Multiple Sclerosis Flashcards
MS - Mx
Treatment in multiple sclerosis is focused at reducing the frequency and duration of relapses. There is no cure.
MS - ACUTE RELAPSE Mx
High dose steroids (e.g. oral or IV methylprednisolone) may be given for 5 days to shorten the length of an acute relapse. It should be noted that steroids shorten the duration of a relapse and do not alter the degree of recovery (i.e. whether a patient returns to baseline function)
MS - Disease modifying drugs
BETA-INTERFERON has been shown to reduce the relapse rate by up to 30%. Certain criteria have to be met before it is used:
- relapsing-remitting disease + 2 relapses in past 2 years + able to walk 100m unaided
- secondary progressive disease + 2 relapses in past 2 years + able to walk 10m (aided or unaided)
- reduces number of relapses and MRI changes, however doesn’t reduce overall disability
Other drugs used in the management of multiple sclerosis include:
- glatiramer acetate: immunomodulating drug - acts as an ‘immune decoy’
- natalizumab: a recombinant monoclonal antibody that antagonises Alpha-4 Beta-1-integrin found on the surface of leucocytes, thus inhibiting migration of leucocytes across the endothelium across the blood-brain barrier
- fingolimod: sphingosine 1-phosphate receptor modulator, prevents lymphocytes from leaving lymph nodes. An oral formulation is available
MS - Mx of Fatigue
Mx of Fatigue in MS:
- once other problems (e.g. anaemia, thyroid or depression) have been excluded NICE recommend a trial of amantadine
- other options include mindfulness training and CBT
MS - Mx of Spasticity
Mx of Spasticity in MS
- Baclofen and Gabapentin are first-line. Other options include diazepam, dantrolene and tizanidine
physiotherapy is important
- Cannabis and Botox are undergoing evalulation
MS - Mx of Bladder Dysfunction
Bladder dysfunction:
- May take the form of urgency, incontinence, overflow etc
- Guidelines stress the importance of getting an ultrasound first to assess bladder emptying
- IF significant residual volume → intermittent self-catheterisation
- IF no significant residual volume → anticholinergics may improve urinary frequency (NB anticholinergics may worsen symptoms in some patients
MS -Oscillopsia
Oscillopsia= When visual fields apper to oscillate!
Mx = Gabapentin 1st line
Multiple Sclerosis - MRI Ix : Example Question
A 65-year-old male presents to the neurology outpatient department with a history of recurrent bouts of unsteadiness and vomiting over the last 10 years, with partial resolution. He has also had episodes of visual problems, which he describes as the sudden loss of vision in the right eye, with an almost complete recovery of vision over the course of the next few weeks. He has a history of type 2 diabetes and is hypertensive and is generally non-compliant with his treatment. He is also a smoker with a 50 pack year history.
His medication includes glimepiride 2mg daily and metformin 500mg TDS. He also takes telmisartan 40mg daily.
On examination, he has nystagmus in the right eye with the fast component towards the right. His gait is ataxic and he has evidence of spasticity in both lower limbs with exaggerated reflexes and bilateral ankle clonus. Fundoscopic examination revealed a pale optic disc.
MRI brain shows diffuse lesions in multiple sites. The report queried demyelinating plaques vs multiple infarcts.
Which of the following would be the most appropriate next investigation?
> MRI spinal cord CSF examination for oligoclonal bands MR angiography of the verterbrobasilar system Titres of anti-Hu antibodies Visual evoked potentials
The diagnosis, in this case, is that of multiple sclerosis and the question aims to assess the candidate’s ability to plan further investigations if the MRI of the brain is inconclusive.
An MRI of the brain is a sensitive imaging modality for the detection of plaques in patients with MS, but it lacks specificity. Over the age of 50, small ischaemic lesions may be difficult to distinguish from demyelination. The presence of spinal cord lesions, however, is quite specific for inflammatory disorders such as MS rather than ischaemic lesions. Thus cord imaging is useful when there is diagnostic difficulty.
Multiple Sclerosis - Diagnosis with MRI
An MRI of the brain is a sensitive imaging modality for the detection of plaques in patients with MS, but it lacks specificity. Over the age of 50, small ischaemic lesions may be difficult to distinguish from demyelination. The presence of spinal cord lesions, however, is quite specific for inflammatory disorders such as MS rather than ischaemic lesions. Thus cord imaging is useful when there is diagnostic difficulty.
