Formal Challenge

NMF nm_fournier at
Thu Feb 12 02:59:09 EST 2004

Hello John H.,

Sorry I did not respond earlier but I have been out of town. With respect to
your question on epilepsy and immunosuppression the field undoubtedly
complex, however, I will present to you that data that is most prudent to
the connection between limbic (temporal lobe) epilepsy and the experimental
allergic encephalomyelitis (EAE) model of multiple sclerosis.  (This email
response was written directly to John H. with relation to the specific
questions that he asked.  Thus this email is rather long, but please free to
respond with your comments).

Complications with the immune system are commonly reported in patients
affected with temporal lobe or limbic epilepsy.  Often these patients report
and are found to exhibit greater incidences of colds, flues, or some other
related immunocompromised illness.  (Ader wrote a chapter on it in
Psychoneuroimmunology. published in the early 1980's  by Academic Press (?),
that can be referenced to show the immunal changes associated with epilepsy.
Also Engel's work is prudent here and can be referenced).  Even direct
hemodynamic measures will reveal that the immune system of epileptics is
essentially compromised and shows the patterns of chronic immunosuppression.

Considering the copious interconnection between the
entorhinal-hippocampal-amygdalar complex with the hypothalamus (specifically
in this case with the anterior hypothalamus), direct influence by these
pathways upon humoral and cellular immunity is extremely likely.
Considering that limbic epileptiform activity will propagate along related
efferent trajectories, activation of the hypothalamic region by this
epileptic activity will routinely elicit potent anterior hypothalamic
effects (a parasympathetically driven immunosuppressive response) on the
nervous system and body.

The original work by my colleagues Falter, Persinger, Chretien (1992) showed
that there is a suppression in the secondary humoral response
(immunosuppression) following lithium-pilocarpine induced seizures.
(Lithium-pilocarpine is a routine model for evoking limbic seizures in rats.
This model can reliably evoke similar mosaics of neuronal damage and
behavioral consequences that are commonly reported in human forms of
temporal lobe epilepsy and hippocampal sclerosis.  Generally, pretreatment
of lithium is 4 hrs. or twenty four hours before a single systemic injection
of the muscarnic agonist, pilocarpine can evoke behavioral convulsions and
electronencephalographic seizures).  In this experiment the animals were
previously exposed to some antigen - in this case they used human serum
albumin (dissolved in Freund's adjuvant") in order to elicit a primary
humoral response.  Giving a second injection of human serum albumin at  some
latter time point will be associated with a heightened immunofacilitative
response (i.e. the secondary humoral response.  This type of immune response
is that basis of the mast cell degranulation-induced anaphylatic shock,
which is associated with the direct vasodilatory action of released
histamine by mast cells on proximal blood vessels and the consequential
accompaniment in blood pressure drop that could lead to affixation).  They
found that if you elicited seizures immediately after injecting human serum
albumin the animals would display a marked immunosuppressive effect five
days later.  However, assessment of humoral and cellular immunity through
antibody binding capacity assays, showed us that a compensatory
immunofacilitative effect occurs approximately 10 days following seizure
induction.  Although they did not explore it in this paper, the original
immunosuppressive effect is ultimately tied to the elevated levels of
glucocorticoids that accompany the seizure induction process.  The
glucocorticoids, or corticotrophins, are potent immunosuppressors - but this
effect is dissipated and accompanied by a rebound in T-cell productivity by
10 days after seizure induction.

Now here is where the issue becomes extremely complex.  In the EAE model,
the inoculation procedure that causes the subsequent central demyelination
is caused from the subcutaneous injection of emulsified extracted spinal
cord (in Freund's complete adjuvant) into the hind footpads into a Lewis
rat.   At different time points after inoculation if you induce epilepsy
(through lithium-pilocarpine) differential activation of the immune system
will occur.  Subsequent studies have shown that if you induce limbic
seizures seven days after inoculation, there is a potent immunosuppressive
response.  The animals also display less severe clinical manifestations of
EAE (this is assessed behaviorally on a 5 point scale). Moreover, these
animals also do not show the eventual conspicuous break down of myelin.
Because the elevation in corticotrophin levels is significantly high the
subsequent suppression of activated T-cell lymphocytic response will occur.
Hence, the demyelinative action that occurs as a response of the
hyperresponse of the immune system (through activated T-lymphocytes) by the
EAE inoculation procedure is consequentially suppressed by the accompanied
immunosuppressive action of the seizures.

