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Multidisciplinary approach to diagnosis and management of Multiple Sclerosis

Nidhiben Anadani MD

Assistant Professor

Department of Neurology

University of Oklahoma Health Sciences Center

9/20/2019

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RELEVANT DISCLOSURE & RESOLUTION

Nidhiben AnadaniI have no relevant financial relationships or

affiliations with commercial interests to disclose.

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LEARNING OBJECTIVES

Upon completion of this session, participants will improve their competence and performance by being able to:

1. Review symptoms, including red flags for diagnosis of Multiple Sclerosis

2. Management of Multiple Sclerosis

3. Importance of multidisciplinary team to treat Multiple Sclerosis

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EXPERIMENTAL OR OFF-LABEL DRUG/THERAPY/DEVICE DISCLOSURE

I will be discussing experimental or off-label drugs, therapies that have not been approved

by the FDA.

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Why is it important to learn about MS

❖ As of 2010 prevalence of MS in US is the highest ever reported, with 727,344 reported cases. (1)

❖ Primary care providers or other subspecialty providers are often the first physician that MS patients present to.

❖ Early diagnosis is important as early initiation of treatment may prevent disability (2).

1) Mitchell T. Wallin et al, Neurology, March05,20192) Joao J Cerqueira et al, Journal of Neurology, Neurosurgery & Psychiatry, Volume 89,

issue 8

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Defining Multiple sclerosis

❖ MS : Immune mediated chronic disease of central nervous system which causes multiple attacks on CNS separated by time and space.

❖ Clinical attack/relapse/exacerbation/CIS (when it is first relapse) : Patient reported new symptoms or objectively observed signs typical of an acute inflammatory demyelinating event in the CNS, current or historical, with duration of at least 24 hours in absence of fever or infection, with complete or partial recovery of symptoms.

❖ Pseudo exacerbation: Recurrence of symptoms experienced before in setting of infection, stress, physical exortion or heat exposure.

❖ Silent attack : appreciated on MRI

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Phenotypes of MS

National Multiple Sclerosis Society.org

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Lublin FD et al, Neurology. 2014 Jul 15; 83(3): 278–286.

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Three tiers for diagnosis of MS

1) Clinical presentation

2) Imaging findings : MRI

3) Ancillary testing : Blood, CSF examination and evoked potential

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Case-1

A 36-year-old female presents to primary care doctor to establish care with following symptoms.

• 04/2018: Itching in both feet lasting for few weeks then persistent paresthesia of both feet

• 05/2018: Blurring of vision in right eye without pain or color vision issue, lasting for one month. Referred to ophthalmologist.

• 07/2018: Paresthesia in both feet progressed up to waist in few weeks with mild gait imbalance associated with urinary urgency and frequency.

What would you do?

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Would this explain her symptoms??

T2 FLAIR

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T2 FLAIR Post contrast

T2 FLAIR

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Case-1 continued

❖ Primary care provider referred her to Neurologist

❖ Symptoms improved after high dose oral steroid (Prednisone 1gm daily for 5 days)

❖ CSF : 16 WBC, IgG index 0.9, 9 Oligoclonal bands, protein 25

❖ Serum: ESR10, CRP0.5, ANA+Ve (1:120), B12-419,Negative AQP-4, MOG, SSA/SSB, RF

❖ Dx: Clinically Isolated Syndrome/Early MS

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Symptoms : RRMS

❖ Most common phenotype, 85% of patients has RRMS

❖ Age : 15-50 years, Mean age of presentation 29 years

❖ Female:male – 3:1, More aggressive disease in African American

❖ Onset : Subacute, over few days

❖ Multiple lesions separated in time and space

❖ Common Syndrome/Symptoms :

1) Cerebral hemisphere :

• Weakness or numbness on one side or the other

• Memory loss and confusion- Rare presentation of a relapse

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2) Optic Nerve :

• Vision loss with pain on moving eye and with altered color vision

• Good recovery of vision with or without steroids

3) Spinal cord :

• Lhermitte’s sign: shock like sensation from neck to all 4 extremity upon neck flexion