MS and Oligoclonal Bands
Oligoclonal bands are found in the CSF in >90% of cases of MS but are not specific for MS. They are also found in Lyme disease Systemic lupus erythematosus Neurosarcoidosis Subacute sclerosing panencephalitis Subarachnoid hemorrhage Syphilis Primary central nervous system lymphoma Sjögren's syndrome Guillain-Barre syndrome Meningeal carcinomatosis Neuromyelitis optica
MS - Ix
Diagnosis requires demonstration of lesions disseminated in time and space
MRI
high signal T2 lesions
periventricular plaques
Dawson fingers: often seen on FLAIR images - hyperintense lesions penpendicular to the corpus callosum
CSF oligoclonal bands (and not in serum) increased intrathecal synthesis of IgG
Visual evoked potentials
delayed, but well preserved waveform
MS DIAGNOSIS
Diagnosis requires demonstration of lesions disseminated in time and space
MS - Mx of acute relapse: Example Question
A 35-year-old female presents to the Emergency Department with three days of increasing weakness in the left arm and reduced visual acuity in the left eye. She was diagnosed with relapsing-remitting multiple sclerosis two years earlier. She takes fingolimod as maintenance therapy and denies any compliance issues.
On examination, she has weakness in wrist extension and finger abduction in the left hand and visual acuity in the left eye was measured at 6/24 with an associated reduction in colour saturation. Her blood tests were unremarkable and in particular, her white cell count was normal. Her MRI scan does show two new enhancing lesions in the right pericallosal region.
How should this be managed acutely?
Commence high dose oral prednisone and wean over a month Commence intravenous dexamethasone Commence natalizumab infusion > Commence high dose methylprednisolone for 3-5 days Biopsy the enhancing lesions
Given that this patient has relapsed on maintenance therapy, and that she has multi-focal signs affecting vision and motor function, she should be admitted to hospital and commenced on high-dose intravenous methylprednisolone.
Acute relapses can be treated with either high dose oral prednisolone or intravenous therapy. The choice depends on multiple factors including the severity of symptoms, the requirement for hospital admission for monitoring, and co-morbidities such as diabetes and depression.
After this patient has recovered from this acute relapse a review of her maintenance therapy should occur, and this may be escalated through her neurologist based on a number of criteria.
Multiple Sclerosis and Disease Modifying Therapies -Example Question
A 43-year-old female presents with a second episode of loss of sensation in her left anterior thigh and right foot. This is her second episode within the past four months. She had recently reported an episode of left anterior shin numbness 1 year ago when an MRI with gadolinium demonstrated ‘spots in her spinal cord’ and she was diagnosed with transverse myelitis. Her past medical history also includes ulcerative colitis, diagnosed aged 27 years old and primary sclerosing cholangitis. Her serum tests are as follows:
Hb 125 g/l
Platelets 274 * 109/l
WBC 7.5 * 109/l
Na+ 139 mmol/l K+ 4.4 mmol/l Urea 4.7 mmol/l Creatinine 78 µmol/l Bilirubin 49 µmol/l ALP 305 u/l ALT 180 u/l
You commence five days of high dose oral methylprednisolone. What is the most appropriate next management?
Interferon beta > Glatiramer acetate Fingolimod Natalizumab Mitoxantrone
The patient presents with a clear history of recurrent relapses of relapsing-remitting multiple sclerosis (RRMS), isolated in time and location. In addition, NICE recommends that any patient experiencing more than two debilitating episodes of RRMS be considered for disease modifying therapies.
A number of 1st line disease modifying therapies are available and the choice is made on a patient-by-patient basis. Interferon beta 1a, beta 1b, glatiramer acetate, diethyl fumarate and teriflunomide are all valid choices. However, deranged liver function is contraindicated in the use of interferons, as in this case, where the patient has a cholestatic pattern of liver dysfunction secondary to primary sclerosing cholangitis. Glatiramer acetate is not contraindicated in liver dysfunction and hence the only suitable choice.
Fingolimod is a sphingosine 1 phosphate receptor modulator affecting lymphocyte migration that has been proven to reduce the number of relapses and slow the rate of number of new MRI lesions. However, it was also associated with increased incidence of varicella zoster, tumour formation and progressive multifocal leucoencephalopathy (PML), another demyelinating central nervous system condition. As a result, fingolimod is reserved for patients who fail 1st line therapies. Similarly, while natalizumab is effective in modifying multiple sclerosis progression, it is also associated with PML and not considered a 1st line treatment. Mitoxantrone is a chemotherapy agent that inhibits DNA synthesis and repair, associated with significant cardiotoxicity, reserved only for RRMS patients who have failed other therapies with rapidly progressive disease.
