CASE REPORTS:
CASE 1: A 56 - year old lady of Scottish extraction, living in Dubai for many years, working as director of company, presented with right upper and lower limb stiffness, paresthesia and difficulty walking of 6 weeks’ duration. (Clinically Isolated Syndrome).
CASE 2: A 48 - year old Indian housewife presented with sudden onset of bilateral lower limb sensory symptoms, with dysesthesia, cutaneous allodynia, pain and sensory level at D4. (Clinically Isolated Syndrome).
CASE 3: A 28 - year old Myanmarese lady working as restaurant staff presented with visual blurring, ataxia, and hemisensory symptoms. (Relapsing - Remitting MS, previously unrecognized).
CASE 4: A 32 - year old Lebanese man, working as hotel staff, already on bi - weekly treatment with Interferon since two years, presented with symptoms of ataxia. (Relapsing - Remitting MS, previously recognized).
CASE 5: A 49 - year old Filipina, working as supermarket assistant, presented with atypical facial pain and non - neurological symptoms, found incidentally on MRI to have lesions fulfilling criteria for MS. (Radiologically Isolated Syndrome).
CASE 6: A 21 - year old Egyptian lady, working as office assistant, presented with recurrent episode of blurring of vision, hemisensory loss, and ataxia; she had previous episodes not recognized to be MS. (Relapsing - Remitting MS, previously unrecognized).
ABSTRACT
Multiple Sclerosis is a common neurological condition among younger people in the UAE. Diagnosis and management of MS and its complications remain difficult and are evolving. We describe the experience in a single-center of managing the condition in the local population. In the period between January 2019 and October 2019, six patients (5 women) were diagnosed with definite MS. Three were started on oral Disease Modifying Therapy (DMT), FINGOLIMOD, one was started on bi-weekly Interferon (PLEGRIDY). We describe here the experience and discuss the pros and cons of early versus delayed treatment.
All the patients fulfilled the Modified McDonald (2017) criteria for Dissemination in Time (DIT) and Dissemination in Space (DIS) at the time of diagnosis. At the time of presentation, two patients presented with Clinically Isolated Syndrome (CIS), one patient presented with Radiologically Isolated Syndrome (RIS), and two others presented with relapse of a recognized (one) and unrecognized Relapsing - Remitting form of MS. Confirmation of definite MS in most of the patients was done by identifying CSF Oligoclonal bands. MRI scan of brain and spine with and without Gadolinium enhancement was done for all patients to fulfill McDonald’s criteria, using Barkhoff’s criteria for typical MS lesions. Patients with MS need to be followed up for several years to identify the benefits of DMT. In patients presenting with CIS, the presence of spinal cord lesions may indicate higher risk of future relapse and conversion to Relapsing-Remitting form of MS; hence, early treatment with DMT may be of greater benefit in these patients. The patients in this series will be followed up on a long-term basis to observe the benefit.
INTRODUCTION
Multiple Sclerosis is one of the commonest serious neurological conditions to affect young people. It is commoner among females, and shows ethnic predilection. Practitioners of clinical neurology newly exposed to a rich ethnic mix of population in the UAE are highly likely to encounter higher numbers of patients with this condition. The diagnosis of MS is not without its challenges; even on date there are many patients treated with expensive and potentially toxic medications over long periods of time before alternate diagnoses are discovered. This not only burdens the patients and the system but also exposes the clinician to litigation. Familiarizing oneself with the latest in the field then becomes of paramount importance.
We summarize in this case series the experience in a single centre of patients presenting either with a Clinically Isolated Syndrome, a Radiologically Isolated Syndrome, or with a relapse of a previously recognized or unrecognized Relapsing - Remitting MS. We describe the clinical presentation, the diagnosis, the radiological findings, the initial management, and the plan for long - term management. We discuss also the rationale for early vs late treatment for patients with CIS who will benefit with Disease Modifying Therapy (DMT).
