We report on the differences between serum BDNF concentrations in healthy controls and in patients with PNES and ES. The results of this PNES-specific group study confirm prior reports of decreased serum BDNF levels in patients with a variety of conversion disorder manifestations.3
Eight of the patients with PNES were taking psychotropic medication, and half had current depression, scoring in the mildly depressed range on the BDI. This is of note given that studies have suggested that chronic antidepressant use increases serum BDNF levels in patients with depression.6
Thus, while BDNF level may play a similar role in the pathophysiology of depression and PNES, the differential response of serum BDNF to antidepressants could highlight an important difference between the 2 disorders. The fact that psychotropics did not increase serum BDNF levels in our study and that there were no BDNF differences between patients with PNES who were depressed and those who did not have depression would suggest that serum BDNF might represent a trait marker of PNES and this could potentially be useful in understanding the pathophysiology of conversion disorders. Other research on patients with somatoform disorders, including functional neuroimaging studies,7,8
implicate other neuropsychobiological processes,9
in what was once thought of solely as a psychological condition.
BDNF dysregulation has been implicated in a number of neurologic and psychiatric illnesses. Decreased serum BDNF levels in adult patients have been reported in depression,6,10
late-stage Alzheimer disease,13
and multiple sclerosis.15
Increased serum levels have been found in schizophrenia,16
and early-stage Alzheimer disease,13
and in children with ES.2
In our study evaluating serum BDNF levels in adult patients with ES, we found decreased levels of serum BDNF in patients with ES, compared to HCs. In fact, the serum BDNF levels between the 2 patient groups were strikingly similar (1,033.45 ± 435.50 pg/mL for PNES compared to 977.48 ± 564.54 pg/mL for ES). This result is unexpected given the findings of elevated serum BDNF levels in children and the studies investigating BDNF concentration in brain tissue from adult patients with ES. Similar results have been found for serum BDNF levels in adults and children with autism. Elevated levels of serum BDNF are reported in neonates with autism18
whereas adults with autism seem to have decreased levels of serum BDNF compared to HCs.14
Maturational CNS differences in adults and children with neuropsychiatric disorders may explain some, but not all, BDNF differences.
We monitored for depression using patient interview, chart review, and BDI-II, to determine depression diagnosis and symptomatology. The HCs and the ES groups did not meet criteria for depression diagnoses. Only 1 patient with ES and 3 HCs endorsed symptoms of mild depression on the BDI-II. Since it has been shown that patients with depression have decreased serum BDNF levels,10
our findings support that the observed decreased serum levels in our ES group were not attributable to a diagnosis or symptoms of depression. Whether milder current comorbid psychological disturbance or previous significant comorbidity might explain the lack of difference between the ES and PNES group and may provide a clue to some explanatory mechanisms may be worth future study.
is the most abundant neurotrophin in the nervous system and binds specifically to the TrkB receptor.20
TrkB receptors exist in either a full-length or truncated form.21
The full-length form contains a catalytic tyrosine kinase domain whereas the truncated form does not. Both receptor types bind BDNF with a similar affinity, but the truncated form can attenuate receptor signaling either by recruiting dominant negative inhibitors or by removing BDNF from the extracellular space via internalization.22
In the CNS, both BDNF mRNA and Trkb receptor mRNA are located throughout the brain, but specifically high concentrations exist in areas such as the hippocampus and entorhinal cortex.23
BDNF is anterogradely transported, stored in mossy fiber terminal boutons, and released acutely following depolarization.24
Animal studies have demonstrated that BDNF crosses the blood-brain barrier25,26
and can be measured in both the CNS and in the periphery. BDNF also has been found in the plasma and serum. The strong correlation between serum and cortical BDNF concentrations in rats during development and maturation27
indicates that central and peripheral BDNF changes occur in parallel. The studies imply that blood BDNF levels may be representative of brain levels; however, a study directly comparing CSF to serum BDNF has not been published to date.
