Back to Journal

SM Journal of Neurology and Neuroscience

Meningoencephalitis in a Lymphopenic Dimethylfumarate Treated Multiple Sclerosis Patient

[ ISSN : 2573-6728 ]

Abstract Background Case Presentation Discussion Conclusions References
Details

Received: 16-Mar-2018

Accepted: 08-Apr-2018

Published: 20-Apr-2018

Emilie Schou¹, Christian Pinkowsky¹, Peter Ellekvist², Julie Hejgaard Laursen¹, Shanu F Roemer¹*

¹Department of Neurology, Herlev Hospital, Denmark
²Department of Infectious Medicine, Herlev Hospital, Denmark

Corresponding Author:

Shanu F Roemer, Faculty of Health and Medical Sciences, University of Copenhagen, Department of Neurology, Herlev Hospital, Ringvejen 75, 2730 Herlev, Denmark, Tel: +45 38681582; Email: shanu.faerch.roemer@regionh.dk

Abstract

Short summary: We report an incidence of bacterial meningoencephalitis with an otherwise low-virulent infectious agent, following monotherapy with dimethylfumarate (DMF) in an elderly woman with Relapsing Remitting Multiple Sclerosis (RRMS). DMF was first lowered to half the dose and eventually discontinued due to persistent lymphopenia.

A well known side effect of DMF is lymphopenia. In elderly patients DMF induced lymphopenia may provoke severe infection with otherwise ubiquitous low-virulent agents. We recommend caution when prescribing DMF to elderly RRMS patients in case of lymphopenia and discontinuation may need to be considered even at mildmoderate lymphopenia in elderly RRMS patients.

Background

DMF is recommendedas a first-tier treatment in patients with RRMS. Since the implementation of DMF in RRMS, five cases of Progressive Multifocal Leukoencephalopathy (PML) have been reported in DMF treated MS. None of these patients had previously received immunomodulatory therapy. According to EMA guidelines treatment with DMF should be discontinued in severe lymphopenia when lymphocyte count drops below 0.5x109 /L [1]. DMF may be administered to other patients with autoimmune disease, such as psoriasis (Fumaderm) and ongoing clinical trials study its effect in patients with T cell lymphoma the exact mode of action of DMF is not clear, however, experimental data highlight its role in inhibiting the NF-κβ signalling pathway leading to T cell apoptosis in subsets of T cells [2].

Case Presentation

We report a 65 year-old woman diagnosed with RRMS in 1995 presenting with aleft optic neuritis followed by a right optic neuritis in 2003. Her last clinical attack was reported in 2009 with a left leg paresis. From time of diagnosis to admission in our department she demonstrated only a slight progression in EDSS from initially 3 to 4. Follow-up brain MRI, however, was suggestive of possible radiographic disease activity and the patient was switched from glatiramer acetate treatment to DMF in 2014. Clinically, she presented with visual impairment and she was able to swim, walk 5 kilometres and required no assistance in walking or activities of daily living.Co-morbidities included hypertension, diabetes mellitus, glaucoma and a previous occipital stroke.

Lymphocyte blood counts were performed prior to initiation of DMF and were all within normal range (baseline white blood cells 7,3x109 /L, lymphocytes 2,1x109 /L). After 6 months of treatment she developed protracted lymphopenia with counts dropping to 0.7x109 /L which further decreased to 0.5x109 /L at 9 month follow-up. DMF dose was lowered to half the dose. In spite of this, lymphopenia dropped to 0.36x109 /L and DMF was discontinued after 18 months of treatment.

One month after cessation of DMF the patient was still lymphopenic and admitted to our department in prolonged status epilepticus. Neurological exam demonstrated near blindness, slurred speech, confusional state and decreased level of consciousness. Moreover, she had a fever (39.20 C). A brain CT scan was without any acute changes. Blood counts revealed leucocytes of 14.1x109 /L and lymphocytes of 0.30x109 /L. Lumbar puncture demonstrated severe polymorphic leucocytosis with 584x106 cells/L. Treatment for bacterial meningoencephalitis concurrent with acyclovir was initiated. A control MRI was performed and demonstrated acute hyperintense changes in the left insula, thalamus and hippocampus consistent with encephalitic changes. Despite prompt microbial therapy, the patient developed respiratory failure and was admitted to the ICU for 3 weeks. Continued EEG monitoring revealed paroxysmal focal activity from the left occipito parieto-temporal region. Extensive infectious work-up including JC virus were all negative except from a positive 16S rRNAPCR for Chryseobacterium in the spinal fluid. The patient was discharged from the hospital no longer able tocare for herself independently and was subsequently readmitted four times with prolonged status epilepticus prior to final dismission to a nursing home.