DETAILED CASE HISTORIES
CASE 1:
This patient, a 54 - year old lady of Scottish extraction, working as director of a hotel designing company, and doing mostly a desk job, noticed difficulty in walking, with the right leg becoming stiff and a tendency to drag the right foot; there is in addition, a difficulty in writing with the right hand. She has mild pain in the right side of neck and some low back pain as well.There is no history of trauma accident fall or injury.
She has been on analgesics since then, and also treated with physiotherapy and chiropraxy; she had some benefit with physiotherapy, and intermittently felt better with the treatment.
There is no h/o diabetes mellitus, hypertension, thyroid disease, arthritis, coronary artery disease, stroke, renal, hepatic or any other illness. About 8 years before this, she was living in Malaysia, and recalled an episode of visual blurring in one of her eyes, which was not completely evaluated, and which recovered spontaneously. She has brother who is 6 years younger to her, who has been on treatment for MS with Interferons for many years, and is currently wheel - chair dependant.
PHYSICAL EXAMINATION:
At the time of presentation, the patient was conscious, alert, oriented; higher mental functions were normal. Speech was normal. Cranial nerves were normal. Fundus examination was normal. Examination of the motor system revealed increased tone on the right side with ankle clonus and bilateral upgoing plantars. All deep tendon reflexes were brisk with MRC Grade 3+ bilaterally. There was mild distal weakness for fine motor actions in the fingers of the hands. There was reduced vibration sense distally on the right side with sensory level at D6 dermatome. Rhomberg’s test was negative, and there was spasticity during gait testing.
Examination of other systems did not yield any findings.
The patient was subjected to Lumbar Puncture; routine CSF evaluation showed no cells, normal protein ( 41.7 mg/dL; range, 15 - 45 mg/dL), and normal glucose (65.6 mg/dL). CSF and serum NMO Ab was negative, whereas Oligoclonal antibodies were positive in both CSF and Serum
Thyroid function tests, liver function tests, renal function tests were all within normal limits.
The patient was started on a 5 - day course of Inj Methyl Prednisolone, which was followed by Inj PLEGRIDY. She has been on this injection once every two weeks for the last 10 months.
CASE 2:
A 48 - year old Indian housewife, living in Dubai for the last twenty years, presented to Emergency Room with complaints of stiffness and lack of sensation of lower extremities for the last one week. She had been seen in one of the clinics, when she first noticed abnormal sensations in the outer aspects of both feet simultaneously 7 days prior to admission. Though treated symptomatically initially, the abnormal sensation along with numbness ascended into the legs and thighs up to the lower abdomen along with feeling of stiffness in the legs over the next few days. She had difficulty in standing with lack of feeling in the feet and difficulty in sitting on the commode, though she had normal control of bladder and bowel. There was no history of trauma, accident, fall or injury. There was no previous history of any significant medical or surgical illness. Specifically, there was no history of joint pains, rashes, any recent visits to any new places, any vaccinations. There was no fever, cough, breathlessness, headache, vomiting, visual symptoms, swallowing difficulties, cognitive difficulties, or memory difficulties. She had history of thyroid disease, well-controlled on hormone replacement therapy, gastro-esophageal reflux disease, and occasional palpitations for which no specific treatment was being taken. She had no history of diabetes mellitus, hypertension, heart disease, liver, kidney, or any other systemic illness.
Physical Examination: At the time of admission showed a conscious, alert, and oriented patient. She had normal speech, cranial nerves, and fundus. Her higher mental functions were intact, and she had normal memory and cognition. Upper limbs showed normal power, tone, and reflexes. Lower limb showed mild spasticity, evident when she was made to stand and walk. Knee deep tendon reflexes were reduced bilaterally, while ankle jerks were increased, and bilateral plantars were upgoing. Sensory system examination showed reduced vibration sense with a level at D6. Coordination was normal.
She underwent extensive evaluation with MRI of cervical, dorsal, and lumbar spine; only one lesion was found in the dorsal spine.
