Multiple Sclerosis Presenting as Intracranial Hypertension in the Setting of COVID-19 Infection

Background


Background
MS is an autoimmune disease affecting the central nervous system myelin [1].MS is typically found in females of childbearing age, with greater prevalence in Caucasian women [1,2].IIH, on the other hand, is a disorder of unknown etiology resulting in isolated raised ICP [3].It typically presents in obese females of childbearing age [3].Patients usually present with a gradual onset of headache, transient visual loss, pulsatile tinnitus, back pain, dizziness, neck pain, visual blurring, cognitive disturbances, and typically horizontal diplopia [4].IIH and MS can present with overlapping symptoms such as headaches and diplopia [5].Furthermore, with the emergence of SARS-CoV-2 that is responsible for the outbreak of COVID-19 infection, neurologic manifestation of the infection has been also reported.[6,7,8].
When patients present with overlapping symptoms of multiple disorders, it makes it di cult for clinicians to differentiate between these disorders.Our patient presented with symptoms of increased ICP.This increased ICP could be caused by MS, IIH, COVID-19 infection.After an extensive work up, we strongly believe that the increase ICP was caused by MS and presented as a clinical attack in this patient.

Case Presentation
A-19-year-old middle-eastern male who initially presented to the primary care clinic with four days history of headaches, and fever.He was seen by a primary care physician who diagnosed him with COVID-19 infection, con rmed on a fast antigen test.The patient was treated with dexamethasone and azithromycin.A few days later, the patient presented to the neurology center after developing acute severe left eye pain, blurred vision, diplopia, and left ear tinnitus.He was also complaining of interment shortness of breath, associated with palpitation.The patient is a non-smoker with ideal body weight (Body Mass Index (BMI) 21).There was no signi cant past medical history and was not taking any medications prior to this event.There was no family history of neurologic disorders.Initial examination showed reduced visual acuity, left sixth nerve palsy, esotropia and asymmetric bilateral papilledema; being worse on the left side.The rest of his examination was normal.These ndings were con rmed by an ophthalmologist, who also excluded the presence of optic neuritis.Two weeks later the patient developed left seventh nerve palsy with slightly worsening of the left sixth nerve palsy.

Imaging:
MRI of the brain was done on the same day he was seen at the neurology center, revealing multiple T2/FLAIR hyperintense plaques predominantly at the subcortical and juxtacortical regions.Neither of these plaques showed restricted diffusion nor displayed enhancement post contrast administration.Mild kinking of both optic nerves was noted (worse on the left) without radiological signs of optic neuritis.Partial empty Sella Turcica was also noted.(Figs. 1 and 2).The contrast images showed focal stenosis of both transverse sinuses (Fig. 3).
Repeat MRI the brain with and without contrast three weeks later (after the development of new onset of seventh nerve palsy) was unchanged from the initial one.MRI of the cervical and thoracic spine with and without contrast was also done at this time and was unremarkable.
At six-month follow up, repeat MRI of the brain without contrast was unchanged from the initial one.MRV of the brain, at this time, showed smaller left venous system (left transverse, sigmoid and upper part of jugular vein), compared to the right one, with smooth tight narrowing of distal parts of both traverse sinuses.There was no evidence of thrombosis noted (Fig. 4).

Other investigations:
A Lumbar puncture (LP) was performed showing an elevated opening pressure of 420 mm H2O, con rming the presence of intracranial hypertension.CSF analysis revealed 0 WBC, 0 RBC, 26.6 protein and 81 glucose.Oligoclonal bands were seen.LP was repeated three weeks later and showed an opening pressure of 230 mm H2O.CSF was also checked for Myelin Oligodendrocyte Glycoprotein (MOG) Antibodies, which were negative.