• Numbness: all 4 extremities (cervical cord), lower extremity(thoracic cord), travelling up starting from feet

• Weakness: one side or the other, foot drop, weakness of hands

• Gait imbalance

• Bowel and Bladder changes: Urinary urgency (most common), frequency, constipation and bowel urgency

• Sexual dysfunction

• Spasticity

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4) Cerebellum or brainstem :

• Ataxia, double vision or vertigo

5) Less common symptoms :

❖ Pain syndrome : Trigeminal neuralgia, Paroxysmal tonic spasms and dysesthetic limb pain

❖ Fatigue :

• Fluctuates with heat, exercise or as day proceeds.

• Relived by a period of rest, often a nap.

• Different from depression associated lack of energy, with other depression features.

• Often herald the diagnosis of MS by years.

❖ Depression and anxiety

* All symptoms gets worse in setting of infection, dehydration, stress (mental/physical), exposure to heat *

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Case-2

A 56-year-old female with known diagnosis of hypertension presents to Primary Care’s office:

❖ 02/2018: numbness and tingling in both hands

❖ 03/2018: EMG and NCS study showed bilateral carpal tunnel syndrome

❖ 09/2018: Saw orthopedic, no improvement with wrist splint and steroid injection in carpal tunnel, also reports some gait imbalance.

❖ 01/2019: MRI of Cervical spine

❖ 02/2019: Referred to Neurologist

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Case-2 further history

❖ 1999: Transient double vision in setting of stress and lack of sleep

❖ 2007: Tingling in all finger tips, constant without progression

❖ 2016: Stiffness in both hands, Rt leg heaviness on walking for a long time causing gait imbalance and urinary urgency

Dx: Relapsing Remitting MS

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Symptoms: other phenotypes of MS

❖ Clinically Isolated syndrome: One demyelinating event

• 60-70% of CIS patients develop MS in 20 years(1)

• Risk increases with number of oligoclonal bands, brain lesions and age at presentation (2)

❖ Secondary progressive MS : About 50-60% of patients with RRMS progresses to SPMS in 10 years. Presents with slow worsening of neurological symptoms.

❖ Primary progressive MS:

• Rare type, constitutes to about 10-15% of MS patients

• Later age of onset (40-50s)

• Equal female to male predominance.

• Slow accumulation of afore mentioned symptoms, mainly spinal cord symptoms.

• No clinical relapse

1) Miller DH et al. Clinically isolated syndromes. Lancet Neurol 2012; 11: 157–169.2) J Kuhle et al, Multiple Sclerosis Journal February 13,2015

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Examination : look for upper motor neuron sign

❖ Cranial Nerves : Decreased visual acuity, optic disc swelling (acute optic neuritis) and optic disc pallor

• Impaired eye movements, double vision which gets better with covering one eye

• Facial weakness or numbness

❖ Motor: Arm or leg weakness, slowing of finger tapping

❖ Sensory: Numbness on one side or the other

❖ Reflexes : Exaggerated reflexes, ankle clonus

❖ Cerebellar: Tremor, ataxia

❖ Gait: Positive Romberg’s test, ataxic gait, foot drop

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Clinical red flag for diagnosis of MS

Andrew J. Solomon et al, Misdiagnosis of multiple sclerosis, Impact of the 2017 McDonald criteria on clinical practice. Oct 31, 2018

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Location : Periventricular, juxtacortical, infratentorial and spinal cord. At collososeptal interface extending outward from lateral ventricle (“Dawson’s finger”). Gray mater lesions (Thalamus).

