Posterior reversible encephalopathy syndrome following Miller-Fisher syndrome
- Catarina Bernardes ,
- Cristiana Silva ,
- Gustavo Santo and
- Inês Correia
- Neurology Department, Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal
- Correspondence to Dr Catarina Bernardes; acatarinabernardes@gmail.com
Abstract
A 71-year-old woman presented to the emergency room with dysphonia, diplopia, dysphagia and generalised weakness since that day. Neurological examination revealed eye adduction limitation, ptosis, hypoactive reflexes and gait ataxia. Blood and cerebrospinal fluid analysis and brain CT were normal. Electromyography revealed a sensory axonal polyneuropathy. She was diagnosed with Miller-Fisher syndrome (MFS) and started on intravenous immunoglobulin. Two days after intravenous immunoglobulin treatment was completed, she developed a sustained hypertensive profile and presented a generalised tonic-clonic seizure. Brain MRI was suggestive of posterior reversible encephalopathy syndrome (PRES) and supportive treatment was implemented with progressive improvement. PRES may be a possible complication of MFS not only due to autonomic and inflammatory dysfunctions, but also as a consequence of its treatment. Patients with MFS should be maintained under close surveillance, especially in the first days and preferably in intermediate care units.
Background
Miller-Fisher syndrome (MFS) is a rare acute or subacute, immunemediated, demyelinating polyradiculoneuropathy. Classically, MFS patients present with the triad of ophthalmoparesis or ophthalmoplegia, areflexia and ataxia. The treatment is based on two aspects: supportive care and immunotherapy, such as intravenous immunoglobulin.1 2
Posterior reversible encephalopathy syndrome (PRES) refers to a disorder of reversible subcortical vasogenic brain oedema in patients with acute neurological symptoms in the setting of renal failure, blood pressure fluctuations, cytotoxic drugs, autoimmune disorders, and pre-eclampsia or eclampsia. Brain imaging usually reveals vasogenic oedema predominantly involving bilateral the parieto-occipital region. It seems to be more frequent in middle-aged women and is increasingly recognised, although the incidence is not known.3 4
The association of MFS and/or intravenous immunoglobulin therapy with PRES has been described in some previous studies.5–8 Here, we report a case of a 71-year-old woman with MFS who developed PRES after intravenous immunoglobulin therapy.
Case presentation
A 71-year-old woman with personal history of arterial hypertension, dyslipidaemia, gastrointestinal haemorrhage due to a bulbar ulcer 1 year ago and pulmonary embolism 11 years ago; medicated with candesartan 16 mg, hydrochlorothiazide 12.5 mg, simvastatin 20 mg, clopidogrel 75 mg and omeprazole 40 mg and without any known medication allergies, presented to the emergency room (ER) of a regional hospital with report of altered voice pitch with a nasal quality since that day. There was a 1-month history of productive cough and she had been medicated with azithromycin 2 days ago for suspected upper respiratory infection. There was no history of previous similar episodes or any familiar history of neurological diseases. In the next hours following her admission, she developed diplopia and dysphagia associated with nasal regurgitation and generalised weakness, having been transferred to the ER of a tertiary hospital for urgent neurology consultation.
At admission, the patient was hypertensive (235/90 mm Hg), without fever and with normal peripheral oxygen saturation. Neurological examination revealed limitation of eye adduction bilaterally, asymmetric ptosis more prominent in the left eye and dysphonia. Limb strength was normal and there was no evidence of fatigability, but deep tendon reflexes were hypoactive. There were no abnormalities in pain sensation. She also presented gait ataxia, but no limb dysmetria. Blood and cerebrospinal fluid (CSF) examinations and brain CT were normal. Due to suspicion of acute inflammatory demyelinating polyneuropathy, she was empirically started on intravenous immunoglobulin 30 g once daily for 5 days and admitted in the neurology ward.
Electromyography was performed on the first day of admission and revealed normal velocity, amplitude and distal latency on motor nerve conduction study; repeated nerve stimulation without decremental answer; and absence of sensory nerve action potentials, suggesting sensory axonal polyneuropathy. Blood analysis at admission included testing for antiganglioside and acetylcholine receptor antibodies, which later came negative. Based on her clinical and electrophysiological findings, she was diagnosed with MFS.
