Case Presentation & DiscussionDr. Mohammed Abdul-LatifDr. Curtis Osborne

Presentation• 59 year old lady• 6/6/16

▫Admitted with cough, SOB and generally unwell▫Admitted to ITU with severe T1RF requiring CPAP.

Managed for severe CAP• 18/6/16- Discharged to the ward after 2 weeks

with improvement in overall self• 6/7/16- Discharged back home, passing PT

assessment and community PT organised. Some generalised weakness described but attributed to ITU stay and severity of illness.

Presentation•7/7/16 – Presented to Southend A&E with

‘unsteadiness’ and ‘slurred speech’. Re-admitted as failed discharge

•Worsened weakness, particularly in the legs. Dysarthia and blurred vision.

•Progressively worsening neurology during admission prompting investigation

Presentation•Background

▫Mobile and independant in ADLs. Lived alone and rarely left the house. No NOK available. Was thinking about moving to sheltered accommodation as finding life increasingly difficult

▫PMH – Large abdominal hernia, T2DM, HTN▫SH – Non smoker, limited ETOH, no

recreational drugs ▫DH – Gliclazide, Ramipril, Atorvastatin▫FH – Nil significant

Examination•Observations stable. Apyrexial•Chest – Bibasal crackles. HS I + II +O•Abdomen – Soft, large reducible hernia•MSK – Pitting oedema shins

Examination•Cranial nerves

▫Mild loss of smooth pursuit▫No opthalmoplegia. ?RAPD R▫Fundoscopy difficult to perform▫Cranial nerves examined otherwise intact

Examination　 　　　　　　　　　　　　　　 　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　　 Right 　　 　　　　 Left

Hip Flexion 　　　　 　 2/5 　 　　　　　 2/5

Hip Extension 　　　　 2/5 　 　　　 　　　 2/5

Knee Flexion 　　 　　 2/5 　 　　　 　　 2/5

Knee Extension 　　　 2/5 　 　　　 　　　 2/5

Ankle Dorsiflexion 　　 4-/5 　 　 　　　　　 4/5

Plantarflexion 　　　　 4/5 　 　　　　　　　 4/5

EHL 　　　　　 4/5 　　　　　　　 4+/5Tone N +

ExaminationReflexes:

　　　　　　　　　　 Right 　　　　　　 Left

B 　　　　　　　 2+ 　　　　　　　　　　　 2+

T 　　　　　　　 2+ 　　　　　　　　　　　 2+

S 　　　　　　　 2+ 　　　　　　　　　　　 2+

K 　　　　　　　 2+ 　　　　　　　　　　　 2+

A 　　　　　　　 1+ 　　　　　　　　　　　 1+

P 　　　　　　　 Up Up

Examination•Sensation:

Pin prick intact in all myotomes

Vibration intact in UL, reduced to the knee bilaterally in lower limbs

Proprioception reduced to ankle bilaterally

Examination•Unable to assess gait (unable to walk)•Dysmetria L>R. Dysdiadokinesis L•Dysarthia

Differentials?

Investigations

Investigations• MRI HEAD: There has been a reduction in the extent of T2/FLAIR

signal abnormality in the midbrain, superior cerebellar peduncles and at the right middle cerebellar peduncle/pons. The superior cerebellar peduncles have reduced in volume since 20/7/2016 and the previously shown pathological enhancement in these regions is also less conspicuous on the current imaging in keeping with an evolving inflammatory process. No new focal FLAIR abnormality is identified and there are no areas of restricted diffusion. No new intracranial abnormality is shown.

• MRI WHOLE SPINE: As before, there is extensive signal abnormality throughout the lower cervical and thoracic spinal cord with a confluent segment extending from T7-T10 and more patchy involvement in the cervicothoracic cord superiorly. The corresponding axial slices show predominantly peripheral lesions and, accounting for artefact on the post-contrast imaging, there is no convincing associated enhancement. There are no definite new cord lesions.

• CT CAP - ?Liver cirrhosis

Investigations•Microbiology

▫Virology –CMV + VZV detected, otherwise NAD

▫Cultures –NAD

•Immunology▫Autoimmune screen NAD (ANCA only mild

positive)▫Neurology Antibody screen – NAD▫Protein electrophoresis – Polyclonal bands

Investigations•Haematology

▫WCC 35 (Neutrophilia)▫Blood film – Toxic shift (Metamyelocytes)

•CSF (At Southend)▫WCC 1, RBC 123, Pro 0.26▫OCB – Matched LgG pattern

Investigations•VEP -Pattern reversal visual evoked potentials

show a well formed response from the left eye with a normal P100 latency. However, there is no reproducible response from the right eye

•SEPs -In summary, the upper limb somatosensory evoked potentials are normal. The abnormalities in the lower limbs (borderline delayed cortical response (P40) when stimulating the right tibial nerve) could be in keeping with central demyelination.