Two non-enhancing lesions were found in the supra-tentorial cerebral white matter on the right side, adjacent to the lateral ventricle in the trigonal area. Her CSF was positive for Oligoclonal bands. She was treated with 5 doses of Inj Methyl Prednisolone 1 gm daily, and then followed up with oral Prednisolone, tapered over three weeks, and her symptoms gradually improved.
She was treated with Inj Methyl Prednisolone 1 gm daily for 5 days; recovery took a prolonged time. CSF studies showed the following findings: CSF: Cell count: nil; Protein: 29.5 mg/dL (normal range: 15 - 45 mg/dL;) Glucose: 83 mg/dL; Gram stain, AFB stain, Fungal stain, pan-cultures: negative; CSF and serum NMO Antibody: negative; CSF and serum Oligoclonal antibodies positive.
She is on follow up at present.
This patient is on follow up for the last 6 months, and not on any specific disease - modifying therapy for Multiple Sclerosis, even though by McDonald’s criteria, she had Definite MS.
CASE 3:
A 28 - year old Myanmarese lady, working as catering staff with a major company in the UAE, presented to Neurology clinic at Aster Hospital, with complaints of progressively increasing blurring of vision, difficulty in walking with unsteadiness, and abnormal feeling in the hands and legs. She had travelled in her native place in the Philippine a month ago, and felt mild bilateral blurring of vision soon after returning to work in Dubai, which she initially ignored. This increased gradually, and three weeks before presentation, she noticed pins and needles in her hands; a week later, these intensified and spread to the feet, and were associated with stiffness in the legs. This was associated with some difficulty in walking. She was brought to the OPD in a wheelchair because the combination of stiffness in the limbs and visual difficulty made it hard to walk, though she was able to walk independently. There was no double vision, no difficulty swallowing, no falls, no loss of consciousness, no seizures, loss of memory or other cognitive difficulties.
She had past history of blurring of vision about two years ago, for which she attended hospital locally in Dubai, was evaluated with MRI and was informed that she had some neurological illness; there had been no follow up, hence she was not on any treatment. There was no history of thyroid disease, arthralgias, skin rash, liver, kidney, heart, pulmonary diseases, diabetes mellitus or hypertension.
Physical Examination at the time of admission showed mild visual blurring, with impairment of both central and peripheral vision. Extraocular movements were normal. Fundus showed bilateral pale discs. There were no other cranial nerve abnormalities. She had normal memory and cognition. She had spasticity in both lower limbs; all her deep tendon reflexes were pathologically brisk and plantars were bilaterally upgoing. There was mild distal ataxia, in the form of finger - nose inco-ordination. Sensory examination was normal. Examination of other systems was normal.
COMPLETE BLOOD COUNT
WBC Count 7.49 10^3/uL (4 - 10)
RBC Count 5.31 10^6 / uL (3.8 - 4.8)
Hemoglobin 11.6 g/dl (12 - 15)
Hematocrit 36.6% (36 - 46)
MCV 68.9 fl (83 - 101)
MCH 21.8 pg (27 - 32)
MCHC 31.7 g/dl (31 - 37)
Platelet Count 214 10^3/uL (150 - 410)
RDW-CV 14.7% (11.6 - 14)
MPV 10.7 fl (7.6 - 10.8)
DIFFERENTIAL COUNT
Neutrophil 63.4 % (40 - 80)
Lymphocytes 31.5 % (20 - 40)
Monocytes 3.3 % (2 - 10)
Eosinophils 1.5 % (1 - 6)
Basophil 0.3 % (0 - 1)
Total Iron Binding Capacity (Fx) 387 ug/dl (250 - 400)
Transferrin Saturation (Fx) 29.46 % (16 - 50)
Ferritin levels 47.8 ng/mL (range 12 - 150)
Hemoglobin electrophoresis showed 94.7% HbA, 2.3% HbA2 and HbF <1%, and HbD was absent (against diagnosis of Beta thalassemia trait). Hence microcytic anemia may be due to iron deficiency anemia, secondary to excessive menstrual loss and inadequate dietary iron intake. Vitamin B12 and Folic Acid levels were not checked.
