Wednesday, 5 October 2016

ADEM: sinister repercussions of Mycoplasma infection

A case of a patient initially treated for pneumonia and then presenting with generalised progressive  weakness was described.

Examination

On systemic examination she appeared unwell with tachypnoea. There were bilateral crackles to the midzones, a large reducible hernia and pitting oedema up to her shins.

Cranial nerve examination revealed saccadic intrusions of pursuit and right rapid afferent pupilllary defect. Fundoscopy was not possible. Cranial nerves were otherwise intact.
Tone was normal on the right but was increased on the left side. There was reduced power distally in the upper limbs. Lower limb examination revealed reduced power (most marked proximally in hips and knees with both flexion and extension scoring 2/5 with distal power more preserved: plantarflexion scored 4/5 bilaterally). Reflexes were brisk throughout except for ankle reflexes which were 1+ bilaterally), plantar response was extensor.
Sensation to pinprick revealed a sensory level at T8. Vibration sense was intact in the upper limbs but reduced to the knee bilaterally in lower limbs. Proprioception was reduced to ankles bilaterally.
Cerebellar examination revealed dysarthria, dysmetria (with left side being more affected than right) and dysdiadokinesis on the left.

Investigations


MRI Head was compared to the one performed few days later and showed that previous abnormal T2/flair signal in midbrain, superior cerebellar peduncles and at the right middle cerebellar peduncles and pons was less conspicuous in keeping with an evolving inflammatory process.


  

MRI Whole Spine revealed an 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.

Microbiology revealed positive CMV and VZV IgG but otherwise no abnormalities. Protein electrophoresis showed polyclonal bands. Autoimmune screen revealed mildly positive pANCA. Haematological investigation showed neutrophilia (WCC 35) and blood film revealed toxic shift (metamyelocytes).
CSF  showed 1 WCC, 123 RBC, 0.26 Protein (normal)


Visual Evoked Potentials showed a well formed response from the left eye with no reproducible response from the right eye.  Somatosensory evoked potentials were normal in the upper limb. Lower limb abnormalities (showing borderline delayed cortical response- P40) could be in keeping with central demyelination.

Differentials

Taking all of the above into consideration a longitudinally extensive transverse myelitis with midbrain/ superior cerebellar peduncle involvement was the pathological process. Neuromyelitis optica (NMO) and Acute Disseminated encephalomyelitis (ADEM) were the top differential diagnoses.

Management

The patient was commenced on 3 day course IVMP followed by oral Prednisolone and a week later transferred to RLH for further investigation and management.
At RLH patient was managed with 4 days of PLEX with weaning of oral steroids. Noticeable neurological improvement was noticed- the patient, who was bedbound on admission and had slurred speech, eventually managed to mobilize with a frame and her speech began to normalise. Full blood count normalized throughout the admission and there were no further temperature spikes.

Diagnosis

Further results were negative for Aquaporin 4, making the diagnosis of NMO less likely. Mycoplasma serology was resulted as positive (1/2560) leading to the diagnosis of ADEM secondary to Mycoplasma Pneumonia. The patient was treated with a 14-day course of Clarithromycin.


Discussion

Acute Disseminated Encephalomyelitis (ADEM) is a widespread acute autoimmune demyelinating disease, which affects brain and spinal cord. Typically, neuroimaging shows multifocal white matter lesions and as such the clinical presentation includes both motor and sensory impairment as well as autonomic dysfunction (in line with presentation of this patient who had reduced power in lower limbs, brisk reflexes and reduced sensation in lower limbs as well as dysarthria and incoordination).

Although incompletely understood, ADEM appears to be triggered by an environmental stimulus in genetically susceptible individuals. Amongst the causes of ADEM the most common is parainfectious but it may be idiopathic or rarely, following vaccination.

Parainfectious ADEM is preceded by a viral or bacterial infectious process. Common bacterial causes include Streptococcus, Mycoplasma pneumoniae and Haemophilia Influenzae. Other associated pathogens include rubella, Epstein-barr virus, herpes simplex virus, human-herpes virus 6, influenza and human immunodeficiency virus.

M. pneumoniae infections can be complicated by neurological disorders, resulting in myelitis, cerebrovascular disorders, servere encephalitis and meningitis. In study conducted by Guleria et al. neurological symptoms were found in 7% of all patients hospitalized for M. pneumoniae.
Antineuronal antibodies have been demonstrated in M. pneumoniae infections with or without CNS disease  (Nishimura et al 1996).