Dawson’s finger Periventricular and juxtacortical

Corpus callosum and infratentorial lesions

MRI brain with and without contrast

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Contrast enhancement : nodular or ring

Ring enhancement (open ring) Nodular enhancement

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Brain atrophy

Thalamic and cortical

atrophy

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Spinal cord lesions : posterior and lateral columns, asymmetrically distributed, short segment (usually 1 vertebral segment). Spinal cord atrophy in progressive disease

Cord atrophy at T3 level

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Blood work

❖ To r/o other inflammatory diseases

❖ Test for : Serum B12, TSH, AQP-4 Ab, Anti MOG Ab, ESR, CRP, ANA ,Anti-Ds DNA, ACE, SSA, SSB, ANCA

❖ 20-60% of MS patients can have positive ANA without systemic symptoms of lupus (1,2)

1) Szmyrka-Kaczmarek M et al. Lupus 2012, 21:412-202) Collard RC et al. Neurology 1997 49:857-61

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CSF

❖ Particularly helpful in ruling out other differential diagnoses

❖ Opening pressure : normal

❖ WBC count : normal to mildly elevated, rarely >20, red flag if >50

❖ Protein : normal to mildly elevated <100 mg/dl

❖ Oligoclonal bands (included in diagnostic criteria) : Seen in about 85-90% of MS patients. High sensitivity (95-100%), low specificity (60-82%) as it can be seen in other CNS inflammatory diseases.

❖ Elevated IgG index, synthesis rate and myelin basic protein (non specific, not included in diagnostic criteria)

OU NeurologyThe Lancet Neurology, 2018-02-01, Volume 17

2017 McDonald’s diagnostic criteria for relapsing multiple sclerosis

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The Lancet Neurology, 2018-02-01, Volume 17

2017 McDonald’s diagnostic criteria for Primary progressive multiple sclerosis

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Management

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Why is it important to learn about management of MS

1. Disease modifying therapies has side effects and compliance issues.

2. Symptom management is utmost important from patient’s perspective, which requires multidisciplinary approach.

3. Important role of vitamin D in treatment of MS.

4. Role of smoking in progression of MS.

5. Importance of treating medical comorbidities in MS patients.

6. Social and financial issues.

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Case-3

A 31-year-old AA female with known diagnosis of MS presents to Neurologist to establish care.

❖ July/2010: Gait imbalance, resolved after IV steroid

❖ April/2012: Bilateral leg weakness with numbness, gait imbalance. Some improvement with steroid. Started using walker

❖ 07/2012: Started using wheel chair

❖ 07//2018: Worsening imbalance and frequent falls. MRI brain showed new cerebellar lesion. Treated with high dose steroid without improvement

❖ DMT: Tried Rebif, copaxone, tysabri, tecfidera and now on copaxone since 08/2018

❖ Symptoms: Bilateral upper extremity tremors, bilateral leg weakness, neurogenic bladder, memory impairment (MOCA of 19/30)

❖ Social situation: Lives with 14-year-old daughter who is care giver for her, no family support, no home health aid.

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01/201501/201506/2018

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Case-3 continued

❖ Primary care provider contacted child protective services and arranged for home health aid.

❖ Referred to social worker.

❖ Referred to Urology given neurogenic bladder.

❖ Neurologist suggested starting Ocrelizumab, patient concerned about side effects.

❖ She finally agreed to Ocrelizumab after her primary care provider agreed with Neurologist.

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Treatment of MS relapse

❖ First identify if it is relapse (typically a new symptom) or pseudo relapse (recurrence of old symptom in setting of infection or stress).

❖ Rule out infection and metabolic causes first. UTI is common mimicker of MS relapse.

❖ High dose IV steroid (1gm methylprednisonlone daily) for 3-5 days (1,2)

❖ Can consider equivalent dose of oral steroid (1250 mg prednisone per day) for 3-5 days (3, 4)

❖ IV IG and Plasma Exchange if no response to steroid

1) Roy Beck et al, The NEJM February 27, 1992. 2) Daniel Ontaneda et al, Annals of Indian Academy of Neurlogy. Oct-Dec 2009. 3)Shuo Liu et al, PLOS ONE , November 27,2017. 4) Sarah Marrow et al, JAMA Neurology, March 5, 2018

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Chronic management: Disease modifying therapy

Alan J Thomson et al. The Lancet, April 21,2018

2019:SiponimodCladribine

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Relapsing Remitting MS Secondaryprogressive MS

Primaryprogressive MS

Interferon Beta 1a and 1b (Avonex, Rebif, Betaseron, Plegridy and Extivia)