Discussion

Chryseobacterium is a ubiquitous bacterium found in soil and plants and has been associated with meningoencephalitis in immunocompromised adults [3,4]. In a study by AH Cross et al., [5] of 144DMF treated patients 14% of the patients developed grade 2 or 3 lymphopenia. The risk of severe lymphopenia was significantly higher at ≥55 years of age. Despite normal baseline lymphocyte count, no prior treatment with natalizumab or concurrent treatment with immunosuppressive or immunomodulatory drugs, our patient developed severe prolonged lymphopenia and subsequently meningoencephalitis not related to JC virus. It remains plausible that the severe lymphopenia secondary to DMF treatment rendered the patient susceptible to meningoencephalitis by an otherwise low pathogenic environmental agent, chryseobacterium. Moreover, higher age could be a possible risk factor of lymphopenia in DMF treatment, which may be associated with an increased risk of opportunistic infections.

Conclusions

Current EMA guidelines and national guidelines recommend discontinuation of DMF when lymphocyte count drops below 0.5x109 /L. Since the occurrence of a fifth case of PML in DMF treated MS patients, updated guidelines recommends risk-benefit stratification in DMF associated lymphopenia. Serial measurements revealing continuous lymphocyte counts between 0.8x109 /L-0.5x109 /L should prompt consideration of testing JC virus seropositivity. This case report highlight the need for risk-benefit stratification in patients ≥55 years of age, even in patients with normal baseline lymphocyte counts. When elderly patients develop lymphopenia due to DMF we suggest considering discontinuation rather than lowering the dose. This case report, to the best of our knowledge, is the first report of severe meningoencephalitis due to chryseobacterium in an adult MS patient treated with DMF. This case report further highlights that DMF induced lymphopenia mimics an immunocompromised state, especially in elderly MS patients, which may increase the risk of serious brain infections completely unrelated to JC virus status.

References

1. Medicines Agency E. Updated recommendations to minimize the risk of the rare brain infection PML with Tecfidera. 2015.

2. Nicolay JP, Müller-Decker K, Schroeder A, Brechmann M, Möbs M, Géraud C, et al. Dimethyl fumarate restores apoptosis sensitivity and inhibits tumor growth and metastasis in CTCL by targeting NF-κB. Blood. 2016; 128: 805-815.

3. Bloch KC, Nadarajah R, Jacobs R. Chryseobacterium meningosepticum: an emerging pathogen among immunocompromised adults. Report of 6 cases and literature review. Medicine (Baltimore). 1997; 76: 30-41.

4. Padmaja P, Verghese S, Bhirmanandham C V, Ajith, Thirugnanasambandham S, Ramesh S. Chryseobacterium meningosepticum-an uncommon pathogen causing adult bacterial meningitis. Indian J Pathol Microbiol. 2006; 49: 293-295.

5. Longbrake EE, Cross AH. Dimethyl fumarate associated lymphopenia in clinical practice. Mult Scler. 2015; 21: 796-797

Citation

Schou E, Pinkowsky C, Ellekvist P, Laursen JH and Roemer SF. Unusual Serious Adverse Effect in a Lymphopenic Dimethy lfumarate Treated Multiple Sclerosis Patient. SM J Neurol Neurosci. 2018; 4(1): 1020

Other Articles

Article Image 1

Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and Obsessive Compulsive Disorder Risk

Brain-Derived Neurotrophic Factor (BDNF) is required for neuron growth and maintenance. Single nucleotide polymorphisms (SNP) are reported in BDNF gene, which reduces proteins activity, Val66Met polymorphism is very well studied and reported as a risk factor for psychiatric diseases. Numerous case-control studies have evaluated the role BDNF Val 66Met (dbSNP: rs6265;196G>A) polymorphism in OCD susceptibility and provided ambiguous findings, hence present meta-analysis was designed to get an exact association between BDNF Val66Met polymorphism and OCD risk. A total of 14 case - control articles were identified through PubMed, Google Scholar, Science Direct and Springer link databases search, up to July 11, 2024. Odds ratios (ORs) with 95% con¬fidence intervals (CIs) were used as association measure. All statistical analyses were done by MetaDiSc (version 1.4).