Impression•Longitudinally extensive transverse

myelitis 　 with midbrain/superior cerebellar peduncle involvement

•?NMO/?ADEM

Management• 21/7/6 – Commenced on 3 days course IVMP

followed by PO Prednisolone• 28/7/16- Transferred to RLH for further

investigation and management• Managed with 4 days of PLEX on admission with

weaning PO steroids• Noticeable improvement in neurology throughout

admission• On admission : bedbound, slurring speech• Eventually managing to mobilise with a frame

with minimal assistance with normalising speech

Management•Spiking temperatures. No organism found

▫WCC persistently raised – likely reactive▫?Murmur TTE + TOE –NAD

•Although improved neurology, she remained very anxious and tearful about prospect of going back home. She was to be assessed for residential home.

Management•FBC normalised through admission•No further spikes in temperature•Seen by psychiatry who commenced

Mirtazipine

Management•AQP – 4 – Negative

Management•AQP – 4 – Negative

•Mycoplasma Serology – POSITIVE 1/2560

Diagnosis•ADEM secondary to Mycoplasma

Pneumonia•Given additional 14 days Clarithromycin

Acute disseminated encephalomyelitis (ADEM)• ADEM is a rare autoimmune disease

•Associated with a sudden, widespread attack of inflammation in the brain and spinal cord

•Also leads to acute demyelination

•Neurologic manifestations include both motor and sensory impairment as well as autonomic dysfunction

Causes Of ADEM•Secondary to multi-systemic diseases - vasculitis syndromes, - collagen vascular diseases

•Idiopathic

•Invasive

•Parainfectious

Parainfectious ADEM•ADEM that is preceded by an infectious

process- Preceding Infection – Often Viral- Common bacterial

include Streptococcus, Mycoplasma pneumoniae and Haemophilus influenzae 

- Vaccination

Mycoplasma and ADEM•Neuroinvasion •Stamm et al 2008

•Parainfectious •Gupta et al 2007

Stamm et al 2008• 45-year-old, previously healthy man had

fever and cough with non-purulent sputum.

•Bilateral basal pneumonia was diagnosed and treated with clarithromycin

•Within 4 days developed a rapidly ascending polyradiculoneuropathy resulting in tetraparesis, facial palsy and ophthalmoplegia

Stamm et al 2008 cont…

•Viral PCR Negative

•Bacterial and Viral serology negative

CSF Day 8 WCC total protein

glucose

4.3 mmol/L 43 (89% Neutrophils)

1.3 g/L 4.3 mmol/L

CSF Day 15

WCC total protein

glucose

794 (84% Neutrophils)

4.6 g/L 1.5 mmol/L.

Stamm et al 2008 cont…• CT Head - brain oedema and

inflammatory/demyelination lesions in the subcortical white matter

•EMG - severe peripheral axonal neuropathy.

•No antiganglioside (GM) 1 or anti-GM2 antibodies

Stamm et al 2008 cont…• Dx- polyradiculoneuropathy (atypical Guillain-Barré

syndrome) and acute encephalitis as complications of bilateral pneumonia caused by M. pneumoniae

• Mx- Clarithromycin with amoxicillin and ceftriaxone then given IVIG (0.4 g/ kg bodyweight/day for 5 days).

• He died of intractable cerebral edema on day 17 of illness, 10 days after the onset of neurologic symptoms.

Stamm et al 2008 cont…• At Autopsy M. pneumoniae RNA detected in brain

tissue by nucleic acid hybridization

• Suggests a role of invasion of the CNS by the organism itself

• Neuroinvasion is more prevalent in patients who have an early onset neurologic complications

• Effects unclear the organism may either cause direct damage or trigger a more violent immunologic reaction

Gupta et al 2009• A 41-year-old man presented with a 2-week

history of lethargy, chills, nausea, vomiting and a productive cough.

• CT Chest showed - Right lower lobe pneumonia.

• Initially treatment - IV Amoxicillin and Doxycycline

• One week later he developed lower limb weakness, which progressed to complete paraplegia with urinary retention

• Subsequent six days later he developed patchy visual loss in both eyes. Fundoscopy showed swollen optic discs bilaterally.

Gupta et al 2009 cont…• Serology suggested recent Mycoplasma pneumoniae infection

with a M. pneumoniae agglutination antibody titre of 1 in 1280.