MS - Second Line Pharmacological Mx
Observational studies have reported that escalation from a first-line therapy to a second-line drug reduces relapse rate at one year.
Evidence suggests that alemtuzumab, natalizumab and fingolimod outperformed other disease-modifying therapies at preventing relapse at 2 years. In addition, natalizumab also reduced 2-year disability progression rates.
Natalizumab is strongly associated with progressive multifocal leukoencephalopathy, an infection of the central nervous system with the John Cunningham virus (JCV). Therefore, JCV antibody status is an essential part of assessing an individual for treatment with natalizumab. Patient’s who are seropositive for JCV are not treated with natalizumab or switched to another drug.
Example Question:
A 42-year-old woman attends neurology clinic for review of her treatment strategy for multiple sclerosis. The patient had first developed symptoms of multiple sclerosis five years previously. Her first episode had involved sensory loss and motor weakness affecting her left leg. An MRI brain scan conducted at this time had demonstrated multiple lesions suggestive of multiple sclerosis. At this point in time, the patient had decided against receiving disease modifying therapy.
One year after her first episode, the patient suffered an episode of optic neuritis. A repeat MRI scan had demonstrated a progression of the previously observed radiographic lesions. Subsequently, the patient had been initiated on treatment with interferon beta. This treatment was continued for two years during which time the patient suffered no further relapses of multiple sclerosis. However, the patient found the unwanted effects of interferon beta to be progressively harder to tolerate and she eventually decided against continuing with this treatment. A subsequent trial of glatiramer acetate was quickly halted due to the patient experiencing severe symptoms of flushing.
Following the cessation of disease-modifying therapy, the patient had experienced multiple further relapses, including one episode where she had required hospitalisation due to cranial nerve involvement. Further assessment during this period found that the patient met the local criteria for aggressive or highly active multiple sclerosis. Accordingly, later line therapies were discussed with the patient who was keen to proceed.
Aside from her history of multiple sclerosis the patient suffered from no other significant medical problems and took no regular medications. The patient was a science teacher that had been unable to work for the past year due to her multiple relapses.
The later line therapy recommended for the patient is natalizumab. What is the essential investigation that must be completed prior to initiation of treatment with natalizumab?
Transthoracic echocardiogram > JCV antibody status Pulmonary function tests Thyroid function tests CMV antibody status
The patient has highly active multiple sclerosis causing significant morbidity. While she had obtained benefit from the standard initial therapies interferon beta and glatiramer acetate, these treatments were ultimately not tolerated. In this situation, consideration of escalation to second-line disease-modifying therapy is appropriate.
MS and Natalizumab
Natalizumab is strongly associated with progressive multifocal leukoencephalopathy, an infection of the central nervous system with the John Cunningham virus (JCV). Therefore, JCV antibody status is an essential part of assessing an individual for treatment with natalizumab. Patient’s who are seropositive for JCV are not treated with natalizumab or switched to another drug.
MS and Rituximab
Rituximab results in B cell depletion through incompletely understood processes. An acute deterioration in cognition and agitation, in the context of an immunosuppressed, should raise strong suspicions of encephalitis or meningitis. The patient might not raise a strong immune response, hence relatively modest number of white cells in CSF and CRP, but the raised CSF protein would be consistent with viral encephalitis
Example Question:
A 66-year-old female is brought into Emergency Department by her distraught husband, who reports that she has not been out of bed for 3 days and seems unable to recognise him. He reports no recent fevers or rigors, she has not complained of cough, dysuria, sore throat or diarrhoea and vomiting prior to being unwell. She is well known to local neurologists: she is undergoing off-label rituximab for difficult to manage relapsing-remitting progressive multiple sclerosis, with previous white matter lesions in her corpus callosum, periventricular white matter, and lower thoracic transverse myelitis.
Over the past 6 years, she had continued to relapse despite interferon beta, natalizumab, mitoxantrone and cyclophosphamide. At baseline, she is weak in her lower limbs and is able to stand only with assistance of a turning apparatus, then able to walk about 3 steps. She is normally cognitively intact and fully orientated, normally responsible for organising the couples finances. Her past medical history includes type 1 diabetes mellitus, autoimmune thyroiditis and previous deep vein thrombosis 5 years ago (warfarin since discontinued). Her medication history includes lantus, novomix, levothyroxine and 3 monthly infusions of rituximab, which had stably maintained her MS for 4 years.