Fourteen case-control studies involving 2,765 OCD cases and 5,585 controls were included in present meta-analysis. The results showed that the BDNF Val66Met polymorphism was not associated with OCD risk (allele contrast odds ratio ORAvsG = 0.96, 95% CI= 0.82-1.12, p= 0.000; homozygote ORAAvsGG = = 0.79, 95%CI= 0.59-1.06, p= 0.0058; dominant model ORAA+GAvsGG = 0.96, 95%CI= 0.86-1. 06, p= 0.17). In conclusion, the BDNF Val66Met polymorphism was not related to increased OCD susceptibility.

Vandana Rai, Pradeep Kumar, and Abhishek Kannojiya*


Article Image 1

The F-Wave and H-Reflex Patterns with Increased Stimulus Intensity in Patients with Cerebrovascular Disease for the Neurological Evaluation of Affected Arm or Leg

The F-wave is a result of α-motor neurons backfiring following an antidromic invasion of propagated impulses across the axon hillock.

Suzuki T*


Article Image 1

A Typical Anatomy of the Hand Representation in Adults who Stutter

Atypical hand preference may be more common in Adults Who Stutter (AWS). One implication is that stuttering may be a manifestation of a more general dysfunction in motor organization and planning. This study was designed to determine whether AWS have atypical motor cortical anatomy compared to controls, and whether there are group differences in handedness that correlate with anatomical measures. Volumetric MRI was used to measure the anterior bank of the Central Sulcus (CS) and Motor Knob (MK), a structure that corresponds precisely to the motor hand representation, in Adults Who Stutter (AWS) and fluent, matched controls divided into three groups (right-handed and left-handed men, right-handed women). There was an interaction between fluency group and handedness-sex group (p=0.024) with reduced CS volume in right-handed men who stutter (p=0.001). For MK volume there was an interaction with the right MK larger in the left-handed male controls, and the left MK larger in the left-handed AWS (p=0.024). AWS and controls did not differ in hand preference score or finger tapping rate. There was a relationship between CS asymmetry and finger-tapping laterality (p=0.042) with a faster right-hand tapping speed associated with a larger left CS and vice-versa. When controls were examined independently, there were no correlations between finger-tapping laterality and anatomical asymmetry; there was a correlation in the AWS (r= 0.642; p= 0.007). Left hander AWS tapped faster with the right hand and had a larger left CS (atypical). One subgroup of right handed AWS (atypical) tapped faster with the left hand and had a larger right CS. Another subgroup of right handed AWS (typical) tapped faster with the right hand and had a larger left CS. These results show that handedness may systematically influence cortical motor representations in AWS. Further study is warranted in a larger sample of adults and in children who stutter.

Foundas LA¹*, Baucom CC², Knaus TA³, and Corey DM⁴


Article Image 1

Ischemic Stroke at Jordan University Hospital: A One-Year Hospital-Based Study of Subtypes and Risk Factors

Objective: To study the ischemic stroke subtypes and risk factors in 100 patients observed at Jordan University Hospital (JUH) over a one-year-period, and to compare the results with another 100 age-and –sex matched controls as well as with studies from other Arab countries.

Methods: One hundred patients with first-ever ischemic stroke admitted to JUH over a one-year period (between January 2013 to January 2014) were studied.

Results: There were 62 males and 38 females (M/F ratio=1. 6), with a mean age of 66 years (range 22-90 years), the majority (80/100) between the age 51-80 years. The most common stroke subtype was lacunar infarcts (36 patients). Fourty-two out of 51 patients had intracranial atherosclerosis. The most common risk factor was hypertension (85%) followed by hyperlipidemia (71%) and diabetes mellitus (65%).

Conclusion: In accordance with other Arab studies and controls, hypertension was the predominant risk factor but lacunar infarcts were more common than in most reports from other Arab countries . This shows the importance of appropriate management of hypertension to reduce the incidence of stroke in Jordan.

