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The varieties of psychosis in multiple sclerosis: A systematic review of cases
Multiple Sclerosis and Related Disorders, Volume 12, February 2017, Pages 9-14
Multiple Sclerosis (MS) is known to be associated with a wide range of psychiatric symptoms, particularly with affective disorders. However, a link to psychotic disorders has not been fully established.
A systematic review of the PubMed/MEDLINE database was performed to identify cases of MS presenting with psychotic symptoms. Variables analyzed included patient demographics, clinical presentation, imaging characteristics and treatment.
Ninety-one cases were identified. The mean age was 34.4, and there was a female predominance. The majority of patients did not have a prior history of MS or psychiatric disease. The majority of cases could be classified as having either Psychotic Disorders or Mood Disorders with psychotic features. Most patients received some type of antipsychotic therapy, with variable success. At least 26 patients were treated with corticosteroids in the acute phase of their psychotic symptoms, and the majority responded favorably. Imaging data was available for 50 patients. Of these, 60% had predominantly fronto-temporal lesions, and most had contrast enhancing lesions.
MS can present with a variety of psychotic symptoms. The presence of enhancing lesions and steroid-responsiveness suggests these could be characterized as flares.
- Multiple Sclerosis (MS) is associated with psychosis.
- The presentation of psychotic symptoms in patients with MS is heterogeneous.
- This includes both Psychotic Disorders and Mood Disorders with psychotic features.
- Psychosis in MS may be associated with white matter lesions and respond to steroids.
- This suggests that psychotic episodes could constitute a “flare”.
Keywords: Multiple Sclerosis, Psychosis, Schizophrenia, Psychiatric manifestations.
Multiple sclerosis (MS) is a chronic autoimmune inflammatory demyelinating disease and the most common demyelinating disease affecting the central nervous system (Compston and Coles, 2002 and Noseworthy et al, 2000). It is the second most common cause of disability in adults in their productive-years (Compston and Coles, 2002 and Noseworthy et al, 2000). MS patients are at increased risk for various psychiatric diseases, particularly affective disorders such as depression and anxiety (Marrie et al., 2015a). Psychiatric comorbidities in MS patients may lead to delays in diagnosis, reduced quality of life and poor adherence to disease modifying therapy (Marrie et al., 2009).
Although the evidence linking mood disorders and MS is strong, a clearcut epidemiologic association of MS with schizophrenia and other psychotic disorders has not been fully established (Marrie et al., 2015a). Nonetheless, it is known that patient with MS may experience psychotic disorders and may even present with psychotic symptoms at disease onset (Pinkston et al, 2007 and Kosmidis et al, 2010). Importantly, corticosteroids and beta-interferon can potentially induce or exacerbate psychotic symptoms, highlighting the necessity of clarifying the characteristics of patient with MS who might be at increased risk (Fragoso et al., 2010). Unfortunately, the literature describing cases of MS with psychosis consists mainly of isolated case reports or small case series.
The objectives of this study were to analyze the clinical and imaging characteristics of patients with MS and psychosis reported in the literature, and to discuss the possible epidemiological, diagnostic and therapeutic implications.
We performed a systematic review evaluating the varieties of psychosis in MS. This study followed a predesigned protocol and current standards for reporting systematic reviews were followed to the extent of our possibilities.
2.1. Eligibility Criteria
We used the following criteria to define inclusion into this systematic review: (1) English, French or Spanish literature and (2) report including individual patient demographic and clinical data. Cases with insufficient clinical information were excluded. Cases reported as drug-induced psychosis (including drugs for treating MS and steroids) were also excluded. Since the span of the literature search predates current criteria for diagnosing MS, a case was considered to have MS according to the author's judgment. We attempted to assess the validity of the diagnosis by review of the clinical data provided in the reference.
2.2. Definitions and classification
Psychosis was defined when the patient was described as having an alteration in one or many of the following domains: delusions, hallucinations, disorganized thinking, grossly disorganized or abnormal motor behavior (including catatonia), and negative symptoms ((American Psychiatric Association, 2013)). The predominant symptom(s) was recorded as well.