On examination, she is not orientated to time or place and appears extremely irritable. Halfway through the examination, she becomes extremely tearful. There is a full range of neck movements and no photophobia.
Neurological examination is difficult due to patient cooperation: pupils are equal and reactive, there is a full range of eye movements and no obvious facial asymmetry. Power in her upper limbs were at least 3/5, lower limbs are unable to counteract gravity. Both plantar responses are upgoing. Her bloods are as follows:
Hb 134 g/l
Platelets 268 * 109/l
WBC 7.8 * 109/l
Na+ 137 mmol/l K+ 4.4 mmol/l Urea 4.5 mmol/l Creatinine 60 µmol/l CRP 5 mg/l HIV negative Glucose 7.4 mmol/l
A lumbar puncture was performed:
WBC 16 /mm³ RBC 150 /mm³ Protein 0.71 g/l Glucose 3.5 mmol/l PCR and gram staining awaited
What is the most appropriate management step?
> Intravenous aciclovir Intravenous methylprednisolone Intravenous immunoglobulin Intravenous rituximab infusion Psychiatric input
This is a difficult question regarding the side effect of rituximab and opportunistic infections. The neurological signs are difficult to interpret. Firstly, there are no hard clinical signs that her MS has deteriorated: her plantars are likely to be upgoing at baseline due to previous transverse myelitis while a symmetrical bilateral mild reduction in power is expected as a result of decompensation during acute illness. As a result, further aggressive immunosuppression would not be appropriate.
Rituximab results in B cell depletion through incompletely understood processes. An acute deterioration in cognition and agitation, in the context of an immunosuppressed, should raise strong suspicions of encephalitis or meningitis. The patient might not raise a strong immune response, hence relatively modest number of white cells in CSF and CRP, but the raised CSF protein would be consistent with viral encephalitis. A CSF:serum glucose of around 1:2 lowers the risk of bacterial CNS infection. The patient should be covered for possible herpes simplex or varicella-zoster encephalitis with intravenous aciclovir while awaiting CSF PCR.
Fatigue Mx in MS: Example Question
A 47 year old female with relapsing-remitting multiple sclerosis (MS) describes increasing difficulty with fatigue, and has had to give up her work as a medical secretary. She has always been careful about ensuring a balanced diet, gentle exercise and early treatment of infection. On review and questioning her mood is good. Her most recent bloods are shown below:
Hb 120g/dl
Platelets 150 * 109/l
WBC 5.2 * 109/l
Na 130 mmol/l
K 3.8 mmol/l
Urea 6.0 mmol/l
Creatinine 68 µmol/l
B12, folate and TFTs are normal.
What is the best course of action?
Advise that she increase caffeine intake Advise that increasing exercise may benefit Trial of vitamin D > Trial of amantadine Trial of ropinirole
The first step in her management should be to exclude anaemia, thyroid dysfunction, sleep or mood disturbance. With the above results and knowledge that she is living a well balanced lifestyle, the next step would be a trial of amantadine.
Amantadine is an anti-viral agent that slows viral replication. It is also known to have some dopaminergic effects; the mechanism of action for reducing fatigue in MS however, remains unclear. It is currently recommended by NICE as a potential treatment, although a Cochrane review in 2006 was inconclusive.
Increasing caffeine intake and levels of exercise would not be recommended in this patient. Similarly, vitamin D has not be proven to be of benefit in MS. Ropinirole is a dopamine agonist used in parkinsons disease but not in MS.
Optic Neuritis
Causes
multiple sclerosis
diabetes
syphilis
Features
unilateral decrease in visual acuity over hours or days
poor discrimination of colours, ‘red desaturation’
pain worse on eye movement
relative afferent pupillary defect
central scotoma
Management
high-dose steroids
recovery usually takes 4-6 weeks
Prognosis
MRI: if > 3 white-matter lesions, 5-year risk of developing multiple sclerosis is c. 50%
‘Hidden’ Diagnosis of MS - Example Question
Trigeminal Neuralgia with Red Flags
A 55-year-old woman attends neurology clinic for follow-up. At her first appointment 6 months previously, a clinical diagnosis of trigeminal neuralgia had been made and treatment with carbamazepine initiated. During clinic review the patient complained of ongoing symptoms with only limited benefit from drug treatment.