Two days after being admitted, she developed respiratory insufficiency and she was admitted in the intensive care unit (ICU). She was kept under invasive ventilatory support for 4 days. During this period, it was necessary to administer antihypertensive medication (enalapril 10 mg twice daily and amlodipine 5 mg once daily) to maintain normotensive status. On the fifth ICU day, first day under spontaneous ventilation, despite the ongoing treatment, she developed a sustained hypertensive profile (systolic blood pressure between 150 mm Hg and 190 mm Hg) (figure 1) and antihypertensive medication was adjusted (enalapril 20 mg two times a day, amlodipine 5 mg once daily and carvedilol 12.5 mg once daily). On the following day, she presented a generalised tonic-clonic seizure (TCS), having resumed invasive ventilatory support. She was also started on levetiracetam 1000 mg three times a day and antihypertensive medication was suspended with a normotensive profile. Brain CT was performed 11 hours after the TCS and showed bilateral and symmetric posterior frontal, posterior parietal and occipital subcortical hypodensities. Brain MRI conducted 16 hours after the episode revealed in fluid-attenuated inversion recovery bilateral and symmetric multifocal and confluent hyperintensity of white matter, predominantly in the parieto-occipital and perirolandic regions with scarce involvement of right protuberance, frontal lobes and cerebellar white matter; there was no enhancement after gadolinium administration in gadolinium-enhanced T1-weighted images and no haemorrhages or haemosiderin deposits were visualised in T2* (figures 2–4). Both clinical and imaging findings were suggestive of PRES. Electroencephalography performed 5 hours after the TCS showed diffuse and asymmetric disorganisation and slowness of electrical activity compatible with diffuse encephalopathy and infrequent paroxysmal activity in frontal regions indicative of epileptogenic potential (figure 5). The lumbar puncture was repeated to exclude infectious encephalitis, having identified an albuminocytological dissociation (92 mg/dL proteins, 4 x 106/L leucocytes and 6 x 106/L erythrocytes), and she was started on methylprednisolone 1 g once daily for 3 days. The patient was maintained under invasive ventilation for 4 days. Due to hard ventilatory weaning, she was submitted for a tracheostomy on the 10th ICU day. On the 13th ICU day, the patient was transferred back to the neurology ward, needing 30% of fraction of inspired oxygen. On neurological examination revaluation, she presented bilateral and global ophthalmoplegia, ptosis, dysphonia, dysphagia, crural predominant tetraparesis (muscular strength grade 3 in superior limbs, grade 2 in left inferior limb and grade 1 in right inferior limb), distal inferior limb hypoesthesia, and generalised areflexia. On the 30th hospital day, the respiratory insufficiency resolved and the tracheostomy cannula was exteriorised. During her hospital stay, she was carried on active rehabilitation, having achieved improvement of general deficits.
Evolution of systolic blood pressure (SBP), diastolic blood pressure (DBP) and mean blood pressure (MBP) and heart rate (HR) since intensive care unit (ICU) admission until the first clinical sign of posterior reversible encephalopathy syndrome (arrow).
Axial fluid-attenuated inversion recovery brain MRI showing scarce hyperintensity of cerebellar white matter.
Axial fluid-attenuated inversion recovery brain MRI showing a focal area of hyperintensity on the right side of the protuberance, and bilateral and symmetric hyperintensity of occipital lobes.
Axial fluid-attenuated inversion recovery brain MRI showing bilateral and symmetric multifocal and confluent hyperintensity of white matter in the parieto-occipital and perirolandic regions with scarce involvement of frontal lobes.
Electroencephalography showing generalised rhythmic activity and rare interictal epileptiform discharges (arrow).
Outcome and follow-up
She was discharged to a rehabilitation centre 46 days after admission. At discharge, there was resolution of dysphagia, dysphonia and hypoesthesia, and improvement of ophthalmoparesis and tetraparesis. On neurological examination, there was bilateral eye abduction limitation, which was more prominent in the left eye, ptosis and paraparesis (muscular strength grade 4+ in the left inferior limb and 4 in the right inferior limb) and the patient was capable of gait with a walker. The patient spent 1 month in a rehabilitation centre with good recovery. At neurology consultation 3 months after hospital discharge, she presented resolution of all deficits without any new seizure episode.
Discussion
In this case, besides the classic triad of MFS (ophthalmoplegia, areflexia and ataxia), the patient presented other cranial nerve involvement with dysphonia, dysphagia and ptosis. Bearing in mind the clinical suspicion of inflammatory polyneuropathy and myasthenia gravis, blood analysis (including antibodies against ganglioside and acetylcholine receptor), lumbar puncture and electromyography were performed. Antiganglioside antibodies were negative, which can occur in a minority of patients with MFS (10%–30%) and first CSF evaluation showed a normal protein level, which can be observed in almost half of the patients with MFS early in the disease course.2 However, later CSF analysis revealed an albuminocytological dissociation and the electromyographical study identified alterations suggestive of a sensory axonal polyneuropathy. MFS was, therefore, diagnosed based on clinical and electrophysiological findings and the patient was started on intravenous immunoglobulin for 5 days, one of the recommended treatments for patients with severe MFS.2
At hospital day 2, the patient showed signs of respiratory distress and was admitted in an ICU. Although rare, this is a possible course of the disease.2 At hospital day 7, 2 days after the completion of intravenous immunoglobulin treatment, the patient developed a sustained hypertensive profile, and was diagnosed with PRES the next day. The diagnosis of PRES is usually established by clinical and radiological findings. In this case, the patient presented with a seizure, which is one of the most frequent clinical signs of PRES (about two-third of all patients), and brain imaging confirmed the diagnosis.3 4