Interestingly, if you induce the seizures on the same day that you inoculate
the animal a potent immunofacilitative (immunoactive) response occurs.  That
is the animals displays a worsening of clinical symptoms associated with

The bidirectional effect of immunal responses accompanying limbic seizures
suggests that the temporal process are scalar (show only magnititude) by
nature.  That is the seizures facilitate the size of the inflammatory
(immunal) response with little or no direct effect on the development of the
inflammatory response.  Moreover, the bidirectional response in immunity is
most likely mediated through the action of circulating corticotrophins.

Considering that Gallagher's work have shown us that the afterdischarge (AD)
duration following limbic stimulation has bidirectional components: that is
ADs that are greater than 10s are accompanied with an increase in
corticotrophin levels (and subsequent immunosuppressive properties),
whereas,  ADs that are less than 10 s are associated with decreases in
corticotrophin, it is very likely that the timing of the limbic seizure in
conjunction with the temporal interval associated with EAE inoculation
alters the magnitude of immune response.  Also bidirectonal compensatory
changes in immunal responses, that is oscillations between immunosuppressive
and immunofacilitation, can be influenced by the time of day treatment and
the original state of immunal response in the animal at the time of
treatment are all well-established findings.  All of this is ultimately
derived through changes in the autonomic nervous system.  This is why
specific treatments for some cancers are more beneficial during the
circadian dominance in parasympathetic activity (i.e. during nocturnal
periods), where immunofacilitative processes are at their highest and
immunosuppressive actions are at their lowest.

One other interesting correlate that has clinical relevance is that frequent
observation that following mild closed head injuries an extremely high
correlation with latter demyelinating processes is found.  The reason for
why this occurrence occurs is not known, but the reference you provided by
McNamara is extremely important for providing some of the theoretical
framework for why this occurs.   A review of the clinical literature will
(or at least should) show you that the lability in the temporal lobe (and
mesial basal regions, i.e. limbic system) is often significantly increasing
following closed head injuries.

In the context of what was presented earlier, I will provide you with my own
theoretical (potential) explanation for this occurrence.  Following an
initial head injury, there may be an associated increase in the lability of
limbic regions (within the entorhinal-hippocampal-amygdala circuits for
evoking epileptiform activity (i.e. seizures)), or at least the
predisposition for developing such liabilities.    A common methodological
practice for assessment of expected head injury cases is the referral to
have magnetic resonance imaging diagnosis.  From this there is a possibility
of a complex interaction from many seemingly independent variables.  When
one considers that major transient changes (lasting ~ 3h.) to the blood
brain barrier permeability occurs following MR imaging (a well-established
finding that has been consistently demonstrated using gadolinium leakage
techniques) and that cholingeric compounds are routinely used for the
treatment of patients with head injury, the accompanied change in
permeability of the blood brain barrier is sufficient to induce slight
microhemorrhaging within the brain that could induce a mild immunal
activation.  Moreover, cholinergic compounds can significantly perturb
already predisposed epileptic foci to discharge (i.e. produce seizures).
Considering from the previous work presented by Falter and colleagues (1992)
and Missaghi and colleagues (1992), the importance of the temporal proximity
between limbic seizures and accompanied immunal response, the original
permeability change in the blood brain barrier and consequential
microhemorrhaging into the surrounding parenchyma is extremely likely to
produce an over-facilitation of this originally mild immunal activation.
The over-faciliation of this immune reaction can over time lead to the
development of demyelinating conditions and related symptomotology.

It should also be noted that the high intensity magnetic fields associated
with MR are not the only manners whereby one could induce transient changes
in blood brain permeability.  One common finding is that  ELF (extremely low
frequency: approximately 1 Hz to 1 kHz range) pulsed electromagnetic fields
can induce significant permeability changes in blood brain barrier (Persson
et al., 1992).  The intensity of some these time-varying electromagnetic
fields are comparable to the type of processes found within natural (i.e.
during some sudden commencement geomagnetic storms) or within some
artificial (i.e. home environment with complex electronic gadgetry)
environments.  A variety of thereotical and experimental reasons have been
given as to why time-varying  fields may possess such biorelevant actions
(see Sandyk, 1999; Terao and Ugawa, 2002; Persinger et al., 1972), the exact
mechanism(s) regading how these  fields can evoke changes in the blood-brain
barrier is currently not know.  Taken together, the consideration that these
commonly occurring environmental conditions can interact significantly with
the processes presented above strongly argue that demyelinating conditions
may be evoked from the complex interaction of a variety of seemingly
separate (or isolated) variables.


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