Management and follow up:
The patient was treated with Methylprednisolone 1000mg intravenously once daily for 5 days.For increased ICP, he was started on Acetazolamide 250mg twice daily and increased two weeks later to 500 mg twice daily.For the COVID-19 infection, the patient had already nished a course of dexamethasone and azithromycin prior to presenting to the neurology center.The patient's headaches and diplopia improved within a week of starting the therapy.However, blurred vision persisted.
Two weeks after the initial presentation, the patient presented with a new onset of left-sided facial droop and diplopia.Neurologic examination revealed mild left cranial nerve six and seven palsy.LP was repeated and the opening pressure was found to be 230 mmH2O.MRI of the brain with and without contrast was repeated and was unchanged from the initial one.The patient was kept on acetazolamide at a dose of 500 mg twice daily.The new symptoms and blurred vision improved within a week.
The patient was referred to a local government's hospital to initiate disease modifying therapy (DMT) for MS, due to the high cost of these medications.The patient received Rituximab over there.The choice of Rituximab was based on their neurologist's decision and the availability of the DMT at the time.
At a three-month follow up, the patient complained only of mild blurred vision, but no other symptoms.He was continued on Acetazolamide at 500 mg twice daily.Throughout this time, the patient was closely followed by the ophthalmologist who documented gradual and signi cant improvement of the optic discs edema.At six-month follow up, the patient did not have any complaints, and ophthalmologic examination revealed very mild optic nerve edema.Repeat MRI of the brain without contrast was unchanged from the initial one.The acetazolamide dose was reduced to 250 mg twice day.

Discussion
This is a very complex patient who presents with three separate entities, COVID-19 infection, demyelinating lesions on MRI and increased ICP with positive oligoclonal bands on LP.It was unclear if these are three separate entities co-existing in one patient.The patient's initial presentation of fever and headaches was typical of COVID-19 infection, which was con rmed with the fast antigen test.His symptoms were very mild and improved within days.A few days later, the patient started having new and acute symptoms, typical of increased ICP.MRI of the brain and LP ndings were most consistent with MS.This made us question that COVID-19 infection was causing his symptoms.
CNS manifestation of COVID-19 have been extensively reported (9,10).There are many different neurologic effects of COVID-19, including: encephalopathy, encephalitis, ischaemic strokes, haemorrhagic strokes, and Guillain Barre Syndrome (GBS) [6, 7, 8 ].In a series from Wuhan, 78 of 214 COVID-19 patients developed neurological manifestations such as agitation, confusion and corticospinal tract signs.These patients, however, tended to be more severely affected, older and with more comorbidities [11].The typical neurological manifestations could be due to the viral infection, causing loss of smell and taste, or to the consequences of severe systemic illness such as sepsis, hypoxia, vasculitis, and hypercoagulability [11].There are rare isolated case reports of demyelination [12].Cerebral venous thrombosis is another rare complication [13].Patients may develop this neurological sequela due to the prothrombotic state triggered by COVID-19 [14,15,16].Brain MRI changes noted were meningeal enhancement, ischaemic strokes, and perfusion changes [15,16,17].CSF examination of white cell response and other immunologic features are typically absent [17].In a study of 52 patients with CNS COVID-19 infection, ICP ranged between normal and slightly elevated in most cases.Less than one third of the patients had slightly increase ICP [18].Only patients with meningitis or meningoencephalitis had increase mononuclear leukocytes and 30% with elevated protein [18].Based on the above data, we do not believe that COVID-19 contributed to our patient's CNS symptoms.At most, it could have been a trigger for his main entity.
We believe that the increased ICP in our patient is directly due to MS, rather than to IIH coexisting with MS.The patient clinical presentation and diagnostic work up do not t the typical picture for IIH.First, he is a male with ideal body weight (BMI 21).Second, following the revised criteria published by Friedman et al in 2013 (Table 1), our patient does not t the "probable" nor the "de nite" diagnosis of IIH.Out of the ve criteria, he only ts three of them.He does not have a normal MRI of the brain or normal CSF composition [4].Based on these criteria, the diagnosis of IIH is excluded in this patient.Third, according to Chen et al, our patient's presentation is atypical for IIH.This is because he has asymmetric papilledema and unilateral facial nerve palsy [19].Peripheral facial weakness is an uncommon nding among IIH patients.A series of 30 children with IIH, identi ed only one child with unilateral facial nerve palsy [20].Another series of 140 adults and children with IIH, identi ed only two patients with unilateral facial nerve palsy [21].When our patient developed facial nerve palsy three weeks from his initial presentation, his LP opening pressure was only 230 mm H2O; making IIH to be less likely to be causing his neurologic symptoms.Based on the above, we believe that the clinical presentation of increased ICP in our patient was due to MS, rather than IIH.
It is possible that multiple sclerosis and IIH exist on a spectrum, as both alter CSF uid dynamics, most often through arachnoid granulations and venous stenosis [22,23].In patients with MS, increased area of transverse and sagittal sinuses can be seen due to out ow stenosis associated with reduced venous sinus compliance [23,24].Although not clearly understood, the increased ICP in IIH is due to disruption in CSF equilibrium.This occurs either due to overproduction or inadequate reabsorption of CSF [3,4].The area of the superior sagittal sinus has been shown to differ between IIH and MS, with no appreciable change and an increase in measurements, respectively [23,24].Bateman et al suggested that MS alters CSF uid dynamics, most often through arachnoid granulations and venous stenosis, therefore can cause increase ICP [22,23].The initial MRI with contrast showed focal area of stenosis in both transverse sinuses.These areas of stenosis persisted six months later, evident on the MRV, supporting the notion that the increased ICP is due to MS.If it was due to IIH, it should have resolved or improved after normalizing the ICP.
Using the revised 2017 McDonald criteria, the diagnosis of MS was con rmed in this patient.He had one clinical attack, objective evidence of more than two lesions on MRI and positive oligoclonal bands in CSF [25].We considered the current presentation as a clinical MS attack.The symptoms of increased ICP are very acute to be due to IIH.The patient also developed seventh nerve palsy which is very atypical for patients with IIH.When he developed the left seventh cranial nerve palsy, his LP opening pressure was only 230 mmH2O.The lack of enhancement on MRI could have been due to him receiving steroids prior to presenting to us.Burnham et al showed that receiving methylprednisolone prior to the MRI completely suppressed gadolinium enhancement of acute MS demyelinating lesion in the majority of patients (26).The lack of enhancement could also have been since the clinical presentation is ICP, rather than focal neurologic de cit from and active white matter lesion.Based on these facts, we chose to treat the patient with intravenous Methylprednisolone.

