphoma is the important differential.

Supportive care is the treatment. The specific interventions are aimed at the airway, the spleen and the small number of severe complications.

Supportive treatment

Rest, with a graduated return to normal activity guided by symptoms.
Adequate hydration, which is the main determinant of whether admission is needed.
Paracetamol 1 g every 6 hours in adults, 15 mg/kg every 6 hours in children.
Ibuprofen 400 mg every 8 hours in adults, 10 mg/kg every 8 hours in children, with caution where thrombocytopenia is significant.
Avoid aspirin in children under 16, given Reye syndrome.
Benzydamine spray or mouthwash, and salt water gargles.
Cool fluids, ice and soft diet.

Antibiotics

Not indicated, since the illness is viral.
Where a bacterial superinfection or coexisting streptococcal infection genuinely requires treatment, use phenoxymethylpenicillin 500 mg four times daily or clarithromycin, and never amoxicillin or ampicillin.
Explain the amoxicillin rash to patients who have already received it, and document explicitly that it is not a penicillin allergy.

Corticosteroids

Not indicated routinely, since they do not shorten the illness and carry risks in a viral infection. They are indicated for specific complications:

Impending or established airway obstruction: dexamethasone 10 mg intravenously in adults, or 0.6 mg/kg to a maximum of 10 mg in children, repeated as required, or prednisolone 1 mg/kg daily tapering over 5 to 7 days.
Severe thrombocytopenia with bleeding.
Autoimmune haemolytic anaemia.
Neurological complications including meningoencephalitis.
Myocarditis and pericarditis.
Severe hepatitis with impending failure.

Airway management

Admit any patient with stridor, drooling, inability to swallow saliva or inability to lie flat.
Humidified oxygen, corticosteroid, and nursing in a monitored setting with anaesthetic support available.
A nasopharyngeal airway is often sufficient and is well tolerated.
Where intubation is required, it should be performed by the most experienced anaesthetist available with a difficult airway trolley and surgical airway equipment prepared, since these airways are oedematous, friable and bleed readily.
Emergency tonsillectomy is occasionally required for airway obstruction unresponsive to corticosteroid, and it is effective, though the operative field is highly vascular and bleeding is greater than in routine tonsillectomy. It should be performed by an experienced surgeon.

Splenic rupture and activity restriction

Avoid contact sports, collision sports, heavy lifting and vigorous exertion for a minimum of 3 to 4 weeks from symptom onset, and until splenomegaly has resolved. Most ruptures occur in the second and third weeks.
Routine ultrasound to confirm splenic normalisation before return to sport is used by some, though spleen size varies with body habitus and the correlation with rupture risk is imperfect. Symptom resolution and a normal examination are the practical criteria for most patients, with imaging for athletes and those in high risk occupations.
Splenic rupture presents with left upper quadrant pain, shoulder tip pain from diaphragmatic irritation, hypotension and abdominal distension. It is a surgical emergency: resuscitate with intravenous access, crossmatched blood and fluids, obtain urgent computed tomography in a stable patient, and involve general surgery. Splenic preservation with observation or angioembolisation is preferred where haemodynamically feasible; splenectomy for instability. Vaccinate and give antibiotic prophylaxis after splenectomy.

Antivirals

Aciclovir reduces oropharyngeal viral shedding but does not improve clinical outcomes, since the illness is driven by the immune response rather than viral replication. It is not indicated in immunocompetent patients. It has a role in severe disease in the immunocompromised, in combination with reduction of immunosuppression.

Complications requiring specific management

Haematological: haemolytic anaemia, thrombocytopenia, aplastic anaemia and haemophagocytic lymphohistiocytosis, the last of which is rare, life threatening and requires immediate haematology involvement with immunochemotherapy.
Neurological: as listed above, managed supportively with corticosteroid and, for Guillain Barré syndrome, immunoglobulin or plasma exchange.
Cardiac: myocarditis and pericarditis.
Renal: interstitial nephritis and glomerulonephritis.
Post transplant lymphoproliferative disorder in immunosuppressed patients, requiring reduction of immunosuppression, rituximab and, where necessary, chemotherapy.
Chronic active Epstein Barr virus infection, a rare severe condition with persistent symptoms and high viral load lasting beyond 3 months.

Prolonged fatigue

Fatigue persists beyond 6 months in around 10 percent. Explain this at the outset, since patients who are not warned interpret prolonged fatigue as treatment failure or as a new illness. Manage with graduated activity, sleep hygiene, and screening for and treatment of depression. Avoid extended investigation in the absence of new findings.