For the classification of psychotic disorders, we followed a pragmatic approach. The literature spans many decades, and therefore, many versions of the Diagnostic and Statistical Manual of Mental Disorders (DSM). If the report did not specify the psychiatric diagnosis according to the applicable DSM criteria, the description of the psychotic event was classified either by the report author's judgment or by review of the clinical data provided (authors BEIY and CRCL). Every effort was made to classify cases according to existing criteria (DSM-5, (American Psychiatric Association, 2013)).
Cases were thus classified into 2 general groups: Mood Disorders (with psychotic features) or Psychotic Disorders. Psychotic Depression, Bipolar Disorder (BD) type 1 with psychotic features and BD type 2 with psychotic features were included in the former, and Brief Psychotic Disorder (BPD), Schizophrenia, Schizoaffective Disorder, Schizoaffective Disorder and Delusion Disorder were included in the later. If cases did not have enough information to be classified or if the symptoms were not classifiable according to DSM criteria this was noted as well. Since all patients included had a diagnosis of MS, we obviated the category of “Psychotic Disorder Due to Another Medical Condition”.
2.3. Search Strategy
A comprehensive search in PubMed database from its inception to May 25th, 2016 was conducted. Controlled vocabulary supplemented with keywords was used to search for “multiple sclerosis” and “psychosis” or “psychotic” or “schizophrenia” or “paranoia” or “delusions” or “hallucinations”, looking for case reports or case series, without any date or language limits.
2.4. Selection of studies
Reviewers working independently and in duplicate reviewed all abstracts and selected full text manuscripts for eligibility (CRCL and RRG). Disagreements at full text screening were resolved by consensus.
2.5. Data collection and management
Working independently and in duplicate reviewers used a standardized web-based form to collect information from each eligible study. Data included demographic characteristics, clinical presentation (both neurologic and neuropsychiatric), MRI findings, immune-modulating or antipsychotic treatment among others.
2.6. Summary measures
Statistical analysis was carried out using SPSS 20.0 (SPSS, Chicago, IL). Categorical variables were compared using Fisher's Exact test and continuous variables using Students T-test.
Our literature search identified 307 citations. The abstract of these references were reviewed for possible relevant studies. We found 150 references considered to be not relevant, 57 references that were neither in English, French or Spanish and 16 references that were review articles. This left us with 84 references that were evaluated for full-text. Of these, 18 references were excluded for a variety of reasons (e.g. dealing with prevalence and/or incidence, full-text unavailable) and 14 were excluded because they did not report individual patient data. The final 52 references were reviewed (Agan et al, 2009, Aggarwal et al, 2011, Asghar-Ali et al, 2004, Awad, 1983, Berna et al, 2016, Blanc et al, 2010, Carrieri et al, 2011, Carson and Searle-White, 1996, Castellanos-Pinedo et al, 2004, Choi and Preuss, 2009, Clarke et al, 1998, Corruble et al, 2004, Davids et al, 2004, Drake, 1984, El Moutawakil et al, 2008, Felgenhauer, 1990, Gabelić et al, 2012, Gardner-Thorpe and Pearn, 2004, Hayhow et al, 2015, Hollender and Steckler, 1972, Hotier et al, 2015, Hung and Huang, 2007, Hussain and Belderbos, 2008, Iñiguez et al, 2000, Jongen, 2006, Kohler et al, 1988, Lebert et al, 1994, Lo Fermo et al, 2010, Mahboobi et al, 2015, Mattingly et al, 1992, Mendez, 1999, Mendhekar et al, 2004, Modrego and Ferrández, 2000, Monaco et al, 1980, Muñoz-Morente et al, 2007, Muzyk et al, 2010, Ozcan et al, 2014, Peselow et al, 1981, Pontikes and Dinwiddie, 2010, Puthenparampil et al, 2016, Reimer et al, 2006, Reiss et al, 2006, Rodríguez-Gómez et al, 2005, Habek et al, 2006, Sharma et al, 2009, Sidhom et al, 2014, Sidoti and Lorusso, 2007, Smith, 2009, Tapos and Sivaswamy, 2013, Testa et al, 1987, Urban-Kowalczyk et al, 2014, and Yadav and Zigmond, 2010). Out of these, 40 were single case reports and 12 were case series, spanning from 1972 to 2016 (Fig. 1), and including 91 patients.
