Neuropsychiatric Symptoms in Pediatric Multiple Sclerosis - PowerPoint Presentation

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Neuropsychiatric Symptoms in Pediatric Multiple Sclerosis

Cynthia Wang, MD

UT Southwestern Medical Center

Children’s Health Dallas

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Disclosures

No relevant disclosures

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Objectives

Recognize key elements of the clinical history, diagnostic evaluation, and treatment methodology for pediatric demyelinating disorders

Understand the approach to the long-term management of neuropsychiatric sequelae of multiple sclerosis including cognitive impairment and mood disorders

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Neuroimmunological

Diseases

Location of inflammation

Brain – Encephalitis

Optic Nerves – Optic Neuritis

Spinal Cord – Transverse Myelitis

Syndromes with overlapping features

Multiple SclerosisNeuromyelitis Optica Spectrum DisorderAcute Disseminated EncephalomyelitisAutoimmune Encephalitis Anti-Myelin Oligodendrocyte Glycoprotein (MOG) syndrome

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Proposed Pathogenesis

Days to weeks

Neurological symptoms

Environmental stimulus

Susceptible individual

- Molecular mimicry

- Blood-brain barrier disruption

HeadacheAltered consciousnessPsychosisSeizures

Blurry visionExtremity weaknessSensory changesIncoordination

Epstein-Barr virus infection

Distance from equator

Obesity

Low vitamin D level

HLA-DRB1*1501

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Neuroimmunology objectives

Acute Therapy

Determination of Cause

Prevention of Future Attacks

Rehabilitation/Symptom Management

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Diagnostic approach

History

Timeline of symptoms – acute to subacute

Preceding infections, stressors

Exam

Mental status exam

Focal neurological deficits: motor, sensory, visualReflexes Coordination

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Diagnostic EvaluationNeuroimaging

MRI brain, spine, orbit w/ and w/o contrast

CSF

cell count, differential, protein, glucose, oligoclonal bands, IgG index

Testing for antibodies associated with CNS demyelinating and autoimmune disorders

Serum

Testing for antibodies associated with CNS demyelinating and autoimmune disordersExclusion of alternative causes, such as infectious, neoplastic, systemic inflammatory, genetic/metabolic, etc

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TreatmentsAcute/first line:

High dose IV corticosteroids

Plasma Exchange (PLEX)

Intravenous immune globulin (IVIG)

Chronic/second line:

B cell depleting therapies (i.e. Rituximab)

Chemotherapies (i.e. Cyclophosphamide)Initiate therapies as soon as possible

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Case Vignette

17-year-old girl develops right face, arm, and leg tingling

She had intermittent headaches during this time and her symptoms were initially attributed to complicated migraines

A few months later, she experiences difficulty using her right hand and was referred for neurological assessment

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Multiple Sclerosis (MS)

MS is a chronic, inflammatory, demyelinating disorder of the central nervous system

Prevalence estimated to be 50-150/100,000 (~1 in a 1000)

More common in Caucasian individuals; females outnumber males 2-3:1

Children and adolescents account for 2-5% of all patients diagnosed with MS

Acute presentations of demyelination typically involve vision loss, motor or sensory deficits, balance and coordination difficulties, bowel and bladder dysfunction

Long-term effects of the disease include cognitive dysfunction and mood disorders

Reich DS, Lucchinetti CF, Calabresi PA. Multiple sclerosis. N Engl J Med. 2018;378(2):169-180.

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The Evolving MS Treatment Landscape

Phase III

FDA-Approved Therapies

1995

2000

2005

2009

2010

2011

Teriflunomide

Dimethyl fumarate

Fingolimod

Natalizumab

IFN

β

-1b

Glatiramer acetate

(20mg)

IFN

β

-1a

IFN

β

-1a

Mitoxantrone

2012

2013

2014

PegIFN

β

-1a

Glatiramer

acetate

(40mg)

Alemtuzumab

Ocrelizumab

Daclizumab

National MS Society. Disease Modification.

www.nationalmssociety.org

/For-Professionals/Clinical-Care/Managing-MS/Disease-Modification. Accessed 10/2/17;

Owens GM.

Am J Manag Care

. 2013;19(16):S307-S312.

2015

Siponimod

Injection/Infusion Therapy

Oral Therapy

2017

Ozanimod

Ponesimod

Cladridine

Biotin

Ibudilast

Ofatumumab

Opicinumab

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Case vignette

Disease-modifying therapies are discussed with the patient and her family, who opt to start natalizumab

In the year following MS diagnosis, she has no clinical attacks or MRI evidence of new disease activity

However, she experiences academic decline (previously A/B student, but now getting mostly C’s and failing a couple of classes)

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MS and Cognitive Dysfunction

40% to 65% of individuals with MS have cognitive dysfunction

Commonly observed deficits involve attention, processing speed, as well as deficits working, semantic, and episodic memory

While MS was initially felt to primarily affect the white matter, more recent imaging studies have shown that significant damage to cortical gray matter also occurs

In pediatric onset MS, reduced volume in the thalamus and corpus callosum correlate with cognitive impairment

The most sensitive means to detect cognitive dysfunction among individuals with MS is neuropsychological testing

Amato MP,

Zipoli V, Portaccio E. Cognitive changes in multiple sclerosis. Expert Rev Neurother. 2008;8(10):1585-1596.Till C et al. MRI correlates of cognitive impairment in childhood-onset multiple sclerosis. Neuropsychology, 2011; 25 (3), 319–332.