Thyroid function, Renal function, hepatic function were within normal limits. Chest Xray and ECG were both normal.
CSF:
Cell count: 0 cells; Protein: 22.9 mg/dL (15 - 45); Glucose: 75.6 mg/dL
CSF and serum Oligoclonal bands positive, with extra Bands observed in CSF : Demonstrates both Intrathecal & Systemic IgG synthesis.
TREATMENT:
She was started on a 5 - day course of Inj Methyl Prednisolone 1 gm daily, with which she improved, and following this, has been started on oral disease modifying therapy with Fingolimod 50 mg daily. She is on regular follow up.
CASE 4:
This 32 - year old Lebanese man works as hotel staff in Dubai. He presented in 2017 with right sided weakness. Evaluation with MRI at that time showed multiple demyelinating lesions, and CSF showed positive Oligoclonal bands. Since then he has been on weekly Inj Interferon (Avonex, 30 mcg weekly, subcutaneously), till 3 weeks before presentation, when he had a relapse in the form of abnormal painful burning paresthesia in both hands. In addition, he gets burning pain when he bends his neck; he has been getting pain in the low back as well. He has noticed difficulty in walking with tendency to sway to the left since the last 12 days which is progressively getting worse.
Physical Examination at the time of admission showed reduced sensations in both upper limbs, and reduced motor power in both upper limbs, up to MRC Grade 4/5 proximally. The deep tendon reflexes in the upper limbs, including bilateral triceps and brachioradialis were reduced; left biceps jerk was brisk; both knee jerks were brisk, ankle jerks were normal. Bilateral plantar reflexes were upgoing. Distal vibration and joint position sense were lost in both feet. Tandem walking was impaired, but Romberg’s test was negative (no sensory ataxia).
A clinical diagnosis of relapse of Multiple Sclerosis was made, and patient was admitted for Inj Methyl Prednisolone, and MRI evaluation.
MRI images of the patient at the time of first presentation in October, 2017, showing extensive lesions in the supratentorial periventricular, juxtacortical, posterior fossa, and spinal cord location, fulfilling criteria McDonald’s and Berkhoff’s MRI criteria for diagnosis of Multiple Sclerosis. This was further confirmed with positive CSF Oligoclonal bands.
TREATMENT:
Since the patient had a relapse while on Avonex (Interferon), a plan was made to change the disease - modifying therapy, as the patient preferred one of the oral drugs. A choice was made to start him on oral Fingolimod, and the patient has been on this therapy for the last 3 months.
CASE 5:
This 49 year old Filipina was referred by physician for evaluation of possible diagnosis of Multiple Sclerosis. She had recurrent admission in the previous month for abdominal complaints. She presented with dizziness, vomiting, loose motions, and upper abdominal discomfort discomfort and pain in the month of July, 2019. She was found to have cholelithiasis, and calculous cholecystitis was diagnosed, and laparoscopic cholecystectomy was performed. She was readmitted a week later with the same complaints, hence she was referred for evaluation to Neurologist and Gastroenterologist for possible other causes of her symptoms. On detailed history taking, she revealed that she had been admitted with similar complaints in 2017, for which she had gone to the government hospital. At that time, she had burning facial pain as well, but this was not completely evaluated at that time. When the facial pain persisted, she visited a private hospital, who evaluated her with MRI brain scan. Some lesions were seen on the scan, and lumbar puncture was performed, but the results were not conclusive, hence the patient was discharged on Gabapentin for the facial pain. She continued this for a month, after which she stopped it and did not continue follow up. She had past history of Type 2 Diabetes mellitus and was on oral hypoglycemic drugs, and over the next few months, she developed right shoulder pain as well as left flank pain, all of which were attributed to diabetes and treated with medicines.