Systematic review procedure.
3.1. Demographics and clinical data
The mean age of the sample was 34.4 years and there was a female predominance (Table 1). Psychotic Disorders were more common than Mood Disorders, with BD and BPD being the most common specific disorders. There was no significant difference in age or sex predominance when comparing the groups of Psychotic Disorders and Mood Disorders (data not shown). Paranoid delusions and hallucinations were the most common symptoms, but there were cases of catatonia, Cotard's syndrome, Capgras syndrome, and Klein-Levine syndrome.
Demographic and clinical characteristics.
|n =91 patients||n (%)|
|Female sex||59 (64.8%)|
|Classification of Psychotic Disorder|
|BD 1 with Psychotic Features||10(10.9%)|
|BD 2 with Psychotic Features||11(12.1%)|
|Symptoms reported= 64|
|Others= Capgras, Cotard, Klein-Levine, Agitation/aggressiveness|
BPD: Brief Psychotic Disorder; BD: Bipolar Disorder
Only 20.9% of patients had a history of MS on presentation (Table 2). Their mean disease duration was 104±96.3 months. Most (34.1%) patients presented with psychotic symptoms and were concurrently (during the initial work-up) diagnosed as having MS. Finally, 24.1% of patients had previous history of psychotic symptoms on presentation. Latency to MS diagnosis in this group was 67±87.9 months. There was no significant difference between groups (Psychotic Disorders or Mood Disorders) according to presentation (data not shown). The majority of patients presented with isolated psychotic symptoms. Out of the 32 patients that presented with concurrent focal neurological findings, the most common were of pyramidal or cerebellar. Out of the 38 patients who had follow-up data, 52.6% had recurrence of their psychiatric symptoms. There was no difference in either of these variables between groups (data not shown).
Clinical presentation and treatment.
|Temporal association between MS diagnosis and presentation|
|Previous history of MS||19(20.9%)|
|Previous history of psychotic symptoms||22(24.1%)|
|Isolated psychotic symptoms on presentation|
|Concurrent focal neurological symptoms on presentation (n=32)|
|Antipsychotic treatment reported=45|
|Immunosuppressive treatment reported= 28|
ND: Not determined; PEX: Plasmapheresis; IVIG: Intravenous Immunoglobulin
Most patients received some type of antipsychotic therapy, with variable success (Table 2). At least 26 were reported as being treated with corticosteroids in the acute phase of their psychotic symptoms, and the majority responded favorably (there was no significant difference between groups). No cases reported exacerbation of their psychotic symptoms. Five cases reported to have psychotic depression who did not respond to medical therapy responded well to electroconvulsive therapy (Corruble et al, 2004, Mattingly et al, 1992, Pontikes and Dinwiddie, 2010, and Urban-Kowalczyk et al, 2014).
3.3. Imaging data
Imaging data was available for 50 patients (Table 3). The majority reported a pattern of diffuse white matter periventricular lesions suggestive of demyelinating disease. However, when the authors specifically noted a predominantly affected region or lobe 60% had predominantly fronto-temporal involvement. All of the patients with Mood Disorders had a predominance of frontal lobe involvement, whereas 57.1% of patients with Psychotic Disorders had a predominance of temporal lobe involvement (p=0.01). Of the 13 patients with reported predominantly temporal lobe involvement, 10 (76.9%) had left sided lesions. Of the 17 patients with reported predominantly frontal lobe involvement, 5 (29.4%) had right sided lesions. Only 20 mentioned results of gadolinium administration and 15 (75%) reported enhancement (7 out of 12 in Mood Disorders and 6 out of 6 in Psychotic Disorders, p=0.1).