• MRI - Increased T2 signal and swelling of the cord extending from T3 to T8, as well as several white matter lesions in the periventricular white matter of the cerebral hemispheres

• Cerebrospinal fluid (CSF) examination showed a mononuclear pleocytosis of 24 mononuclear cells per microlitre

• A diagnosis of acute disseminated encephalomyelitis (ADEM) secondary to M. pneumoniae was suspected

Gupta et al 2009 cont…• IV methylprednisolone was commenced at 1 g daily.

• No clinical improvement over the next 3 days so treatment changed to high-dose oral prednisolone and plasma exchange.

• A total of 10 exchanges was carried out over 3 weeks. Vision improved to and he regained normal lower limb power and sphincter control over the next 2 months.

• The dramatic response to plasma exchange in the present case supports a hypothesis that the ADEM was secondary to an immune complex-mediated vasculopathy

Aetiology of Parainfectious mycoplasma• Neurologic manifestations occur approx 10/7 after the

onset of the initial respiratory tract infection

• Cross reaction of M. pneumoniae-induced antibodies with brain tissue (as it does with RBC for cold agglutination)

• Antineuronal antibodies have been demonstrated in M. pneumoniae infections with or without CNS disease (Nishimura et al 1996)

• Auto-antibodies deposit as immune complexes in the CNS causing myelitis

Investigations• CSF - CSF Gram stain and bacterial cultures are usually

negative. The CSF leukocyte count is elevated predominantly mononuclear pleocytosis and most cases of M. pneumoniae-associated ADEM have a normal CSF/serum glucose ratio

• Serologic testing:– Mycoplasma Serology or PCR. IgM antibodies can be

detected shortly after the acute infection, may persist for up to 6 months and are followed by IgG titer elevation

- A positive cold haemagglutinins titer. Presence of cold hemagglutinins is non-specific for M. pneumoniae disease and they can be seen in other viral infections, collagen vascular diseases and a variety of systemic disorders

• MRI Head/ spinal cord - Characteristic findings of an ADEM are patchy asymmetric or diffuse signal changes of gray and white matter as well as multifocal, asymmetric foci of high signal intensity on flair and T2 weighted images

Management Options• Antibiotic therapy has been temporally associated with

clinical improvement in some cases of M. pneumoniae-associated ADEM/ATM

• Corticosteroids are useful in the initial management of ADEM and transverse myelitis with their main contribution being the shortening of the duration of neurologic findings (only if no infective source identified).

• Intravenous immune globulin is usually used in ADEM cases, which fail to respond to corticosteroids.

• Plasmapheresis has been used as a last therapeutic measure

Conclusion•Patient presented with worsened

neurology after a severe chest infection•Cerebellar + Thoracic Spine involvement•Blood tests largely unremarkable except

for Mycoplasma serology•Importance of translating wide

differential into investigations

References• Ning MM, Smirnakis S, Furie KL, Sheen VL. Adult acute disseminated encephalomyelitis

associated with poststreptococcal infection. J Clin Neurosci. 2005;12:298–300.

•  Höllinger P, Sturzenegger M, Mathis J, Schroth G, Hess CW. Acute disseminated encephalomyelitis in adults: a reappraisal of clinical, CSF, EEG, and MRI findings. J Neurol. 2002;249:320–9.

• Beleza P, Ribeiro M, Pereira J, Ferreira C, Jordão MJ, Almeida F. Probable acute disseminated encephalomyelitis due toHaemophilus influenzae meningitis. Dev Med Child Neurol. 2008;50:388–91

• Stamm B, Moschopulos M, Hungerbuehler H, Guarner J, Genrich GL, Zaki SR. Neuroinvasion by Mycoplasma pneumoniae in acute disseminated encephalomyelitis. Emerg Infect Dis. 2008;14(4):641-3

• Gupta A, Kimber T, Crompton JL, Karagiannis A. Acute disseminated encephalomyelitis secondary to Mycoplasma pneumoniae. Intern Med J. 2009 Jan;39(1):68-9

• Tsiodras S, Kelesidis T, Kelesidis I, Voumbourakis K, Giamarellou H. Mycoplasma pneumoniae-associated myelitis: a comprehensive review. Eur J Neurol. 2006 Feb;13(2):112-24.

• Nishimura M, Saida T, Kuroki S, Kawabata T, Obayashi H, Saida K, Uchiyama T. Post-infectious encephalitis with anti-galactocerebroside antibody subsequent to Mycoplasma pneumoniae infection. J Neurol Sci. 1996 1;140(1-2):91-5.

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