She was asked to visit the out-patient department with her previous reports, and was seen again 1 week later. The MRI images showed periventricular lesions highly suggestive of, but not pathognomonic of MS; CSF report was available, but the report for Oligoclonal bands was not available. Antinuclear antibody was positive at 3+, but dsDNA and SmDNA were both negative. As per these records, the diagnosis considered was Trigeminal neuralgia, and patient was discharged on Gabapentin.
FLAIR Axial MRI images showed multiple periventricular and juxtacortical lesions in the supratentorial compartment; screening MRI of the spine suggested additional lesions in the cervical and dorsal spinal cord. The lesions in the brain did not enhance with Gadolinium. Additional study of the spine with Gadolinium, as well as CSF study for Oligoclonal bands was planned, but could not be completed due to insurance issues.
CASE 6:
A 21 - year old Egyptian lady was referred in the last week of October to the OPD at Aster Hospital with the complaints of increasing double vision and ataxia. She first noticed double vision in last week of September, and initially ignored it. In early October, she noticed unsteadiness while walking, which she ignored for a further one week. Since about a week prior to presentation, she started feeling abnormal sensation in the left side of the body especially the left leg and left flank from the chest down, and had a lack of sensation on the left thigh and leg; she occasionally couldn’t feel the left thigh even on scratching it deeply when it itched. With these complaints she approached a neurologist at Aster Clinic who then referred her to OPD at AHM as possible MS.
She had h/o left facial numbness a few years ago that remained undiagnosed, and in 2016, she had an episode of left sided double vision that was not fully evaluated.
Physical Examination: At the time of admission, her visual acuity was recorded as follows:
VISUAL ACUITY (UNAIDED)
OD : 6/60p
OS :6/36
NVN :N6 OU
Detailed eye examination revealed the following:
ANT SEGMENT: No abnormality found in either eye
PUPIL - Normal size, reacting to light - both Direct and Consensual
FUNDUS both eyes - media clear; Disc vertically oblong with hazy margins with water marks and old inflammatory pigments around disc; cup normal / disc pallor ++ /more temporally
Fundus: No abnormality detected; Intraocular pressure: 15 and 17 mmhg by nct
DETAILED NEUROLOGICAL EXAMINATION
She had reduced movement in the left eye (lateral rectus weakness); other cranial nerves were normal. Motor system showed normal power and tone in the muscles. Deep tendon reflexes were brisk at the knee and ankle; upper limb deep tendon reflexes were reduced. Plantars were bilaterally upgoing. There was loss of vibration sense on the left side in the lower limb with sensory level for vibration at D6 on the left side. There was no limb or gait ataxia.
The MRI findings of lesions in the various locations including juxtacortical, periventricular, posterior fossa, spinal cord, along with few lesions of more than 6 mm size, were considered sufficient to diagnose Definite Multiple Sclerosis in this 21 - year old patient who had previous history of undiagnosed neurological illness at age 18 years and one more episode prior to this; based on the clinical history and MRI picture, there was evidence of dissemination in time as well as space.
TREATMENT:
She was treated with an initial 5 - day course of Inj Methyl Prednisolone 1 g daily, with which she improved, and has been started on oral Fingolimod, and is on regular follow up.
DISCUSSION
The diagnosis of Multiple Sclerosis can be straightforward if dissemination in time and space can be established at any point of time. The difficulty arises when a patient of appropriate age presents for the first time with a neurological illness, and the MRI criteria are not sufficient to confirm Definite Multiple Sclerosis. In our series, this situation prevailed in Patient 2, a 48 year old Indian housewife, who presented with sensory symptoms localizing to the dorsal spine; initial imaging showed a symptomatic lesion in the dorsal spinal cord, and few non - specific lesions in the brain. When all the other tests were normal, only CSF Oligoclonal bands were the means to establish the diagnosis. This patient went for further opinions from other neurologists in India, and, being reluctant to start any treatment, was satisfied when there was divided opinion among neurologists. Only long - term follow up can resolve this issue.