MRI findings in 50 patients with available data.
|Diffuse Periventricular lesions||46 (92%)|
|Not reported||4 (8%)|
|Predominant region affected|
|Temporal lesions||13 (26%)|
|Frontal lesions||17 (34%)|
|Parietal lesions||4 (8%)|
|Not reported||13 (26%)|
|Contrast administration=20||Enhancement: 15(75%)|
Psychiatric comorbidity is common in patients with MS, and it has been associated with lower quality of life and reduced adherence to disease-modifying therapy. Systematic-reviews have established that psychiatric disorders such as depression, anxiety and BD are much more common in patients with MS than in the general population, with some studies reporting a prevalence of depression in over half of all patients (Marrie et al, 2015 and Jun-O'Connell et al, 2016); moreover, affective disorders negatively impact quality of life in patients with MS (Jun-O′Connell et al., 2016). However, studies evaluating the incidence and prevalence of psychosis are scarce, heterogeneous and inconclusive. Studies often do not discriminate between psychotic symptoms in general or specific psychotic disorders and none report the absolute incidence of psychosis. The prevalence of psychotic symptoms ranges from 0.41–7.46%, while the prevalence of schizophrenia ranges from 0–7.4% (Marrie et al., 2015a).
A study using administrative data with strict criteria for classifying patients found an identical prevalence of schizophrenia (0.93%) in patients with MS compared to the general population (Marrie et al., 2013). Another related study compared a large MS registry with reference data from the general population found a prevalence of 0.2% in cases vs. 1.5% in controls, a finding that showed a trend towards significance (Marrie et al., 2009). Subsequent studies using the same registry reported a total incidence of 0.8% (Marrie et al., 2011). Another large population based study searched for the prevalence of autoimmune disorders in 16,722 patients with schizophrenia and found a prevalence of 0.84% (Eaton et al., 2010). A recent large population-based Canadian study including 44,452 patients with MS and 220,049 controls reported a prevalence of 1.28% in patients compared to 1.03% in controls, a statistically significant difference (Marrie et al., 2015b). These figures are markedly lower than those reported (7.5%) in a Taiwanese population-based study that used administrative data to classify cases (Kang et al., 2010).
It is clear from these studies that psychotic disorders in MS are therefore much more uncommon than other psychiatric comorbidities. Of note, many of the previous studies dealt with the prevalence/incidence of schizophrenia and not of any psychotic symptom or other psychotic disorders (future epidemiological studies would do well to make these distinctions). In our study, only a minority was classified as having schizophrenia, but BPD and BD with psychotic features constituted almost half of the sample. In one small study including 37 patients and 37 controls the authors found only a single case of a BPD (Espinola-Nadurille et al., 2010), but the prevalence of BD in MS (where patients might present with psychotic features) has been estimated to be as high as 16.2%, significantly more common in patients than controls (Marrie et al., 2015a). Of course, the precise cause-effect association cannot be established (active MS increasing risk for psychotic symptoms vs. psychotic disorders increasing risk for MS), and in some cases the co-occurrence of psychotic symptoms or disorders and MS could be due to chance. Despite the possibility of a low prevalence of a pure psychotic presentation of MS, a delay in diagnosis or treatment could be catastrophic.
A potential etiological relationship between MS and psychosis was suggested after schizophrenia and other psychotic disorders were first associated with genetic markers of immune activation (Sperner-Unterweger and Fuchs, 2015 and Benros et al, 2014). Autoimmune diseases such as systemic lupus erythematosus may present with neuropsychiatric symptomatology, including seizures, mood disturbances or psychosis. This association has been hypothesized to be caused by brain inflammation or brain-reactive antibodies, concurrent severe infections as well as common etiologic and genetic factors (Suvisaari and Mantere, 2013 and Andreassen et al, 2015). Inflammatory cytokines and adhesion molecules have been found to be elevated in the blood and cerebrospinal fluid in patients with schizophrenia and BD (Sperner-Unterweger and Fuchs, 2015 and Suvisaari and Mantere, 2013). Genetic studies have shown a strong signal for schizophrenia on chromosome 6p22.1, a region also associated with immune mechanisms and the human leucocyte antigen and immune-related single-nucleotide polymorphisms have been found to overlap in schizophrenia and MS in at least 21 independent loci (Suvisaari and Mantere, 2013 and Andreassen et al, 2015). Inflammatory white matter pathology has also been specifically associated with schizophrenia possibly contributing to altered functional connectivity. A recent systematic review of studies evaluating neuropathological or neuroimaging studies found that there is both ultrastructural analysis and functional neuroimaging evidence suggesting white matter microglial activation and active demyelination (Najjar and Pearlman, 2015). All this evidence suggesting neuroimmune imbalance in schizophrenia and related psychotic disorders could at least partly explain a link between MS and psychosis.