M.pneumoniae may lead to ADEM either by neuroinvasion or immune complex-mediated vasculopathy.

ADEM and the role of neuroinvasion (Stamm et al 2008)

Stamm et al described a case of 45-year-old previously healthy man who presented with fever, cough and non-purulent sputum.  Diagnosis of bilateral basal pneumonia was made and the patient was treated with Clarithromycin. Within 4 days, however, rapidly ascending polyradiculoneuropathy  developed, resulting in facial palsy, opththalmoplegia and tetraparesis. Viral PCR and bacterial and viral serology were negative.
CT head showed brain oedema and inflammatory/ demyelinating lesions in the subcortical white matter, whilst EMG revealed severe peripheral neuropathy.
No antiganglioside (GM) 1 or anti-GM2 antibodies were discovered.
Differential diagnoses included polyradiculoneuropathy (atypical Guillain-Barré syndrome) and acute encephalitis as complications of bilateral pneumonia caused by M. pneumoniae. The patient was commenced on Clarithromycin with Amoxicillin and Ceftriaxone  then given IVIG (0.4 g/ kg bodyweight/day for 5 days).
He died of intractable cerebral edema 10 days after the onset of neurologic symptoms.  At Autopsy M. pneumoniae RNA detected in brain tissue by nucleic acid hybridization.
The case suggests a role of invasion of the CNS by the organism itself. Interestingly, neuroinvasion is more prevalent in patients with early onset neurologic complications. The effects of the neuroinvasion, however, remain unclear. The organism may either cause direct damage or trigger a more violent immunologic reaction.

Parainfectious ADEM (Gupta et al 2007)

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 and the patient was commenced on IV Amoxicillin and Doxycycline.
One week later he developed lower limb weakness, which progressed to complete paraplegia with urinary retention. Six days later patchy visual loss in both eyes follows and fundoscopy revealed swollen optic disc bilaterally.
Serology suggested recent Mycoplasma pneumoniae infection with a M. pneumoniae agglutination antibody titre of 1 in 1280.
MRI showed 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, whereas CSF revealed a mononuclear pleocytosis of 24 mononuclear cells per microlitre.
A diagnosis of acute disseminated encephalomyelitis (ADEM) secondary to M. pneumoniae was made and patient was commenced on IV methylprednisolone was commenced at 1 g daily.  This resulted in no improvement over the course of the next three days, so treatment was changed to high-dose oral prednisolone and plasma exchange.
A total of 10 exchanges were carried out over 3 weeks. This resulted in improved vision and the patient regaining normal lower limb power and sphincter control over the next two months.
This dramatic response to plasma exchange supports a hypothesis that the ADEM was secondary to an immune complex-mediated vasculopathy


Key points

Neurologic manifestations occur approximately ten days after the onset of the initial respiratory tract infection

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.
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 (non-specific)

MRI Head/ Spinal Cord:  characteristic findings: patchy asymmetric or diffuse signal changes of gray and white matter and multifocal, asymmetric foci of high signal intensity on flair and T2 weighted images.

Management: 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 case of no response to steroids.
Last therapeutic measure: Plasma Exchange

In this case:
Patient presented with worsened neurology (cerebellar and thoracic spine involvement) after a severe chest infection. Blood tests were unremarkable except for Mycoplasma serology. This shows the importance of translating a wide differential into investigations.



References and recommended reading
1.Garg R K. Acute disseminated encephalomyelitis. Postgrad Med J 2013; 79(): 11-17.
2. Ning MM, Smirnakis S, Furie KL, Sheen VL. Adult acute disseminated encephalomyelitis associated with poststreptococcal infection. J Clin Neurosci. 2005;12:298–300.
3. Sotgiu S, Pugliatti M, Rosati G, Deiana A, Sechi P. Neurological disorders associated with Mycoplasma pneumoniae infection. Eur J Neurol 10: 165-168, 2003.

4. Guleria R, Nisar N, Chawla TC, Biswas NR. Mycoplasma pneumoniae and central nervous system complications: a review. J Lab Clin Med 146: 55-63, 2005.
5.  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.
6. 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
7. 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
8. Gupta A, Kimber T, Crompton JL, Karagiannis A. Acute disseminated encephalomyelitis secondary to Mycoplasma pneumoniae. Intern Med J. 2009 Jan;39(1):68-9
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.

10. 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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