Bahou Y*, Ajour M, and Jaber M


Article Image 1

Longitudinal Language Changes Associated with MRI Anatomy in Children with Autism Spectrum Disorder

Background: Language ability is one of the strongest predictors of prognosis and developmental course in Autism Spectrum Disorder (ASD). A range of language abilities occur in ASD and although many have delays in language it remains unclear why some children’s language continues to lag, while others do not. Abnormal anatomy and function of language-related regions has been found in ASD, however, how these differences relate to language development over time is undetermined.

Methods: This study examined longitudinal changes in language functions in children with ASD and investigated whether cortical language region anatomy was related to these changes in language. Eighteen boys with ASD, 2-8 years old were evaluated (Time 1) and re-examined about 3.5 years later (Time 2) at ages 7-10. MRIs were collected at Time 2 to evaluate gray matter volume of anterior (Pars Triangularis, PTR; pars opercularis, POP) and posterior (Planum Temporale, PT; Posterior Superior Temporal Gyrus, pSTG) language regions and the microstructure of the arcuate fasciculus.

Results: Eleven boys had relative decline in language functions (decline group) and 7 boys had no relative change in language (no change group). The no change group had larger PT and right PTR volume relative to the decline group. In addition, the right PTR was correlated with the language change score, with larger right PTR associated with less language decline. There was a trend for non-right-handers to have more language decline than right-handers.

Conclusions: Results suggest differences in cortical language anatomy may play a role in language development, with further studies warranted.

Tracey A Knaus¹˒²*, Jodi Kamps³˒⁴, and Anne L Foundas⁵


Article Image 1

A New Analysis Method of F-Waves to Obtain

From the observation of different F-wave waveforms, we introduce a new method of differentiating these waveforms, by assigning each with an “F-wave waveform value”, which can be used in the clinic to evaluate the effects of rehabilitation. F-wave waveform values were determined by creating a window from minimum onset latency to maximum onset latency in measurable waveforms. We then calculated the correlation coefficient of each waveform, using Microsoft Excel, and identified F-waves as those with a correlation coefficient of greater than 0.9 or equal to 1.0. The number of different F-wave waveforms types was determined from the number of identified waveforms. We applied F-wave waveform values to evaluate neurophysiological change and the effects of rehabilitation following hemiplegia. In the future, F-wave waveform values should be considered as an important tool when assessing the effects of rehabilitation on impaired neurological responses.

Toshiaki Suzuki¹˒²*, Yoshibumi Bunno¹˒², Makiko Tani¹˒², Chieko Onigata², Yuuki Fukumoto¹, Marina Todo², Hirofumi Watanabe³, Toshihiro Ohnuma¹˒²˒³, and Naoko Komatsu³


Article Image 1

Neuroprotective Effect of Organic and Conventional White Grape Juice against Carbon Tetrachloride Damage in Different Brain Areas of Rats

The consumption of nutrients containing phenolic compounds has been reported due to the benefits they produce on human health. Therefore, the objective of this study was to investigate the antioxidant and neuroprotective effect of the administration of organic (OGJ) and conventional (CGJ) white grape juices from Niagara variety on the oxidative stress in cerebral cortex, hippocampus and cerebellum after the treatment with carbon tetrachloride (CCl4 ) as well as on some biochemical parameters in serum of rats. Adult male rats (~300g; n=6-8/group) were orally treated (gavage) with 7μL/g of OGJ, CGJ or water, for a period of 14 days. On the 15th day it was administered CCl4 (3.0mL/kg). After 4h the animals were euthanized and the cerebral cortex, hippocampus and cerebellum were dissected and used for the analysis of oxidative stress parameters. We observed that CCl4 enhanced lipid peroxidation (TBARS) and protein damage (carbonyl), reduced the nonenzymatic antioxidants defenses (sulfhydryl), and changed the activity of the enzymatic antioxidants defenses catalase (CAT), Superoxide Dismutase (SOD) in the brain of rats. CCl4 also enhanced glucose, Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) and Gamma-Glutamyl (GGT) and decreased total cholesterol and High-Density Lipoprotein (HDL) in serum of rats. CGJ and OGJ were able to prevent or ameliorate most of these alterations. Consequently, regular intake of white grape juice could be considered as an adjuvant in the therapy of oxidative damages, revealing a possible antioxidant and neuroprotective agent.