In the other patients, the issues were easier since the number of lesions on MRI scans were sufficiently large for the diagnosis to be seriously considered. Even then, diagnosing MS solely on imaging criteria is fraught with risk if there are no clinical events; this is exemplified by our Patient number 5, who never clearly reported an episode which could be considered a relapse. Her MRI brain, however, is quite similar to those of other patients who have been diagnosed with definite MS. We could not complete the evaluation, unfortunately, though MRI of the spine and CSF studies were planned, due to insurance issues. The problem of Radiologically Isolated Syndrome continues to plaque MS care givers.
In the case of Clinically Isolated Syndrome, by definition, the patient presents with the first episode of neurological illness which may be considered as Possible MS, and the clinician then has to look for additional evidence to support the diagnosis of Definite MS, as defined in the 2017 Modification of McDonald’s criteria. In our small series, Cases 1 and 2 can be considered to be CIS, if the old history of visual blurring in Case 1 8 years prior to presentation with current illness is not considered as the initial event. While Cases 3 and 6 had clear history of prior episodes which could be classified as MS relapses, in Case 4, the diagnosis was already established by prior CSF Oligoclonal bands.
Except in Case 4, all the other patients were diagnosed de novo; hence the burden of diagnosis as well as initiating long - term, potentially toxic, and definitely expensive disease-modifying therapy lay with us.
There are two schools of thought in this regard: those who advise early institution of disease-modifying therapy, and those who advocate that we should wait at least till the first or second relapse, so that we don’t treat all those MS patients who have few or no relapses, as also all those non - specific demyelinating syndromes that get mis-labelled as MS. While this is an area of intense, ongoing debate, there are a few studies which have pointed out clinical and MRI features that may help us to decide which candidate deserves early treatment, and which factors do not help us to decide this.
For example, among patients who present with CIS or RIS, detection of asymptomatic lesion in the spine is considered to increase their chance of conversion into full-blown MS within the next 5 years. The sensitivity of this finding is 87.5, specificity is 91.5%, while the positive predictive value is 84% (Okuda et al, 2011, Neurology). Factors that do not predict such conversion include: gender, number of T2 lesions on MRI, Oligoclonal bands, and IgG index. Other factors that have been more commonly associated with later conversion to Clinically Definite MS include VEP findings, younger age, and Gadolinium - enhancing lesions on follow - up MRI.
In the two patients who presented with CIS, Case 1 had spinal cord lesions as well as enhancing lesions on MRI; these factors predict progression to Clinically Definite MS, hence she should be started on DMT, and has been placed on a regimen of bi-weekly PLEGRIDY.
In Case 2, there is one spinal cord lesion, but this is the symptomatic lesion; there are no enhancing lesions. VEPs were normal, and her age (48 years) puts her in a slightly older age bracket. Based on these criteria, the chances of progression to CDMS are somewhat lower in her; she has been placed on long - term follow up.
Cases 3 and 6 had previous episodes which were suggestive of MS; their MRI findings fulfilled McDonald’s 2017 criteria for Definite MS; and in Case 3, this was further confirmed with CSF OCB. Both had spinal lesions; neither showed enhancing lesions; both had abnormal VEPs, and both are young (in their 20s); based on these criteria, the chances of frequent future relapse are higher in these individuals, hence they have been started on DMT (both on Fingolimod).
Case 4 had already been diagnosed previously with MS, was on Interferon, and had a relapse while still on DMT, hence he was changed to oral Fingolimod at his own preference.
Case 5 is a RIS; in her case, the diagnostic study is not yet completed. It remains to be seen whether she has spinal lesions, and what her VEP findings will be. It would be interesting to follow up this patient to find out the natural history of some one who never had a relapse, to see if she develops a clinical relapse or the MRI findings show any evolution over time.
In conclusion, therefore, it may be said that the diagnosis of MS can be challenging despite all the advances made in medical science. With new therapies and new advances in investigational methods, it is imperative that a complete diagnosis be made in every patient. Patients have to be fully informed about the condition, along with the pros and cons of treatment or of withholding treatment.