BDNF has been studied in the CNS of patients with ES and in animal models of ES for over a decade. Multiple studies have demonstrated increased expression of BDNF after seizures, as follows. In kindling models, both mRNA and protein levels of BDNF are elevated after seizures.28
While the increase in BDNF mRNA is transient, it appears that protein levels remain elevated for longer. Recent studies demonstrate that BDNF protein levels are elevated in the hippocampus for up to 45 days postseizure in a kainic acid model of ES.29
In human patients with temporal lobe epilepsy, there is an increase in both BDNF mRNA30
and protein levels31
in tissue taken from the hippocampus and temporal lobe. One study has directly examined serum BDNF levels in children with ES.2
Their data revealed that serum levels in children with ES are elevated compared to HCs (p
= 0.0249) (mean sera BDNF = 30,000 pg/mL in the ES group, and 10,000 pg/mL in the HCs).
A model that may provide a unifying hypothesis on the decreased serum BDNF findings in ES and PNES may be related not to seizures, but to stress, which has been shown to lower BDNF.32
The stress of seizures may be a shared characteristic between the 2 groups and could be further investigated. We, however, were unable to find studies of animal models for BDNF and PNES, or for conversion disorders in general. A possible mechanism for epileptic seizures may come from recent animal studies examining electroconvulsive-induced seizures in mice. Epigenetic mechanisms have been implicated in experiments examining electroconvulsive seizures (ECS)–induced demethylation within the regulatory region IX of BDNF.33
Furthermore, plasticity studies showed that Gadd45b
is associated with ECS-dependent demethylation and that seizures may trigger demethylation in promoters of BDNF.34
ECS and kindling-induced seizures have also been shown to increase full-length and truncated forms of Trkb mRNA expression in the brain.35
In addition, lesions of the major afferent pathways to the hippocampus have been reported to increase truncated, but not full-length, Trkb mRNA.36
Taken together, these studies set up a paradigm where repeated seizures and possible epileptogenic lesions could simultaneously increase central BDNF, and also increase signaling through the attenuating truncated Trkb pathway. This aberrant signaling could potentially lead to decreased serum levels of BDNF in seizure patients over time.
Seizure frequency and temporal proximity did not appear to influence the BDNF levels in either PNES or ES group. It has been suggested that AEDs could downregulate BDNF. One study found that phenobarbital, valproate, and phenytoin reduced BDNF mRNA levels in rat cingulate cortex, hippocampus, and thalamus37
; however, we found no study that has yet investigated the effects of AEDs on serum BDNF levels in adults. In the present study, all but one of the patients in the ES group reported AED use during study. One of the patients with ES in our study was taking valproate, and 3 were taking phenytoin. The rest were taking other newer AEDs. Three patients were currently taking an AED for a reason other than for their seizures. Five had been prescribed AEDs at some point in the past, including 1 valproate, 1 phenytoin, 1 lamotrigine, 2 levetiracetam, and 2 oxcarbazepine (some in combination). The numbers of AEDs taken were too small to discern the potential impact of psychotropic (mood-stabilizing) properties of the AEDs in either group. Downregulation of BDNF by AEDs did not appear to be a mechanism in this study, as the majority of patients with PNES were not on AEDs. It is unknown if serum BDNF levels would be reduced in patients with ES not taking AEDs, thus, comparing patients with epilepsy taking AEDs and those off AEDs may be of great value in future studies.
Despite small sample sizes, our study was powered to show a difference between groups based on the large differences noted in the literature. A limitation is that our HCs were on average 19.8 years younger than our patients. So, although the differences between the HC and patient groups remained significant after regression adjustment for age and BDI-II (1,011.35 pg/mL for the ES group and 1,036.59 pg/mL for the PNES group, compared to 4,272.85 pg/mL for the HCs), this finding should ideally be replicated on a sample that includes elderly controls. A recent study, however, examined both whole blood and serum concentrations of BDNF and found that there were no significant age-related changes, even when controlling for gender.2
A strength of our study is that the ES group was without comorbid psychiatric or neurologic illness. There was also considerable variety among the patients with ES with regard to seizure frequency and most recent ictal event. Furthermore, in both PNES and ES patient groups, there was little variance among individual serum BDNF levels ( and ). Additional studies incorporating children and adult patients with epilepsy not on AEDs are necessary to provide further insight into the physiology of BDNF in seizures.