Advice and follow up

Explain the natural course: fever settles in 1 to 2 weeks, pharyngitis in 1 to 2 weeks, lymphadenopathy over weeks, and fatigue over weeks to months.
No return to contact sport for at least 4 weeks.
Avoid alcohol while liver function is abnormal.
Transmission is by saliva, so avoid sharing utensils and kissing during the acute illness, though isolation is unnecessary given the prolonged asymptomatic shedding that follows.
Repeat full blood count and liver function where these were markedly abnormal.
Persistent lymphadenopathy beyond 4 to 6 weeks, particularly if progressive or with B symptoms, requires imaging and node biopsy.

Clinical toolsCalculators

BMI GCS EDD Parkland Formula

Corrected Sodium Corrected Calcium Anion Gap Creatinine Clearance Insulin Calculations qSOFA Wells PE Wells DVT CHA₂DS₂-VASc HAS-BLED CURB-65 Centor/McIsaac

Bilateral Vestibulopathy

Bilateral impairment or loss of peripheral vestibular function, producing unsteadiness and oscillopsia rather than vertigo, since there is no asymmetry between the two sides to generate a sense of spinning. This absence of vertigo is precisely why the condition is missed, often for years, while patients are investigated for cerebellar and neurological disease.

Functional consequence

Loss of the vestibulo ocular reflex means that images are not stabilised on the retina during head movement, producing oscillopsia. Loss of vestibulospinal input means balance depends entirely on vision and proprioception, so patients are severely destabilised in darkness and on uneven or compliant surfaces where both of those channels are degraded.

Causes

Ototoxicity, principally aminoglycosides, which accounts for around 15 to 20 percent. Gentamicin is the classical agent and can produce complete bilateral vestibular loss with entirely preserved hearing at conventional doses and normal serum levels, since vestibulotoxicity is not dose predictable.
Idiopathic in around 20 to 50 percent.
Bilateral Ménière disease.
Meningitis, particularly bacterial.
Autoimmune inner ear disease, including Cogan syndrome with interstitial keratitis, and systemic vasculitis.
Neurodegenerative disease, notably cerebellar ataxia with neuropathy and vestibular areflexia syndrome, which combines cerebellar ataxia, sensory neuropathy and bilateral vestibulopathy and is commonly caused by biallelic RFC1 repeat expansions.
Bilateral vestibular schwannomas in neurofibromatosis type 2, and after bilateral tumour surgery.
Superficial siderosis, producing hearing loss, ataxia and vestibular loss with characteristic magnetic resonance findings.
Sequential bilateral vestibular neuritis, which is uncommon.
Congenital, in association with syndromic hearing loss including Usher type 1 and CHARGE syndrome, presenting as delayed independent walking.

Unsteadiness of gait, markedly worse in the dark, on uneven ground, and when visual or proprioceptive cues are removed. Patients describe being unable to walk at night without a light and being unsteady in the shower with the eyes closed.
Oscillopsia: the visual scene appears to bounce or jump during walking, running or driving on a rough surface. Patients report being unable to read road signs while walking or to recognise faces of people passing them.
Absence of vertigo, unless the loss developed asymmetrically.
Falls, and in the elderly this may be the only presentation.
Cognitive complaints, including spatial memory and navigation difficulty, since vestibular input contributes to hippocampal spatial processing.
Anxiety and avoidance of activity, with progressive deconditioning.
History of aminoglycoside exposure, meningitis, or the systemic conditions listed above. Ask specifically about intravenous gentamicin, which patients rarely volunteer.

Examination

Bilaterally positive head impulse test, with catch up saccades on turning to both sides. This is the key bedside finding.
Positive dynamic visual acuity: a drop of three or more lines on the Snellen chart when the head is oscillated at 2 Hz compared with the static acuity.
Positive Romberg test, dramatically worse with eyes closed, and inability to perform tandem gait.
Wide based unsteady gait, worse with eyes closed.
No spontaneous nystagmus, which is expected since the loss is symmetrical.
Examine for associated neurological signs: cerebellar signs, peripheral neuropathy with absent ankle reflexes and impaired vibration sense, and ocular abnormalities.

The diagnostic criteria require chronic vestibular syndrome with unsteadiness worse in darkness or on uneven ground, or oscillopsia during walking or head movement, plus objectively reduced bilateral vestibular function on testing.