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Silveira C, Guedes R, Maia D,

Curral

R, Coelho R. Neuropsychiatric Symptoms of Multiple Sclerosis: State of the Art. 

Psychiatry

Investig

. 2019;16(12):877-888. doi:10.30773/pi.2019.0106

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Case vignette

The patient undergoes neuropsychological testing which reveals deficits in attention, processing speed, verbal memory, and visuomotor processing with a normal full scale IQ

Our neuropsychologist and education specialist work with her school to implement an individualized

eduation

plan (IEP) with accommodations for areas of weakness

The following semester, her grades have improved to mostly B’s

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Case vignette

However, at her follow-up clinic visit, the patient reports symptoms of lack of enjoyment of normally pleasurable activities and poor sleep

She also notes some periods of excessive energy and lack of need for sleep

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Psychiatric symptoms in MS

Psychiatric symptoms in MS are highly prevalent and frequently overlooked in clinical settings

The psychological burden of having a chronic illness combined with the biological mechanisms of the disease likely are key contributors

In one study of relapsing-remitting MS patients, 95% reported significant psychiatric symptoms including dysphoria (79%), agitation (40%), anxiety (40%), and irritability (35%)

Diaz-

Olavarrieta

C, Cummings JL, and Velazquez J. et al. Neuropsychiatric manifestations of multiple sclerosis. 

J Neuropsychiatry Clin Neurosci. 1999 11:51–57

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MS and Depression

The lifetime prevalence of major depressive disorder (MDD) in individuals with MS is approximately 25% to 50%, which is approximately 2 to 5 times more common than in the general population.

The most common depressive symptoms in MS include irritability, memory/concentration problems, fatigue, insomnia, and poor appetite.

Lesions associated with MDD include the left arcuate fasciculus, prefrontal cortex, anterior temporal lobe, and parietal lobe.

Additionally, atrophy in the frontal, parietal, and occipital lobes is associated with the development of depression among individuals with MS

Silveira C, Guedes R, Maia D, et al. Neuropsychiatric symptoms of multiple sclerosis: state of the art. 

Psychiatry

Investig. 2019;16(12):877-888.

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MS and Bipolar disorder

Bipolar disorder is also twice as common in MS patients as in the general population with a lifetime prevalence of bipolar disorder to be 5.8%

Notably, some medications used to treat MS relapses such as corticosteroids can precipitate mania

Pseudobulbar affect (i.e. inappropriate laughter, crying) is a syndrome observed in up to 10% of people with MS

Marrie

RA et al. Mental comorbidity and multiple sclerosis: validating administrative data to support population-based surveillance. 

BMC Neurol. 

2013;13:16

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MS and psychosis

The prevalence of psychotic symptoms in MS ranged from 0.41% and 7.46%, 2-3 times higher than in the general population

Psychotic symptoms reported in MS patients include hallucinations and delusions (mostly paranoid), irritability/agitation, sleep disturbance, grandiosity, blunted affect, and rare symptoms like catatonia and transient catalepsy

Psychotic symptoms in MS are associated with a higher lesion load in the medial temporal lobes

Kosmidis

MH et al. Psychotic features associated with multiple sclerosis. 

Int

Rev Psychiatry. 2010;22:55–66. 

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Treatment of Mood disorders in MS

Treatment of depression should be individualized and tailored to the patient’s preferences

In screening for depression, simply asking patients questions about mood or using a standardized screening tool such as the PHQ-9 can be helpful

A combination of pharmacological and psychotherapeutic strategies is typically most effective

Hind D et al. Cognitive

behavioural

therapy for the treatment of depression in people with multiple sclerosis: a systematic review and meta-analysis. 

BMC Psychiatry. 2014;14:5

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Treatment of Mood disorders in MS

Selective serotonin reuptake inhibitors (SSRIs) are generally considered the treatment of choice for depression in MS given good safety and efficacy data

Serotonin-norepinephrine reuptake inhibitors (SNRIs) can be good alternatives when a patient has comorbid neuropathic pain and other somatic complaints

Among psychological interventions for the treatment of depression in MS, cognitive-behavioral therapy has shown the most benefit

Peer support groups have be very helpful for patients coping an initial diagnosis and social connection to individuals with similar challenges

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Case vignette

The patient was started on lamotrigine and reports improvement in depressed mood and less mood lability

She has gained 20

lbs

since her MS diagnosis and her BMI was noted to be 35

On questioning, she reports eating fast food frequently and rarely exercises

She estimates only getting 5-6 hours of sleep at night and has frequent nighttime awakenings

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Health promotion in multiple sclerosis

Obesity is a risk factor for developing MS and accelerate disease progression

Up to 50% of individuals with MS can suffer from obstructive sleep apnea

Fatigue occurs in ~80% of individuals with MS

Increasing research on diet and the gut microbiome suggests this may be a prospective area of improving health in those with MS

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Case vignette

The patient was referred for a polysomnogram and revealed clinically significant OSA

She was referred to a multidisciplinary obesity program and counseled on diet and exercise

She lost 30

lbs

over the following year and OSA symptoms improved

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Take home points

Most of current research has focused on acute treatments and disease-modifying approaches to tackling multiple sclerosis

The neurocognitive, emotional, and behavioral aspects of the disease are less well studied but neuropsychiatric symptoms are higher compared to the general population

School/vocational accommodations for cognitive deficits and evidence-based treatments for mood disorders are the mainstay of improving function

A healthy lifestyle including improvements in diet, exercise, and sleep can alleviate MS symptoms and improve general brain health