Multiple Sclerosis

Diagnosis (Solomon 2019)

1. Identification of a typical MS syndrome (i.e. optic neuritis, internuclear ophthalmoplegia, cerebellar syndromes, transverse myelitis)
2. Objective evidence of CNS involvement (i.e. afferent pupillary defect suggestive of optic neuritis)
3. Demonstration of dissemination in SPACE (periventricular, cortical / juxtacortical, infratentorial brain, spinal cord)
4. Demonstration of dissemination in TIME (MRI or CSF)
5. No better explanation other than MS (atypical characteristics of MS may include hyperacute onset, vascular territory signs, age >50, isolated trigeminal neuralgia, fluctuating ocular/bulbar weakness, nonremitting, fever, meningism)

Imaging

• FLAIR:
  • lesions are hyperintense
  • Dawson's fingers are characteristic perpendicularly extending lesions from the lateral ventricles
• T1:
  • lesions are iso- or hypointense
  • thinned corpus callosum
• T1 + contrast:
  • active lesions show enhancement
  • open ring sign - incomplete enhancement around periphery

Cognitive phenotypes In an examination of 1,212 patients with MS using Rao brief repeatable battery and stroop color and word test, 5 cognitive phenotypes were recognized (DeMeo et al 2021

• Preserved cognition (19.4%) - no substantial difference from HC
• Mild - verbal memory / semantic fluency (29.9%) - MRI data showed hippocampal atrophy may be a potential explanation
• Mild - multidomain (19.5%)
• Severe - executive/attention (13.8%)
• Severe - multidomain (17.5%)
• Typically more severe cognitive symptoms were associated with greater disease duration and heavier white matter burden.

Treatment

• Disease modifying therapy (DMT) (Yamout et al, 2020).
  • Monoclonal antibodies - natalizumab, ocrelizumab, etc.
  • oral agents - cladribine, fingolimod, dimethylfumarate, teriflunomide
  • older injection therapies - glatiramer acetate, interferon beta
    • interferon was originally thought to be associated with depression or suicidality, though this has been challenged (Goeb, 2002)
• MS flares or acute relapses
  • IV steroids for 3-5 days (does not improve long-term disability)

Symptomatic treatment of neuropsychiatric symptoms

Fatigue occurs in up to 80% of patients with MS, often described as the symptom most affecting their quality of life (Feinstein, Freeman, and Lo, 2015)

• Multifactorial - medications, depression, avoidance, sleep disorders, substances (Tobin 2019).
• Limited efficacy in relapsing remitting and progressive MS, studies of amantadine, carnitine, energy conservation program, aerobic exercise training, and progressive resistance training yielded equivocal results (Feinstein, Freeman, and Lo, 2015)
• Some benefit from yoga was found in fatigue though due to mostly low power of studies data was considered inadequate to draw meaningful conclusions (Cramer et al, 2014)
• Lisdexamfetamine did not show improvement in fatigue as a secondary outcome in a study on cognition (Morrow et al, 2013)
• Encourage weight loss (Tobin 2019).

Cognitive dysfunction occurs in up to 40% of relapsing remitting and 60% of primary progressive MS, most frequent affected domains include processing speed, memory, and executive function (Feinstein, Freeman, and Lo, 2015)

• Manage factors that impact cognition (mood, anxiety, fatigue, sleep) (Feinstein et al, 2019)
• Chronic anticholinergic medications, such as those used to treat bladder dysfunction, can significantly reduce processing speed (Kalb et al, 2018)
• Limit cannabis use (Feinstein et al, 2019).
• Donepezil study without benefit (Feinstein, Freeman, and Lo, 2015)
• Studies of cognitive retraining and exercise with positive results (Feinstein, Freeman, and Lo, 2015; Kalb et al, 2018)
• Some benefits in secondary outcomes for L-amphetamine (Feinstein, Freeman, and Lo, 2015)
• Improvement on some measures of processing speed in a phase II study of lisdexamfetamine (up to 70mg QD), though patients reported no subjective improvement (Morrow et al, 2013)

Depression a third to a half of patients with MS will develop major depressive episode during their lives (Feinstein, Freeman, and Lo, 2015)

• Treatment largely follows same algorithms as depression in general psychiatry (psychotherapy, exercise, psychotherapy, ECT) (Tobin 2019)
• Limited efficacy with pharmacologic treatment with mixed efficacy in studies of desipramine and paroxetine (Feinstein, Freeman, and Lo, 2015)
• Studies of cognitive behavioral therapy for depression in MS yielded good results

Anxiety

• No published RCTs on anxiety in MS - treat as you would in general psychiatry clinic (Tobin 2019).

