A research team at the University of California, Riverside School of Medicine has identified a pathway involving astrocytes, a class of central nervous system support cells, that could shed light on why seizures happen in a subset of multiple sclerosis, or MS, patients.
Study results, available in ASN Neuro, improve scientific understanding of how seizures arise in MS and could provide the foundation for better therapies to manage treatment-resistant seizures in MS and other brain diseases.
Characterized by progressive episodic decline in neurological function, MS affects more than 900,000 people in the United States. This autoimmune disease damages the fatty sheath – myelin – that protects nerve fibers, which hinders the speed of signals in the central nervous system.
While not classically considered a defining symptom of the disease, seizures occur three-times more often in MS patients than healthy individuals and may portend a flare-up of symptoms. MS patients that experience seizures also have a decreased quality of life and higher mortality rate. The mechanisms that cause seizures in MS patients remains poorly understood.
“During a seizure, there is a dysfunction between inhibition and excitation and a bunch of neurons fire together without control,” said Seema Tiwari-Woodruff, an associate professor of biomedical sciences and senior author on the paper.
Neurons are cells in the central nervous system that transmit information between the body or other neurons to allow us to move, feel, and think.
Astrocytes provide the fastidiously maintained environment that the neurons need to perform by controlling the molecular signals present in the brain. Seizures can occur when astrocytes are unable to keep up with this task.
Tiwari-Woodruff and her colleagues examined postmortem brain tissue obtained from MS patients who experienced seizures (7 samples) and MS patients that did not (21 samples).
The team found that astrocytes in the hippocampal samples taken from MS patients with seizure showed signs of being less able to regulate the kinds of signals likely to cause a seizure.
They observed reduced synaptic glutamate (EEAT2), impaired water and potassium ion buffering (AQP4) and altered gap junction coupling between astrocytes (CX43) in MS patients with seizures. In addition, connections between astrocytes were altered in MS patients with seizures, a finding also noted in epileptic brains but never observed before in MS patients.
“The most exciting aspect of the study was discovering that astrocytes in the brains of MS patients with seizures looked a lot like astrocytes in epileptic brains,” said Andrew S. Lapato, a postdoctoral fellow at the University of Colorado, Anschutz Medical Campus who as first author conducted the work as part of his graduate studies in Tiwari-Woodruff’s lab.
“Researchers might be able to enhance the support roles of astrocytes or compensate for their dysfunction to prevent or treat seizures in MS patients.”
EAAT2 is the most widely distributed glutamate transporter in mammalian brains. A reduction in EAAT2 allows the neurons to fire more frequently, resulting in increased seizure activity. The reduction in this transporter has been observed in both patients with MS and temporal lobe epilepsy.
AQP4 maintains the extracellular space volume that allows for ion movement across the connective tissue of the nervous system. A reduction in AQP4 allows the concentration of extracellular potassium ions to increase, which may depolarize neurons and lead to hyperexcitability and protracted stimulation-evoked seizures. The researchers found these results are analogous to epilepsy, suggesting a similar process in MS patients with seizures.
Previous studies found CX43, the major connexin isoform expressed by astrocytes, is altered in response to inflammation or demyelination. Increased CX43 expression is also common in patients with epilepsy. While this study was unable to draw a more definitive link between CX43 and seizure activity, it opens another pathway to explore in future studies.
For this study, the team obtained 28 brain tissue samples from the National Institute of Health NeuroBioBank/Human Brain & Spinal Fluid Resource Center brain bank at the University of California, Los Angeles. The samples in the study were 57% female and 43% male patients. The samples for MS with seizures represent male and female patients almost equally.
“One of the treasures of having post-mortem brain tissues for our study is that we can use them to see how expressed proteins differ among MS patients,” Tiwari-Woodruff said. “If we don’t know what the disease looks like, then we don’t know what we can do to treat it.”
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) (1) which predominantly affects young adults, often female (2), and is of autoimmune origin (3). Because of the high variability in its clinical presentation, MS shows a wide range of different signs and symptoms (4).