In the literature, there are some case reports of MFS and PRES, with or without association with intravenous immunoglobulin. One report presents a case of a 71-year-old woman with MFS who had PRES before intravenous immunoglobulin, suggesting MFS and consequent hypertension as causes of PRES.5 A case of iatrogenic PRES was reported in a 53-year-old man with high blood pressure 4 days after completing intravenous immunoglobulin treatment for MFS.8 Another report of a 54-year-old woman with MFS developing PRES 24–48 hours after intravenous immunoglobulin therapy without a hypertensive episode is a remainder for considering PRES even without blood pressure fluctuations.6 Finally, a case report of a 29-year-old woman with MFS/Bickerstaff brainstem encephalitis suggested PRES in association with intravenous immunoglobulin treatment as symptoms appeared 48 hours after the first infusion, although authors have assumed the possibility of PRES as another manifestation of the ongoing autoimmune overlap syndrome.7
In our case, there are two factors that may have contributed to the development of PRES, MFS itself and intravenous immunoglobulin treatment.3 The pathophysiological mechanisms of PRES are not yet well known. Nevertheless, two of the most consensual mechanisms are blood pressure fluctuations and inflammatory dysfunction. A rapid and severe blood pressure peak could exceed the autoregulatory response leading to hyperperfusion and blood−brain barrier breakdown, allowing interstitial extravasation typical of PRES. Although autonomic dysfunction seems to be less frequent in MFS than Guillain-Barré syndrome (GBS), it is not uncommon and can lead to hypertension, hypotension or cardiac arrhythmia.2 9 10 As it has been described for GBS, dysautonomia could have a lead role in blood hypertension development, precipitating PRES.3 11 12 On the other hand, endothelial dysfunction might arise from direct effects of excessive circulating cytokines.3 4 In MFS, a focal inflammatory response develops against myelin-producing Schwann cells or peripheral myelin, resulting in high levels of cytokines that alter capillary permeability and contribute to blood−brain barrier disruption.1 2 12 Furthermore, immunoglobulin, one of the most used MFS treatments, has also been associated with PRES. In general, it is a well-tolerated treatment. However, some rare neurological side effects can occur, PRES being one of them. It is classified as a delayed adverse effect (latency of 3−4 days), but it can appear in the first hours after administration. The pathophysiology remains unknown, but cerebral vasospasm, serum hyperviscosity and vasogenic oedema were some of the proposed mechanisms.13
Although there is no specific treatment for PRES, the identification of risk factors and adoption of preventive measures, such as monitoring and management of hypertension are essential.4 In this case, a trial with corticosteroids was performed. Although there is no solid evidence to support their use, some case reports have been presented with beneficial clinical results.14 15
Overall, it is important to bear in mind that PRES is a possible complication of MFS not only due to autonomic and inflammatory dysfunctions, but also as a consequence of its treatment. Patients with MFS should be maintained under close surveillance, especially in the first days and preferably in intermediate care units, since although rare, complications, such as PRES, can dramatically alter the prognosis of the underlying disease and can be associated with irreversible sequela of a disease otherwise self-limited.
Patient’s perspective
Everything started with a cold. I felt very sick with strong cough attacks. About 1 month later, I noticed my voice was changing and getting a nasal tone. I went to the emergency room and while I was waiting to be seen by a doctor, I started feeling worse: I tried to drink a glass of water and it came out of my nose, I started noticing double vision and feeling weaker. I was seen by an otorhinolaryngologist and he told me I had to be transferred to a central hospital to be seen by a neurologist. I don’t remember anything since then until I woke up in the intensive care unit many days later. It was terrifying… I didn’t know where I was, I couldn’t move or speak, I had a tube through my throat and I didn’t know anyone. I had no idea what was going on. This happened during the COVID-19 pandemic, so everyone around me was wearing white smocks, masks and gloves and I couldn’t have any visits from my relatives. It was a tough time. Fortunately, all the health professionals (doctors and nurses) helped me through this. Slowly, I started to improve. I was able to breathe on my own and they removed the tube from my throat, and I was able to speak. I started sitting in an armchair, then taking a few steps with help. When I was discharged, I was already able to walk with a walker. I went to a rehabilitation centre and after 1 month, I went home walking by myself. I feel tired now more frequently than before, but I never thought I could do everything by myself again. I don’t understand why this happened, after all it was just a cold, but it is a miracle I am here!
Learning points
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Posterior reversible encephalopathy syndrome (PRES) is an increasingly recognised rare complication following Miller-Fisher syndrome (MFS).
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PRES may occur due to autonomic and inflammatory dysfunctions related to MFS, but also as a consequence of its treatment.
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Identification of risk factors and adoption of preventive measures are crucial since there is no specific treatment for PRES.
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Patients with MFS should be maintained under close surveillance, especially in the first days and preferably in intermediate care units.
Ethics statements
Footnotes
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CB and CS contributed equally.
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Contributors CB and CS contributed to the conception and design of the study, acquisition of data, analysis and interpretation of data, drafting the article and final approval of the version to be submitted. GS contributed to the analysis and interpretation of data and final approval of the version to be submitted. IC contributed to the conception and design of the study, analysis and interpretation of data and final approval of the version to be submitted.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer-reviewed.
- © BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.
References
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