Pseudobulbar affect present in up to 10% of MS patients, mainly in secondary progressive MS patients (Feinstein, Freeman, and Lo, 2015)

• Dextromethorphan plus quinidine helpful and endorsed by American Academy of Neurology
• No controlled trials, though SSRIs and TCAs are commonly used (Tobin 2019).

Cannabis use

• Higher rates of alcohol or psychoactive substance use were found among younger patients, those still employed, and those who had less severe MS symptoms (Murphy 2017)
• Cannabis use has been reported to alleviate spasticity, anxiety, depression, insomnia, pain, and bladder dysfunction
  • However, clinical trials of cannabis have failed to consistently detect significant beneficial effects (Zajicek et al. 2003)
  • Adverse effects include cognitive dysfunction, increasing or exacerbating depression, and psychosis (Zajicek et al, 2003)
  • * Cannabis use leads to more cognitive impairment, especially processing speed and memory. A study of chronic (smoked) cannabis users that stopped use revealed significant improvement across cognitive domains (processing speed, executive function, learning and memory both verbal and visual) (Feinstein et al, 2019).

Euphoria sclerotica (Murphy et al, 2017)

• Subjective state of physical well being and lack of concern towards one's disability
• associated w/ disease progression, extensive lesion burden (esp. frontal lobe), and cognitive impairment
• can be confused w/ hypomania but not associated with overactivity, speech disturbance, or psychotic symptoms

Psychosis

• variety of presentations (persecutory delusions, affective psychotic disorder such as MS, steroid-induced psychosis) (Murphy et al, 2017).
• regarding steroid related psychosis - dose is the most significant risk factor (Dubovsky et al, 2012).
• Treatment consists of
  • steroid decrease or d/c
  • symptomatic treatment with antipsychotics

References

Cramer, H., Lauche, R., Azizi, H., Dobos, G. & Langhorst, J. Yoga for Multiple Sclerosis: A Systematic Review and Meta-Analysis. PLoS ONE 9, e112414 (2014). https://pubmed.ncbi.nlm.nih.gov/25390344/

DeMeo et al. Identifying the distinct cognitive phenotypes in multiple sclerosis. JAMA Neurology. 78(4) 414-425 (2021). https://pubmed.ncbi.nlm.nih.gov/33393981/

Dubovsky et al. The neuropsychiatric complications of glucocorticoid use, steroid psychosis revisited. Psychosomatics. Mar-Apr 2012;53(2):103-15. (2012) https://pubmed.ncbi.nlm.nih.gov/22424158/

Feinstein, A., Freeman, J. & Lo, A. C. Treatment of progressive multiple sclerosis: what works, what does not, and what is needed. Lancet Neurol. 14, 194–207 (2015). https://pubmed.ncbi.nlm.nih.gov/25772898/

Feinstein, A., Meza, C., Stefan, C. & Staines, R. W. Coming off cannabis: a cognitive and magnetic resonance imaging study in patients with multiple sclerosis. Brain 142, 2800–2812 (2019). https://pubmed.ncbi.nlm.nih.gov/31363742/

Goeb JL et al. Psychiatric side effects of interferon-beta-1b and depression: a prospective investigation. J Neurol. 2002. Jul;249(7):815-20. https://pubmed.ncbi.nlm.nih.gov/12140662/

Kalb, R. et al. Recommendations for cognitive screening and management in multiple sclerosis care. Mult. Scler. J. 24, 1665–1680 (2018). https://pubmed.ncbi.nlm.nih.gov/30303036/

Morrow, S. A. et al. Lisdexamfetamine dimesylate improves processing speed and memory in cognitively impaired MS patients: a phase II study. J. Neurol. 260, 489–497 (2013). https://pubmed.ncbi.nlm.nih.gov/23001556/

Murphy R, et al. Neuropsychiatric syndromes of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2017. Aug;88(8):697-708. https://pubmed.ncbi.nlm.nih.gov/28285265/

Solomon AJ. Diagnosis, differential diagnosis, and misdiagnosis of multiple sclerosis. Continuum. 2019. Jun;25(3):611-635. https://pubmed.ncbi.nlm.nih.gov/31162308/

Tobin WO. Management of multiple sclerosis symptoms and comorbidities. Continuum. 2019. Jun;25(3):753-772. https://pubmed.ncbi.nlm.nih.gov/31162315/

Yamout et al. Consensus recommendations for the diagnosis and treatment of multiple sclerosis, 2019 revisions to the MENACTRIMS guidelines. Multiple Sclerosis and Related Disorders. 2020. Jan;37:101459. https://pubmed.ncbi.nlm.nih.gov/31670208/

Zajicek et al. Cannbinoids for treatment of spasticity and other symptoms related to MS (CAMS study), multicenter randomized placebo-controlled trial. Lancet. 2003. Nov 8;362(9395):1517-26. https://pubmed.ncbi.nlm.nih.gov/14615106/