The appearance of seizures has previously been recognized as part of the MS disease spectrum (5). Although seizures are a rare manifestation in patients with MS, several studies indicate that the risk of developing seizures and epilepsy is three to six times higher in patients with MS compared to the general population (6–9).
However, the underlying cause of the simultaneous occurrence of both diseases could not be described so far (4), and the pathophysiological mechanisms explaining this relationship are subject of current research (10). In addition, it is not clearly understood whether and to what extent the manifestation of seizures and epilepsy in MS patients affects the clinical course and the long-term prognosis (7, 9, 11).
The aim of this study was to identify and describe the patients who presented with MS and with seizures and epilepsy of the Department of Neurology at the University of Regensburg in Germany between 2003 and 2015. A comprehensive overview as well as a detailed characterization of this group of patients has been generated to allow the investigation of a potential contribution of inflammation and evolution of the lesions driving MS pathogenesis and progression to the manifestation of seizures and epilepsy.
Discussion
Even though seizures only affect a minority of patients with MS, they are still a serious problem (5). The occurrence of seizures has previously been considered as part of the disease spectrum of MS. Several studies indicate that the risk of developing seizures is up to six times higher in MS patients compared to the general population (6–9).
It is well-known that MS is not only a disease of the white matter of the cerebral cortex, but also affects the gray matter (16, 17) and that atrophy and lesions in this part of the brain are more frequent than previously suggested (4). This leads to the assumption that cortical and subcortical lesions as well as surrounding oedema in MS may play an epileptogenic role. An increased number of these lesions in MS patients with comorbid seizures and epilepsy has been reported as compared to MS patients without seizures (5, 12, 18).
NMR-tomographic studies have shown an association between gray matter lesions and the appearance of epilepsy (7, 19–21). A recent study of Burman et al. demonstrated an association between epilepsy and a progressive disease course, possibly due to gray matter lesions (22, 23). The increased lesion load possibly results in a demyelinated area with a higher risk of epileptogenic potential (24). Furthermore, some medications used in treating MS, such as baclofen or interferon beta, may increase the risk of generating seizures. The proconvulsive properties of some drugs could be due to metabolic interference with antiepileptic drugs or due to direct neurotoxic effects (25, 26).
While the prevalence of epilepsy in the general population is about 0.27–1.7%, it seems to be three to six times higher in MS patients (27). Based on several studies by different authors, prevalence rates of seizures or epilepsy between 0.5 and 8.3% have been reported (5, 27). We observed a prevalence for seizures of 1.74% and for epilepsy of 1.42% in our MS cohort, because only 18 of the 22 patients met criteria for epilepsy while the other four patients presented only one seizure. Accordingly, the frequencies reported by us are lower than the frequency of people having MS and seizures or epilepsy previously reported in other studies as shown in Table 2.
Table 2
MS patients observed in other studies of different MS centres and countries and the amount of concomitant seizures in these patients.
| References | Patients with MS (n) | Patients with MS and EP (n) | Patients with MS and EP (%) | Country | Diagnostic criteria for MS |
|---|---|---|---|---|---|
| Benjaminsen et al. (25) | 431 | 19 | 4.4 | Norway | Poser/McDonald |
| Burman et al. (22) | 14545 | 502 | 3.5 | Sweden | – |
| Catenoix et al. (28) | 5041 | 67 | 1.3 | France | Poser |
| Eriksson et al. (29) | 255 | 20 | 7.84 | Sweden | Poser |
| Etemadifar et al. (30) | 3522 | 81 | 2.3 | Iran | McDonald |
| Lund et al. (31) | 364 | 24 | 6.6 | Norway | Poser |
| Moreau et al. (7) | 402 | 17 | 4.25 | France | Poser |
| Olaffson et al. (9) | 188 | 5 | 2.65 | Iceland | Poser |
| Shaygannejad et al. (32) | 920 | 29 | 3.15 | Iran | McDonald |
| Sokic et al. (20) | 268 | 20 | 7.5 | Serbia | Poser |
| Striano et al. (33) | 270 | 13 | 4.8 | Italy | McDonald |
| Uribe-San-Martín et al. (10) | 310 | 10 | 3.2 | Chile | McDonald |
| Viveiros et al. (34) | 160 | 5 | 2.5 | Brasil | McDonald |
| Zare et al. (35) | 920 | 29 | 3.15 | Iran | McDonald |
Such varying results could be due to selection bias and differences in methods, definitions and diagnostic criteria (30, 34). For example, the accuracy of the MS diagnosis as well as the definition of epilepsy and its distinction toward non-epileptogenic, paroxysmal manifestations of MS, such as tonic spasm of the extremities, play a crucial role (36).