On her previous assessment, the patient had reported pain episodes associated with the cheek and jaw of the right side of her face. Subsequently, in addition to similar ongoing episodes, the patient had suffered from two episodes of pain affecting the forehead and peri-orbital region on the left side of her face. On one occasion, she had suffered from both right and left sided pain at the same time. She reported that the carbamazepine treatment had initially reduced the intensity of the pain episodes by perhaps 50 %, but that the severity of recent attacks had again worsened to their original level. When her drug history was checked, it was apparent that the carbamazepine dose had been titrated up appropriately by the patients GP.
The patient also stated that following her previous clinic appointment she had been discussing the situation with her sister, who had reminded the patient that their mother had suffered several episodes of visual loss during her life but had not undergone any medical investigation.
Cranial nerve examination demonstrated normal eye movements and pupillary responses. There was no evidence of facial nerve weakness, however a subjective numbness of sensation was noted in the left cheek region (this had not been noted on previous examination in clinic). There were no lesions around the head and neck or inside the mouth. Peripheral neurological examination was remarkable for borderline dysdiadochokinesia in the right upper limb and a positive Babinski response in the right lower limb.
What is the most appropriate investigation for this patient?
Visual evoked potentials Three-plane fine-slice MRI brain with contrast CSF oligoclonal bands CT brain with contrast > Standard protocol MRI brain with contrast
The patients previous clinical diagnosis of trigeminal neuralgia clearly needs to be reviewed in light of several red-flag features. In particular, the limited response to carbamazepine, the occurrence of simultaneous bilateral pain and the history of pain associated with the ophthalmic division are inconsistent with a typical presentation of trigeminal neuralgia. Moreover, the patient has developed some soft neurological signs that are suggestive of CNS lesions in various areas of the brain.
Multiple sclerosis is the most likely alternative diagnosis, although other causes of trigeminal pain such as space occupying lesions, malignant invasion of the trigeminal nerve or thalamic infarction are also possibilities. The best investigation to assess for all these differentials is standard protocol MRI brain with contrast. Demyelination or trigeminal nerve infiltration would not be reliably noted on CT brain with contrast making this less likely to progress the diagnosis. Visual evoked potentials and CSF oligoclonal bands are other investigations that may support a diagnosis of multiple sclerosis but would not confirm or refute this diagnosis in isolation.
Typical cases of trigeminal neuralgia are considered to result from contact between blood vessels and the trigeminal nerve. Such vascular contacts can be observed on specialised MRI protocols requiring fine-slicing in three-planes. However, given the additional expense and the fact that such contacts can be a normal variant, this investigation is not normally performed. A standard protocol MRI brain is sufficient to assess for the important differentials of trigeminal neuralgia discussed above.
MS Diagnosis - Example Question
A 24 year-old university student presents with a 10 day history of visual disturbance. He reports changes in his visual acuity where he has been experienced some blurring of his vision which is considerably worse after having been for a run. He thinks it is related to some pain he developed on his right eye prior to the onset of his vision loss. He has no previous history of visual problems and is normally fit and well. He takes no regular medications.
On further questioning he reports that 6 months ago he had some sensory changes on his lower limbs. He felt they were numb and this persisted for a few weeks. He thought it was due to his sporting activities, as he is an avid hockey player.
He drinks 20 units of alcohol at the weekends and does not smoke.
His blood results are shown below:
Hb 134 g/l Platelets 250 * 109/l WBC 8 * 109/l Na+ 134 mmol/l K+ 4.1 mmol/l Urea 4 mmol/l Creatinine 60 µmol/l
Which investigation below would be most useful to diagnose this patient?
EEG CT head HIV serology > Contrast MRI brain and spine Anti-NMO antibodies
This young man presents with the classic symptoms of optic neuritis. Changes in vision(usually blurriness but can occasionally present as loss of red colour vision). He describes Uhthoff’s phenomenon.
His history of a previous episode of paraesthesia is consistent with a previous first CIN episode. This gentleman requires urgent investigations. He should have a lumbar puncture which would show oligoclonal bands- which should be paired with a serum sample for comparison.
The correct answer is contrast MRI brain and spine and this will show a gadolinium enhancing consistent with an acute demyelinating lesion. Most likely it would also show an old lesion in his cord which would be diagnostic of MS.
http://emedicine.medscape.com/article/1146199-workup
Neuromyelitis optica is a demyelinating condition associated with NMO antibodies (Aquaporin 4 antibodies) which presents with demyelination of the optic nerve and spinal cord. It follows a more severe course than traditional MS. In this instance, an MRI with contrast will be the most appropriate investigation to yield a diagnosis.