Conclusion
MS, IIH, and COVID-19 infection can coexist.However, our patient did not t the de nite or probable criteria for IIH, and ful lled the McDonald's criteria for MS.COVID-19 infection was very mild and should have not caused signi cant symptoms.We have done extensive work up on the patient to rule out any other pathologies that can fully explain his presentation.We believe that the MS caused the increased ICP, rather than IIH co-existing with MS, or COVID-19 infection causing the symptoms.Further work is required to con rm that MS can cause an increase in ICP and set criteria to differentiate it from other causes.This will also help draw better diagnostic and treatment guidelines for those patients.

De nite Diagnosis
If the patient ful lls criteria A-E.

Probable
If criteria A-D are met, but the measured CSF pressure is lower than speci ed for a de nite diagnosis.

Figure 1 MRIFigure 2 MRI
Figure 1 MH designed the study, analysed the data, reviewed, revised and nalized the manuscript.MA collected the data and did the rst draft.Both authors approved the nal manuscript.Normal brain parenchyma without evidence of hydrocephalus, mass, or structural lesion and no abnormal meningeal enhancement on MRI, with and without gadolinium, for typical patients (obese women), and MRI, with and without contrast, and MRV for others; if MRI is unavailable or contraindicated, contrastenhanced CT may be used.Elevated lumbar puncture CSF opening pressure (≥25 cm CSF in adults and ≥28 cm CSF in children [25 cm CSF if the child is not sedated and not obese]) in a properly performed lumbar puncture. E