Moreover, the different composition of the study populations may have also contributed to the varying results. Some of the listed studies might have included all MS patients with seizures independent of these having other reasons for developing seizures than MS.
For example, Catenoix et al. reported a prevalence rate of 2.0% for MS patients with seizures whereas the prevalence rate was less (1.3%) when excluding all patients that might have had other reasons for seizures than MS (28). It has also to be noted that some studies might have included MS patients who developed their first seizure long before MS onset, making a relation between the two diseases rather unlikely (37). Furthermore, it should be emphasized that no strict diagnostic criteria for MS existed before 1983 and that magnetic resonance imaging (MRI) was first introduced in the diagnostic criteria of MS in the mid-1980s (12). It cannot be excluded that the prevalence rate may have been underestimated because of the retrospective design of our study.
With a percentage of 77.3 %, women were significantly overrepresented in our study population. The same gender preference was shown in other studies by various authors (6, 7, 27, 35, 37), suggesting an increased occurrence of epilepsy especially in women with MS. In addition, in this study, patients presented with an average age of 25.3 years at the onset of MS. Other studies too reported their patients being relatively young when MS was diagnosed for the first time (10, 38).
This in turn raises the suspicion that the risk of developing epilepsy is highest among the younger MS patients (10, 38). However, as MS is generally more likely to affect younger people and among these predominantly women, these numbers probably reflect the distribution in the general MS population (2, 6, 35).
The most common symptoms at the first onset of the MS disease manifestation were sensory disturbances followed by visual impairment. Symptoms of these functional systems are among others the most common disease manifestations in MS patients (39).
Considering the time of first manifestation of seizures and epilepsy in MS patients, it must be noted that seizures may occur in any subtype of MS and at any time during the disease course. Furthermore, the appearance of epileptic symptoms is possible even before the onset of MS. However, it should be emphasized that MS itself can exist long before becoming clinically apparent for the first time (5, 11, 27). The predominant MS subtypes in our study were RRMS and SPMS. No PPMS patients were present in our cohort but PPMS patients have been reported in other studies in which the presentation of MS and epilepsy has been investigated (6, 10, 21, 22, 25, 26, 28, 30, 40).
As already mentioned, focal pathologies of the brain occurring in MS patients, which are likely supposed to cause increased excitability of the cerebral cortex, might be the underlying cause of seizures in these patients (7, 20, 25). The lower frequency of seizures in patients with PPMS may be linked to the fact that these patients show a lower burden of cerebral lesions, predominantly in form of non-periventricular distribution (23).
Various studies have shown that epilepsy usually occurs in early stages of MS (11). Seizures may be the first symptom of MS, however most seizures occur during the disease and thus after diagnosis of MS (32). The present study confirms that the majority of seizures occur in patients already diagnosed with MS. Seizures occurred about 14.92 years (range one to 30 years) after the first manifestation of MS and thus much later as compared to previously published numbers (7, 20, 28, 32, 35). However, some studies also reported a larger range between the first manifestation of MS and occurrence of epilepsy which are in line with the range presented in the current study (25, 33, 40).
These differences may be explained by the fact that some of these studies are older and were published at a time when uniform diagnostic criteria for MS were not yet available and diagnostic options (e.g., MRI) were limited. Consequently, this may have led to a later diagnosis of MS and a shorter duration until the first onset of epilepsy.