Transverse Myelitis vs MS - Example Question
A 17 year old Caucasian male with no past medical history presents with his first episode of sudden onset left leg weakness and numbness on his anterior left thigh, of sudden onset and persistent after 4 days. On examination, you note 3/5 weakness on flexion of his left hip and loss of sensation to light touch, pain and temperature on his anterior left thigh in the sensory nerve root L1 distribution. A contrasted MRI scan of the patients spine reveals a hyperintense T2 signal partially within the left side of the cord at the L1, with corresponding enhancement with gadolinium. No masses were observed. Further imaging of the brain is awaited. What is the diagnosis at present?
Multiple sclerosis Left spinal cord tumour Left anterior spinal ischaemic stroke > Left transverse myelitis Guillain Barre syndrome
The history, examination and radiological evidence are strongly suggestive of partial L1 transverse myelitis. The key question is whether this represents a diagnosis of multiple sclerosis (MS) or not. The diagnosis of MS is determined by the McDonald criteria, first proposed in 2001 and most recently revised in 20101. The lesions or clinical episodes suggestive of acute demyelinating episodes must be disseminated in both time and place. As a result, a patient presenting with only one symptomatic episode can be diagnosed with MS if their MRI scans demonstrate demyelinating plaques that are:
i) distinguished in age from the current symptomatic lesion
ii) In at least two of 4 areas typical of MS (periventircular, juxtacortical, infratentorial, spinal cord white matter).
In this case, only one episode in time and space has been demonstrated so far. Although a risk of future MS diagnosis is acknowledged, and may go on to be proven following MRI of the head, the diagnosis remains transverse myelitis at present.
It is often quoted that in patients diagnosed with transverse myelitis after their first symptomatic episode, only a small proportion go on to be diagnosed with MS later in their lives. However, more recent evidence suggest the pattern of transverse myelitis is important: only 5-10% of patients with complete transverse myelitis will be diagnosed with MS, with a viral febrile illness the most likely underlying cause. Patients with incomplete transverse myelitis have up to 72% risk of MS-consistent plaques found on MRI head, with 60-90% subsequently being diagnosed MS within 5 years2.
Old MS plaques appear better defined on T1 and T2 imaging than acute lesions. Contrast studies with gadolinium is also helpful: acute plaques tend to enhance to a greater degree on T1 imaging, correlated to acute inflammation that persists for up to 8 weeks and diminishes on treatment with glucocorticoids.
NEW UNEXPECTED Neurology in MS patient on Nataluzumab
A 36-year-old lady on natalizumab for relapsing-remitting multiple sclerosis develops left leg weakness. Over 3 weeks this progresses to left hemiparesis and visual impairment. She also notices poor memory and struggles to process numbers at work as an accountant. Examination reveals left-sided 4/5 power, right homonymous hemianopia, and an abbreviated mini-mental state score of 21/30. Routine blood tests are unremarkable. MRI brain shows new multiple confluent lesions in the parietooccipital and right motor white matter areas as well as the left occipital area, with no mass effect or enhancement. Which of the following tests is likely to be most helpful in establishing a diagnosis?
Serum glucose HIV serology > JC Virus serology Cerebral angiogram Full blood count (FBC)
The diagnosis here is progressive multifocal leukoencephalopathy (PML). This is a demyelinating disease of the CNS characterised by widespread lesions due to brain infection of oligodendrocytes by the JC Virus (JCV). These are visible on an MRI and have a characteristic appearance. The signs correspond to the areas occupied by the lesions. PML occurs almost exclusively in immunocompromised patients such as those with HIV or on immunotherapy. You should consider PML in your differential in such patients when they present with new odd neurology and an abnormal MRI scan.
This question’s other aim is to introduce to you one of the newer therapies in multiple sclerosis (MS) called nataluzumab. It is actually very frequently used in MS and indeed now approved for the treatment of relapsing-remitting MS (RRMS) in more than 50 countries. It is a monoclonal antibody that inhibits the migration of leucocytes into the central nervous system, hence reducing inflammation and demyelination. It is given as an IV infusion once a month. It is indicated in patients getting relapses despite treatment with interferon-beta or patients who just have rapidly evolving severe RRMS. It has been shown to decrease the risk of progression of disability by 42-54% and the annualised rate of relapse by 68%. The two principle side-effects are hepatotoxicity and increased PML risk, and we monitor patients for these with monthly liver function tests (LFTs) and 6-monthly JCV serology. It would not be unreasonable of them to expect you to know something about nataluzumab in the exam (especially to recognise PML as a side-effect) given that the drug is now in such common use.