Clarice M. Peripolli, Tatiane Gabardo, Fernanda de Souza Machado, Mariane Wohlenberg, Juliana D.O. Lima, Alice S. Oliveira, Marina Rocha Frusciante, Niara da Silva Medeiros, Sheila Pereira Feijó, Filipe V.V. Nascimento, Caroline Dani, and Cláudia Funchal


Article Image 1

Global Evidence for the Key Role of the Dopamine D2 Receptor Gene (DRD2) and DRD2 Receptors in Alcoholism

It has been over 27 years since Blum & Noble discovered the first association of the DRD2 A1 allele in severe alcoholism, suggesting reward as the real phenotype, not alcoholism. This has been acknowledged by an explosion of research in the arena of Psychiatric Genetics. To date, a PubMed search listed 6,839 studies (5-15- 17). The A1 allele has been associated with substance use disorders other than alcoholism, including cocaine, nicotine dependence, polysubstance abuse and many Reward Deficiency Syndrome (RDS) behaviors substance and non-substance related. Certainly following extensive controversy, the emerging evidence suggests that the DRD2 is a reinforcement or reward gene. In fact, it could represent one of the most prominent single-gene determinants of susceptibility to severe substance abuse/reward deficiency. While, however, the environment through epigenetic impact and other genes, when combined, still play the larger role, targeting the DRD2 gene through the novel genetic rewriting of the DNA code at the mRNA level may hold the greatest promise to date for potentially “curing” the RDS phenotype.

Kenneth Blum¹⁻⁹˒¹²*, Mark S Gold²˒¹⁵, Lloyd G Mitchell¹⁰˒¹¹, Kareem W Washington¹⁰, David Baron², Panayotis K Thanos¹³, Bruce Steinberg¹⁴, Edward J Modestino¹⁴, Lyle Fried⁷, and Rajendra D Badgaiyan¹²


Article Image 1

Depression in Alzheimer

Background: Pharmacological treatment for AD and depression are unfortunately few and of limited efficacy to cure the disease.

Objectives: To assess the combined effects of rivastigmine and citalopram on Alzheimer’s Disease.

Methods: Longitudinal clinical prospective study with 1278 AD patients on rivastigmine 9,5mg/patch and citalopram 20-40 mg/day over 48 months was assessed on the basis of NINCDS-ADRDA, MMSE, DSM-IV, FRSSD, GDS, HRS-D and follow up of the patients.

Results: Four years after the baseline assessment, there were no significant differences in MMSE, Geriatric depression scale and Hamilton rating scale for depression between patients treated with rivastigmine alone or combined rivastigmine with citalopram with or without depression (p>0.05). Functional Rating Scale for symptoms of dementia, Activities of Daily Living of patients with AD and depression treated with rivastigmine was significantly worse than patients treated with rivastigmine and no depression (p=0.027).

Conclusions: The combination of rivastigmine and citalopram had no better results than rivastigmine alone in patients with AD.

Magda Tsolaki*, Krishna Prasad Pathak, Eleni Verikouki, Chaido Zchou Messini, Tara Gaire, and Paschalis Devranis


Article Image 1

Anxiety and Its Features in Parkinson

Anxiety is one of the most clinically significant psychiatric syndromes in Parkinson’s Disease (PD). It is estimated to affect up to 50% of individuals with PD and is associated with higher levels of dependency and poorer quality of life. Although it is common, it remains widely under recognised by patients, carers and clinicians, and has not been extensively studied [1]. Therefore, in spite of its significant impact, the symptomatology, chronology, and neurobiology of anxiety in PD are not well understood.

Recently, anxiety in PD has been associated with increases in motor fluctuations and gait disturbances including freezing. Freezing of gait (FOG) is the temporary inability to walk and is one of the most debilitating symptoms of PD. It is associated with an increase in falls, injuries and dependency. The associations with motor symptoms have significant consequences for the quality of life of people living with PD. This review summarizes the most recent data on the epidemiology, associated features and possible mechanisms underlying anxiety in PD.

Perri Carlson-Hawke¹˒²*, Belinda Brown², and Simon Hammond¹