Glatiramer acitate (Copaxone)

Teriflunomide (Aubagio)

Dimethyl Fumarate (Tecfidera)

Fingolimod (Gilenya)

Siponimod (Mayzent) Siponimod (Mayzent)

Cladribine (Mavenclad) Cladribine (Mavenclad)

Natalizumab (Tysabri)

Ocrelizumab (Ocrevus) Ocrelizumab

Alemtuzumab (Lemtrada)

Mitoxantrone Mitoxantrone

Injectable

Oral

Infusion

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Symptom management

1) Walking and balance: Dalfampiridine (Ampyra), physical therapy

2) Spasticity: Stretching exercises, baclofen, tizanidine, flexeril, valium and medical marijuana (1)

3) Pain: Gabapentin, lyrica, amitriptyline, duloxetin, cymbalta, carbamazapine (for trigeminal neuralgia and Lhermitte’s phenomenon) and medical marijuana(1)

4) Bowel and bladder dysfunction: Stool softeners, urology evaluation, ditropan, flomax, bladder training

5) Depression: SSRIs and other antidepressants, counselling

6) Fatigue: Exercise, high protein diet, good quality sleep, energy conservation technique, amantadine, provigil and nuvigil

7) Cognitive: Neuropsychology, OT evaluation

8) Social and financial support: medications, handicap equipment, MRIs

1) BarbaraS. Koppel et al. Neurology April 29, 2014

OU NeurologyAlberto Ascherio et al. Vitamin JAMA Neurol. 2014;71(3):306-314.

Risk factor management: Vitamin D

❖ Low vitamin D is a risk factor for developing MS

❖ Increased risk of relapse and

progression with low

vitamin D level

❖ Monitor and supplement

vitamin D

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Risk factor management: Smoking

❖ Smoking is a significant risk for development of MS with overall odds ratio of 1.25-1.51.

❖ Cessation of smoking at the diagnosis of MS can delay conversion to secondary progressive stage.

Hawkes CH et al Multiple Sclerosis Journal, 2007 Jun;13(5):610-5Ryan Rmajunam, et al. JAMA Neurol. 2015;72(10):1117-1123

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Management of comorbidities

Natalie C Edwards et al, Patient Related Outcome Measures. February 13, 2018

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Management of comorbidities

❖ Coexisting medical comorbidities significantly delays the diagnosis of multiple sclerosis(1)

❖ Physical and mental comorbidities are associated with increased morbidity at the time of diagnosis (2).

❖ Vascular comorbidities are associated with rapid progression of disease(3).

❖ Depression, diabetes and ischemic heart disease shown to increase mortality rate in MS patients(4).

1) Anja Thormann et al, Neurology Oct17,2017. 2) R. A.Marrie et al Neurology Jan 13, 20093) R.A. Marrie et al. Neurology March 30, 2010. 4) R.A. Marrie et al. Neurology July 21,2015

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Systemic side effects of DMT

❖ Interferon: Migraine, depression

❖ Interferon, teriflunomide, fingolimod, dimethylfumarate, siponimod, natalizumab: LFT elevation

❖ Teriflunamide, fingolimod, siponimod: Hypertension

❖ Alemtuzumab: risk of autoimmune diseases (Thyroid disease, ITP)

❖ Mitoxantrone : CHF

❖ Majority of oral and IV infusion medications: Risk of infection and very small risk of cancer

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Multidisciplinary model

Primary Care

Provider

Neurologist

Psychologist

Psychiatrist

Physical and Occupational

therapy

Urologist

Ophthalmologist

Nurse coordinator

/Infusion nurse

Social worker

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Take home points

1) High index of suspicion in young female with recurrent episodic neurological symptoms.

2) Early diagnosis and treatment is utmost important to prevent disability.

3) Keep in mind, symptoms fluctuate with weather, stress and infection.

4) Vitamin D, cessation of smoking, exercise and other lifestyle changes helps.

5) Management of other comorbidities is crucial to reduce morbidity and mortality.

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Questions??