MS - Diagnosis: Example Question
A 31-year-old woman is reviewed in the neurology clinic. For the past 6 months she has been presenting to her GP with a variety of symptoms including lethargy, heat intolerance, pins/needles and limb numbness. For the past 4 weeks she has also been complaining of shooting pains in her right hand.
Her GP has arranged a number of blood tests including thyroid function tests and vitamin B12 which were reported as normal.
A neurological examination today demonstrates no consistent neurological findings.
A MRI is requested:
SEE PASSMED MRI ‘Dawson Fingers’
What is the most likely diagnosis?
> Multiple sclerosis Pituitary tumour Ependymoma Acute disseminated encephalomyelitis (ADEM) Systemic lupus erythematosus
The MRI shows multiple white matter plaques penpendicular to the corpus callosum giving the appearance of Dawson fingers - a classic MRI finding in multiple sclerosis.
Lethargy is a clue in this question. It is very common feature in patients with multiple sclerosis. Other features such as pain and heat intolerance and also seen.
MS - Mx with Natalizumab - Example Question
A 37-year-old woman has been diagnosed with relapsing remitting multiple sclerosis and is considering further therapeutic options including natalizumab. She has had two severe relapses despite treatment with glatiramer acetate. She is currently still able to work, but is very fatigued and feels her mobility is limited.
On examination, she has brisk reflexes bilaterally, with mild weakness in her proximal left leg and reduced sensation in the left foot.
She has highly active disease on her brain MRI with multiple acute and sub-acute plaques present. She also has a single lower cervical cord lesion.
Before considering a new therapy, aside from HIV and general immunological status, which of the following investigation results is of greatest importance?
Cytomegalovirus status Syphilis serology Hepatitis C serology EBV serology > JC virus status
Natalizumab is a therapy approved for the management of highly active relapsing-remitting multiple sclerosis (RRMS) and is given as a once-monthly infusion. Natalizumab has been shown to greatly reduce relapse rates in RRMS.
It is a humanised monoclonal antibody against the cell adhesion molecule (CAM) 4-integrin. Natalizumab prevents leukocyte adhesion to endothelial VCAM1, thus preventing the migration of immune cells into the CNS.
An extremely rare, severe and almost universally fatal adverse side effect of Natalizumab is progressive multifocal leukoencephalopathy (PML). Only patients who are seropositive for JC virus are at risk of developing PML with exposure to natalizumab, and therefore checking the JC virus status of patients who are considering natalizumab therapy is mandatory.
It is also worth noting that some patients with low titres of JC virus are still commenced on natalizumab under close monitoring and that duration of natalizumab therapy is proportional to the risk of developing PML, i.e..short duration therapy (1-2 years) carries a very low risk of developing PML, even in those with a low positive JC virus titre. Ultimately, patients who are JC virus positive should not receive natalizumab and another therapy should be considered.
MS Diagnosis - Establishing Disease disseminated in both space and time
McDonald’s criteria are MRI criteria used in the diagnosis of multiple sclerosis. Introduced in 2001, revised in 2005 and again recently in 2010. The latest revision improves sensitivity from 46-74% with a slight trade-off in specificity (slight deterioration from 94-92%)
The diagnosis of multiple sclerosis requires establishing disease disseminated in both space and time.
Dissemination in space:
Dissemination in space requires at least 1 T2 bright lesion in two or more of the following locations:
periventricular
juxtacortical
infratentorial
spinal cord
Dissemination in time:
Dissemination in time can be established in one of two ways:
i) A new lesion when compared to a previous scan (irrespective of timing)
- T2 bright lesion and/or gadolinium-enhancing lesion
ii) Presence of an asymptomatic enhancing lesion and a non-enhancing T2 bright lesion on any one scan (i.e 2 lesions of differing ages that satisfy the dissemination in space criteria)
MS and Pregnancy
A knowledge of the issues surrounding pregnancy in MS is important, since females of a child-bearing age are a high risk group for developing the disease.
NICE guidance states that ‘relapse rates may reduce during pregnancy and may increase 3 to 6 months after childbirth before returning to pre-pregnancy rates’. It also states that pregnancy does not increase the risk of progression of disease; the net effect of protection during pregnancy and subsequent increased relapse rate carries no increased risk of exacerbation.