In addition, the patients’ better understanding of their disease, their education, the use of self-help groups and a resulting more conscientious and cautious lifestyle as well as progress in therapy, especially immunotherapy, may cause a later appearance of seizures in MS patients (39). Since there was no patient in this study who showed seizures as the first symptom, it is suggested that the likelihood of developing seizures and epilepsy may rise with the duration of MS and the number of lesions (19).
Some authors mention that, although all types of seizures may occur in MS, seizures of focal onset are more common than tonic-clonic seizures of unknown onset, with a high proportion of focal to bilateral tonic-clonic seizures among seizures of focal onset (7, 18, 27, 34). This is in line with the results of our study, in which 77.3% of affected individuals had seizures of focal onset of which 82.4% developed into focal to bilateral tonic-clonic seizures. Only 22.7% initially had tonic-clonic seizures of unknown onset. This supports the assumption that local inflammation and lesion evolution in the brain could be the cause of developing epilepsy when already having MS (10, 25). Three of the five patients with tonic-clonic seizures of unknown onset were classified as having unknown epilepsy. No patients with a proven generalized epilepsy were identified (14).
Whether and to what extent the manifestation of seizures and epilepsy in MS patients influences the clinical course and the long-term prognosis of the MS has not been sufficiently clarified (7, 9, 11). Patients with MS and simultaneously existing seizures or epilepsy show a higher EDSS score as compared to MS patients without epileptic manifestations (18, 28, 41). In addition, seizures are associated with the earlier loss of walking ability and, consequently, use of a wheelchair, as well as earlier death (26).
When studying the patients’ medical records, it was apparent that seizures differed in both severity and frequency, so that some patients where more affected than others by their disease. In addition, it could be seen that epilepsy in some patients was halted when using anticonvulsive therapy while the epilepsy of the other patients seemed to be drug resistant and difficult to control by medical therapies, so these patients presented recurring seizures. Similar findings were reported in a study by Dagiasi et al. in which the number of seizure free patients was rather low (42).
In the literature, two different patterns of epilepsy are distinguished in the case of simultaneously existing MS: the so-called “benign” and “progressive” course of epilepsy. The benign form contains an unchanged or even decreasing frequency of seizures and a regular pattern of their appearance. The progressive course, however, describes a frequent occurrence of seizures and a constant development of new types of seizures (37).
In our study, 50.0% of patients with MS suffered from SPMS. Five patients had their first seizure after developing SPMS, which leads to the assumption that the increased load of cerebral lesions occurring in MS patients may act as a risk factor for the development of epilepsy. Four patients suffered from seizures before RRMS transformed to SPMS. This on the other hand suggests that epilepsy as a comorbidity of MS could lead to a higher severity of the disease, to an increasing disability and to an earlier development of SPMS.
While some authors believe that seizures in MS are usually harmless and show an adequate response to antiepileptic therapy, Engelsen et al. in contrary, have the opinion that there is a poorer prognosis of treatment efficacy of seizures among MS patients (6). Possibly there is a higher risk for developing status epilepticus including all its serious consequences in patients with MS. As described above, in our study, status epilepticus was confirmed in three individuals, whereas for one patient the data were inconclusive.
It is possible that MS patients with concomitant seizures experience a more severe disease course as MS patients without seizures. Thus, seizures could probably be considered as an additional factor aggravating disease. This might be because seizures can affect disability itself and lead to increased neuronal damage with the resulting consequences (43).
Whether the appearance of both disorders is coincidental or MS acts as a non-specific trigger for developing seizures and epilepsy or indeed is the direct cause of seizures is still under debate (28). However, the increased incidence of epileptogenic activities in MS patients as compared to the non-MS population suggests a causal relationship between the two diseases (26).
reference link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6563689/
More information: Andrew S. Lapato et al. Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures, ASN Neuro (2020). DOI: 10.1177/1759091420979604