Some reports were not included in the systematic review due to incomplete individual patient data but are still worthy of discussing (Table 4). Many of these cases would probably fall within the BPD category in our series, and in general the imaging findings would be consistent with our results.
Relevant findings in studies not included in the systematic review.
|Diaz-Olavarrieta et al., 1999||Cross-sectional||44 patients with MS (mean age 33 years)||Evaluation of neuropsychiatric symptomatology||10% had hallucinations|
|7% had delusions|
|100% had fronto-temporal lesions in MRI|
|Harel et al., 2007||Prospective||651 patients with MS (mean age 43.6 years; illness duration 11.5 years)||Evaluation of “dysregulation of affect”||17 (3.9%) had psychosis|
|Feinstein et al., 1992||Case series||10 patients with definite MS and psychotic symptoms (mean age 39.6 years)||Description of cases||20% had history of psychiatric disease|
|Paranoia and hallucinations|
|High MRI lesion burden of temporal lobe predominance|
|Lyoo et al., 1996||Cross-sectional||2783 inpatients in psychiatric institutions (75% affective disorders)||Description of MRI findings||23 (0.83%) had WM lesions meeting MS criteria|
|4 had schizophrenia|
|76% had frontal lesions|
|Pine et al., 1995||Cross-sectional||2720 patients admitted to psychiatric units||Description of MRI findings||10 (0.37%) had WM lesions meeting MS criteria|
|Most had mania and psychosis|
|Honer et al., 1987||Case series||8 patients with established MS referred to a psychiatric clinic (mean age 38 years, disease duration 11 years)||Description of cases||4 (50%) had psychotic symptoms|
|1 had steroid-induced mania (later diagnosed with BD), 1 had BD, 1 had “organic personality disorder”, 1 had “organic hallucinosis”|
|Predominant temporal lobe lesions|
MS: Multiple Sclerosis; MRI: Magnetic Resonance Imaging; BD: Bipolar Disorder; WM: White-matter
We found that most cases had diffuse, periventricular involvement on MRI. Overall, fronto-temporal predominance was most common. However, when individualized by type of disorder, all patients with Mood Disorders with psychotic features in whom imaging was reported had predominantly frontal involvement, while temporal involvement was more common in patients with BPD and other Psychotic Disorders. This is in agreement with the findings of Feinstein et al., (1992) who suggested more common temporal involvement in patients with psychosis and without prominent affective symptoms. Although this might be an oversimplification of the complexities involved in the neuroanatomical and neurofunctional correlates of psychosis/schizophrenia and BD, studies have traditionally implicated temporal structures (medial temporal lobe, supratemporal gyrus and insula, among others) in the former and frontal structures in the latter (Okazaki, 1998, Pantelis et al, 2009, De Peri et al, 2012, Jardri, 2013, Chitty et al, 2013, and Dell'Osso et al, 2014). Admittedly, involvement of both temporal and frontal regions often overlaps in these diseases and some authors have suggested a common physiopathology substrate (Okazaki, 1998 and Hanford et al, 2016). Our findings are at least consistent with these hypotheses of an alteration in fronto-temporal circuitry in the generation of psychotic symptomatology, although fronto-temporal periventricular lesions are the most common presentation in MS in general.