With regard to Interferon β 1a in pregnancy, most neurologists would advise stopping when pregnancy is considered, due to inconsistent and conflicting data in the area. The BNF advises against use in pregnancy ‘unless potential benefit outweighs risk’.
If a person with MS is thinking about pregnancy, they must have the opportunity to talk with a healthcare professional with knowledge of MS about:
fertility
the risk of the child developing MS
use of vitamin D before conception and during pregnancy
medication use in pregnancy
pain relief during delivery (including epidurals)
care of the child
breastfeeding.
Example Question:
A 27 year old lady with relapsing-remitting multiple sclerosis (MS) is referred to your clinic. She was diagnosed at age 18 and has been managed on interferon β 1a, with only four relapses in her total history. She has made good recovery from all four relapses and the only finding on neurological examination is of mild dysdiadochokinesis of the left arm. She scores functionally very well on an expanded disability status scale (EDSS) and has no disability as a result.
She is planning her first pregnancy and wanted advice on how her MS may be affected. She has already been advised on stopping interferon β 1a in preparation for pregnancy. Aside from the impact of stopping interferon β 1a, she wants to know how pregnancy itself will affect her MS. Which of the following is most accurate?
> Relapse rates may decrease during pregnancy, increase at 3-6 months post-partum then return to pre-pregnancy rates. There is an increased risk of developing visual disorders associated with MS. There is a 30% chance that her RRMS will evolve into progressive MS. There is a 15% chance that her relapse rate will decrease for the five years following pregnancy. Relapse rates may increase during pregnancy, then return to pre-pregnancy rates at 9 months post-partum.
NB: In this scenario the use of the expanded disability status scale (EDSS) was referred to. This provides an index of clinical disability and may be used to quantify disease progression. It has widespread use in clinical trials.
Lhermitte’s Syndrome
Paraesthesiae in limbs on neck flexion - Assoc with MS!
Uhthoff’s Phenomenon
Worsening of vision following rise in body temperature - Assoc with MS!
MS - Prognosis
Good Prognostic Fx:
- Female sex
- Young age of onset (i.e. 20s or 30s)
- Relapsing-remitting disease
- Sensory Sx only
- Long interval between first 2 relapses
- Complete recovery between relapses
The typical patient carries a better prognosis than an atypical presentation
MS - Features
May present with non-specific features e.g. 75% of patients have only significant lethargy
VISUAL:
- Optic Neuritis
- Optic Atrophy (End stage disease of optic neuritis)
- Uthoff’s phenomenon - worsening of vision following rise in body temp
- Internuclear ophthalmoplegia
SENSORY:
- Pins and needles
- Numbness
- Trinomial neuralgia
- Lhermitte’s syndrome - paraesthesiae in limbs on neck flexion
MOTOR:
- Spastic weakness - most commonly seen in legs
CEREBELLAR:
- Ataxia - more often seen during acute relapse than as presenting Sx
- Tremor
Others:
- urinary incontinence
- sexual dysfunction
- intellectual deterioration
MS - Painful involuntary contractions of the leg muscles ?
Mx = BACLOFEN
Anti spastic agent, activates GABAb receptors
CNS depressant used as a skeletal muscle relaxant
MS and DMARDS
NICE recommends that any patient experiencing more than two debilitating episodes of RRMS be considered for disease modifying therapies.
A number of 1st line disease modifying therapies are available and the choice is made on a patient-by-patient basis.
Interferon beta 1a, beta 1b, glatiramer acetate, diethyl fumarate and teriflunomide are all valid choices. However deranged liver function is contraindicated in the use of interferons, an alternative would therefore be
Glatiramer acetate which is not contraindicated in liver dysfunction.
Fingolimod is a sphingosine 1 phosphate receptor modulator affecting lymphocyte migration that has been proven to reduce the number of relapses and slow the rate of number of new MRI lesions. However, it was also associated with increased incidence of varicella zoster, tumour formation and progressive multifocal leucoencephalopathy (PML), another demyelinating central nervous system condition. As a result, fingolimod is reserved for patients who fail 1st line therapies.
Similarly, while natalizumab is effective in modifying multiple sclerosis progression, it is also associated with PML and not considered a 1st line treatment.
Mitoxantrone is a chemotherapy agent that inhibits DNA synthesis and repair, associated with significant cardiotoxicity, reserved only for RRMS patients who have failed other therapies with rapidly progressive disease.
