An Overview of Neuropsychiatric Symptoms, Clinical Features, and Management Options for Individuals Living with Multiple Sclerosis

Multiple sclerosis (MS) may lead to impaired mobility and cognition as well as dependency to perform activities of daily living, and individuals with MS may experience psychiatric symptoms associated with this disease. The intersection of psychiatry and neurology was recognized by Jean-Martin Charcot, who first defined MS as a clinical and neuropathologic entity and noted psychiatric symptoms in people with the disease. Neuropsychiatric symptoms in MS may occur in affective (relating to emotions and mood) and higher cortical processes such as thinking, reasoning, attention, and alertness. 

The accumulation of focal areas of inflammatory, demyelinating, and neurodegenerative changes seen in the central nervous system (CNS) allows for a plausible link between MS and neuropsychiatric manifestations. Such clinical features must be viewed in the context of the chronic, relapsing, unpredictable, and potentially disabling disease course associated with MS and the accompanying psychosocial stressors (eg, anxiety, loss of professional and social competencies). Synaptic plasticity, inflammatory biomarkers, and loss of neurotransmitter nuclei projections further strengthen this connection between disease and clinical manifestations. 

Recognizing psychiatric manifestations, understanding their origin, and providing proper treatment are imperative to comprehensive care of people with MS.

Biologically Based Causes
Whereas the pathologic hallmark of MS is focal inflammation leading to demyelination in both white and gray matter of the CNS, diffuse hyperactivation of glial cells, axonal loss, and neuronal degeneration are the main factors that drive disability. In the past 10 years, seminal work has supported that MS-related disability relies on widespread synaptic and network dysfunction in the CNS due to the chronic neuroinflammatory process.¹ In accordance, evidence suggests that MS-related psychiatric manifestations reflect a disconnection syndrome due to diffuse inflammatory and neurodegenerative brain damage.² The involvement of specific biologic processes in the development of psychiatric symptoms in MS confirms that psychiatric symptoms are not merely psychologic consequences of having a disabling chronic disease.²

Major Depressive Disorder
Major depressive disorder (MDD) is the most common psychiatric condition seen in people with MS, with an estimated annual prevalence of 15% to 25% in younger cohorts (age 18–45 years).³ However, this may be an underestimation, due to atypical presenting symptoms, such as a pervasive low mood; functional changes; negative thinking patterns, such as overfixation on the disease; and fatigue. Completed suicide, suicidal attempts, and suicidal ideation are also seen in higher numbers in people with MS than in the general population or in other neurologic or chronic medical diseases.^3,4 Despite the supposition that illness severity illness may be associated with the occurrence of MDD,^5,6 no clear association has been established. Studies in the past decade^7,8 established a connection between the occurrence of MDD and volume changes in the hippocampal and thalamic areas and reduced surface areas in certain frontal and temporal regions.

Bipolar Affective Disorder
Bipolar disorders are not often linked with MS, but the prevalence rate of bipolar affective disorder (BPAD) in people living with MS is twice that in the general population^9,10 with rates of 0.3% to 2.4% reported.¹¹ Unlike with MDD, a genetic contribution to BPAD is probable given reports of familial clustering of both BPAD and MS. Furthermore, one of the genetic loci linked to BPAD (chromosome 6q, 21–22 region) is located within or close to the histocompatibility human leucocyte antigen system¹² within which certain haplotypes are overrepresented in people with MS.¹³ Support for a connection between the incidence of bipolar disorder and radiologic outcomes is limited, but a study of 61 participants found lower putamen and nucleus accumbens volumes in imaging studies of people with MS who also had bipolar disorder.¹⁴ 

Pseudobulbar Affect
Pseudobulbar affect (PBA) is a condition that entails episodes of uncontrollable or sudden laughing, crying, or anger disproportionate to or incongruent with the emotion typical for the situation. PBA can be socially burdensome and associated with reduced quality of life in people with MS. PBA is a disconnection syndrome resulting from the loss of cortical or brainstem inhibition of a putative center for laughing and crying¹⁵ possibly due to lesions in the cerebro-ponto-cerebellar pathways involved in appropriate emotional adjustments to social and cognitive contexts. Because clinician judgment remains the gold standard for diagnosis of PBA,¹⁶ and the overlap of symptoms in MDD and PBA may make recognition difficult, it is not surprising that a study found the prevalence of PBA to be only 2.4%.¹⁶ PBA is relatively rare in individuals with MS, but it is associated with greater disease severity in MS.¹⁷

Psychosis
Psychosis, in relation to MS, is understudied in regard to its incidence, prevalence, and heterogeneity of presentation. Reported prevalence rates range from 0.4% to 7.46%.¹⁸ People with MS may experience psychotic disorders or present with symptoms of psychosis at disease onset or as a relapse.¹⁹ In some circumstances, new-onset symptoms of psychosis or the development of a psychotic disorder may be a manifestation of inflammatory demyelinating disease and may benefit from therapies such as steroids.²⁰