Vestibular testing, which is required for diagnosis

Video head impulse testing with horizontal vestibulo ocular reflex gain below 0.6 bilaterally.
Caloric testing with a reduced response bilaterally, conventionally a sum of bithermal maximal peak slow phase velocity below 6 degrees per second on each side.
Rotational chair testing with a horizontal gain below 0.1 at 0.1 Hz and a phase lead above 68 degrees. Rotational testing is the most sensitive method for detecting bilateral loss and can identify partial loss missed by other tests.
At least one of these objective tests must be abnormal to establish the diagnosis.

Additional assessment

Pure tone audiometry, since concurrent hearing loss points to specific causes and influences rehabilitation.
Vestibular evoked myogenic potentials to assess otolith function.
Magnetic resonance imaging of the brain and internal auditory meati to exclude bilateral schwannomas, superficial siderosis with its characteristic hypointense rim on gradient echo sequences, and cerebellar atrophy.
Neurological assessment with nerve conduction studies for peripheral neuropathy, particularly where cerebellar ataxia with neuropathy and vestibular areflexia syndrome is suspected. Genetic testing for RFC1 repeat expansion where the triad is present.
Autoimmune screen: erythrocyte sedimentation rate, antinuclear antibody, antineutrophil cytoplasmic antibody, and syphilis serology.
Detailed drug history with specific enquiry about aminoglycosides, including intravenous courses during hospital admissions for other reasons.
Full blood count, renal function, glucose, vitamin B12 and thyroid function.

There is no treatment that restores lost vestibular function. Management centres on rehabilitation using sensory substitution, prevention of further loss, and falls prevention.

Treat identifiable causes

Stop and permanently avoid all ototoxic drugs, and flag the record clearly.
Immunosuppression for autoimmune disease: prednisolone 1 mg/kg daily initially with steroid sparing agents under rheumatology supervision, which may arrest progression in Cogan syndrome and vasculitis.
Treat the underlying systemic or neurological condition.
Identify the cause of superficial siderosis, which is usually a chronic source of subarachnoid bleeding, and treat it surgically where identified.

Vestibular rehabilitation, adapted to the absence of function

The strategy differs fundamentally from unilateral loss. There is no residual function to adapt, so the goal is substitution rather than adaptation.

Substitution training using vision and proprioception, teaching patients to use saccadic and pursuit strategies and pre programmed compensatory eye movements to reduce oscillopsia.
Gaze stabilisation exercises are still valuable in partial loss, where residual function can be enhanced.
Balance training progressing through conditions of reducing sensory input, always within safe limits.
Gait training with an emphasis on visual scanning strategies and on shortening stride and widening base on uneven terrain.
Aerobic conditioning, since deconditioning compounds the disability.
Programmes must be prolonged, typically 6 months or more, and outcomes are more modest than in unilateral loss.

Practical adaptations and safety, which matter more here than in any other vestibular condition

Night lighting throughout the home, particularly on stairs and the route to the bathroom, since darkness removes the visual channel on which the patient now depends entirely.
A walking aid, which provides both support and additional proprioceptive input through the hand.
Remove home hazards: loose rugs, trailing cables, poor lighting, and low contrast steps.
Advise against swimming alone and against swimming underwater, where disorientation is potentially fatal because visual and proprioceptive cues are removed simultaneously.
Advise against working at height, on ladders and with dangerous machinery.
Driving assessment, since head movement while driving produces oscillopsia. Many patients can drive safely with adaptations, but this requires formal assessment.
Review all medications for those that impair balance, particularly sedatives, antihypertensives and anticholinergics.
Falls prevention: strength and balance training, vitamin D supplementation where deficient, bone density assessment and osteoporosis treatment, and a formal falls service referral.

Emerging interventions

Vestibular implants, which deliver motion encoded electrical stimulation to the ampullary nerves, have shown restoration of a partial vestibulo ocular reflex and functional improvement in early trials and are available in a small number of specialist centres. They remain investigational.
Sensory substitution devices delivering head position information through vibrotactile or tongue based stimulation have shown benefit in trials but are not widely available.

Psychological support and follow up

Anxiety and depression are common and disabling. Screen for them and treat.
The condition is frequently misattributed for years before diagnosis, and patients often derive substantial benefit simply from having an explanation.
Regular review with objective vestibular testing to detect progression, annual falls risk assessment, and audiological review where hearing is also affected.
Genetic counselling where a hereditary cause is identified.

Infectious Mononucleosis

Overview

Clinical Features

Diagnosis

Management

Overview

Clinical Features

Diagnosis

Management