Although it is clear that MS may present as acute onset psychosis in a patient with no previous history of psychiatric disease, it is unclear whether this constitutes a MS “flare”. The study design of our series is unable to draw firm conclusions in the matter. However, there are some points that suggest an affirmative answer: one, the majority of patients presented with isolated psychotic symptoms (no focal neurological findings); two, in general, patients responded poorly to antipsychotic treatment and over 90% of those who received corticosteroids actually improved in their psychotic symptoms; and three, 75% of patients evaluated with contrast-enhanced MRI had an enhancing lesion on presentation. Of course, neither treatment nor gadolinium MRI data were available for all patients. This could highlight another controversial issue. Since psychosis is an established (but uncommon) side-effect of corticosteroids, physicians may be reluctant to administer them in a patient in an acute psychotic state for fear of exacerbating the symptoms (Sechi et al, 1987 and Bloch et al, 1994). However, our results seem to imply that if selected appropriately, patients with MS and acute-onset psychosis might actually benefit from steroid treatment. Of note, the two patients who underwent IVIG and PEX also had resolution of their psychotic symptoms. This issue warrants further investigation.
The possibility of a MS presenting as an acute psychotic episode also raises the important question of possible diagnostic overshadowing (Hayhow et al., 2015), a form of bias in which somatic symptoms may be misattributed to pre-existing psychiatric pathology. Although data acquisition is inherently limited by our methods, we found that patients with no previous history of MS but with a history of psychotic symptoms had their first episode a mean of 67 months before being diagnosed with MS. Of course, chart reviews of those initial episodes in the search for neurological signs and symptoms suggestive of demyelinating disease are impossible. Considering the increasing availability of MRI imaging, it would be expected that more and more cases of first-psychotic episodes be eventually found to have white matter abnormalities suggestive of MS. However, besides first-psychotic episodes or schizophrenia where brain imaging is mandatory in the initial work-up, patients with affective disorders might often not have imaging done, and as we saw in our series, BD with psychotic features and Psychotic Depression are not unusual in patients with MS and psychosis.
There are several limitations in this study, some inherent in the methods used to find the relevant cases. We excluded literature that was not in English, Spanish or French. Both the criteria for diagnosing and classifying psychotic disorders and MS have changed various times in the last decades, which could lead to selection bias. Many of the reviewed papers did not have all relevant information or described some findings (such as MRI, psychiatric history or therapeutic course) only partially. Although we did not specifically exclude patients with pre-existing psychiatric disease in our analysis, we did not include cases or case series of patients with MS and a previously diagnosed BD. Patients with this comorbidity might have presented psychotic features not so defined in the titles or abstracts, and therefore these could have been missed. Nonetheless, this is the largest case series reported to date of patients with MS and psychosis.
In conclusion, these results suggest that in some circumstances, new-onset psychotic symptoms or the development of a psychotic disorder might be a manifestation of inflammatory demyelinating disease. Such episodes may benefit from immunomodulatory therapy much as other typical MS exacerbations. Although the co-occurrence of psychotic symptoms and MS could be due to chance, an association between MS and psychotic disorders is at least plausible.
Conflict of interest
The authors declare no conflict of interest.
Sources of funding
No external funding was received.
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a Neurology Service. University Hospital, "Dr. Jose E. Gonzalez", Autonomous University of Nuevo Leon, Monterrey, Mexico
b Division of Endocrinology, University Hospital "Dr. Jose E. Gonzalez", Autonomous University of Nuevo Leon, Monterrey, Mexico
c Knowledge and Evaluation Research Unit, Division of Endocrinology, Diabetes, Metabolism and Nutrition, Department of Medicine, Mayo Clinic, Rochester, MN, USA
d Department of Neurology, Multiple sclerosis Center, University of Massachusetts Memorial Medical Center, Worcester, MA, USA
⁎ Correspondence to: Departamento de Neurología. Hospital Universitario “Dr. José E. González”. Universidad Autónoma de Nuevo León, Madero y Gonzalitos S/N, Monterrey NL 64460, México.
© 2016 Elsevier B.V., All rights reserved.