Anxiety
Anxiety is a natural emotion related to the diagnosis of MS. Based on population data, anxiety disorders affect 20% to 40% of people with MS vs 4% globally.²¹ Studies on the prodromal symptoms of MS indicate that many people develop anxiety years before other clinical manifestations,²² suggesting that anxiety is not solely a comorbidity of MS or a reaction to the diagnosis; rather, it may be a manifestation of early neurodegenerative processes. Animal studies provide evidence for a neural circuit concerned with fear and anxiety that involves the hippocampus, amygdala, nucleus accumbens, insular cortex, and medial prefrontal cortex. Recent studies have assessed white matter lesion load and fMRI activity in prefrontal and hippocampal areas of people with MS compared with healthy participants to support the biologic basis for anxiety in MS.^23,24

Fatigue
Fatigue in MS is a subjective lack of physical or mental energy that is perceived by the individual or caregiver to interfere with usual and desired activities. Whereas fatigue is not generally considered a neuropsychiatric symptom, fatigue can affect the behaviors and mood of individuals with MS, and its prevalence must be understood because clinicians may mistake it for depression, apathy, or anhedonia. A prevalence of fatigue of 36.5% to 97% in people with MS has been reported.²⁵ Many theories and recent data suggest that primary fatigue is due to mechanisms of the disease itself, such as lesion burden in neurotransmitter pathways or gray matter areas such as the cerebellum or cortical areas responsible for complex thought or motor movements. In addition, immune dysfunction in cytokines, monocytes, and microglia has been correlated with primary fatigue.²⁶

Stereotypes and Stigma Associated With MS
Despite many advances in treatment and earlier diagnosis of MS, the diagnosis may cause fear of progression and disability.²⁷ People may fear losing the ability to walk, or needing to use assistive devices, leading to distress related to possible interference of MS with social involvement, partnership and family roles, and employment or productivity. The resulting reactions can include anxiety and stress. Prolonged stress increases risk of mental disorders, in particular anxiety disorders and depression,²⁸ posttraumatic stress disorder, and personality disorders, and may contribute to the onset of psychosis.^28,29 Therefore, early recognition of factors that contribute to stress, intervention with cognitive behavioral therapy to promote healthy coping skills, and adjustment mechanisms are instrumental to an individual’s ability to adapt to the diagnosis. 

Sexual Dysfunction and Impaired Body Image
Often overlooked, as many as 85% of men and 74% of women with MS report sexual dysfunction, manifesting as diminished libido, erectile dysfunction, dyspareunia, or symptoms that interfere with intimacy, including spasticity, pain, and fatigue.³⁰ These symptoms are interlinked with an individual’s newly changed perspective on body image, informally described as how individuals subjectively perceive and appraise their own bodies. Hypersexual behavior, consistent with disinhibition, has also been reported.³¹ Preliminary evidence suggests that a more negative body image is associated with higher levels of psychologic distress in MS, indicating that body image may be a target for intervention.³²

Medication-Based Manifestations
Steroid-induced psychosis is a well-known but rare occurrence. The Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) classifies steroid-induced psychosis under Substance/Medication-Induced Psychotic Disorders. To meet DSM-5 criteria, steroid-induced psychosis must include hallucinations or delusions after steroid exposure, with no other explainable cause. However, given the co-occurrence of psychosis in MS, often associated with MRI changes,²⁰ it is often difficult to ascertain the cause in an individual presenting with acute symptoms, with the range varying from 2% to 60%.³³

Although not a psychiatric symptom, fatigue or lethargy commonly occurs as a side effect of pain, antispasmodic, or bladder medications used to treat MS symptoms. As one of the 9 DSM-5 criteria for MDD, iatrogenic causes must be considered in the diagnostic process. 

There is considerable variability in substance use among people with MS. The most common substances used include alcohol and cannabinoids. Mental health diagnoses, such as anxiety and depression, are prevalent with excessive alcohol consumption³⁴; among cannabinoid users, results are mixed, with some studies³⁵ showing improvement in depression after cessation and other studies^36,37 illustrating a benefit in mood symptoms due to better pain control.

Clinical Considerations and Conclusions
Neuropsychiatric signs and symptoms can be difficult to diagnose in people with MS, because the presenting symptoms may be mistaken as symptoms of the disease itself. They can also occur frequently either as the initial presenting complaint before a definitive neurologic diagnosis or more commonly with disease progression. Strategies to reduce disability progression by means of appropriate and efficacious medication selection, limiting doses of iatrogenic agents where possible, and the addition of appropriate psychotherapeutic interventions are vital for proper management of neuropsychiatric symptoms in MS. Psychologic interventions, such as cognitive behavioral therapy and psychoeducation, have a vital role in optimizing coping skills that modulate stress and increase self-efficacy (Table). An interprofessional approach, requiring input from neurologic, psychiatric, and psychologic services, is an optimal model in regard to treatment of neuropsychiatric symptoms in people with MS. Future studies to highlight gaps in access to these models of care and patient outcomes in varied, larger populations are needed as many of our current studies are small and non-diverse with respect to economic, ethnic and cultural factors.