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4 Clinical Application ofAnti-seizure Medication asDrug Therapy
451
(3) Neurotransmitter abnormalities: The accumulation of metabolites such as
ammonia and phenylpyruvic acid in the serum may affect the normal synthesis,
release and transport of neurotransmitters, leading to abnormal neurotransmitter
function, which in turn affects neuronal excitability and contributes to the
occurrence of seizures.
(4) Neuroinammatory Response: In the uremic state, inammation may increase
in the body, leading to inammatory reactions and damage to the nervous system. These inammatory responses can activate neuronal excitability and cause
seizures.
Treatment
Etiology is not a determining factor in the selection of ASMs in patients with renal
disease. Age, type of epilepsy (focal or generalized), drug interactions and creatinine clearance rate are determining factors in selecting medications.
It is important for patients with renal disease to consider the pharmacokinetics,
metabolites, renal excretion rate, protein binding rate, and additional postdialysis
supplemental dosage requirements of each ASM.During hemodialysis, drugs with
high water solubility and low protein binding rates are readily cleared by dialysis.
Therefore, gabapentin, topiramate, phenobarbital, and levetiracetam require supplemental dosing after hemodialysis. In contrast, drugs with high protein binding rates,
such as phenytoin sodium, carbamazepine, and valproate, are less likely to require
supplemental dosing after dialysis.
Phenytoin is one of the oldest ASMs, and its main action is to inhibit voltagegated sodium channels, thereby stabilizing the inactivated state of these channels,
decreasing the release of glutamate and enhancing the release of GABA [344]. The
drug is excreted directly from the urine in less than 5% of patients, so it is safe for
use in patients with UE.The mechanism of action of carbamazepine is similar to
that of phenytoin, and carbamazepine is metabolized primarily in the liver and does
not require dose adjustments in cases of renal failure [345]. The mechanisms of
VPA include blockade of voltage-gated sodium and calcium channels and enhancement of the GABAergic system, and less than 3% of this drug is excreted in the
urine; therefore, no dose adjustment is needed in patients with UE [346].
In recent years, levetiracetam has become one of the most commonly used drugs
for partial and generalized seizures. Its anti-seizure effect is exerted by inhibiting
the release of synaptic vesicle protein SV2A.A small portion of the drug is bound
to plasma proteins, and 2/3 is excreted directly by the kidney [345]. Therefore, the
drug requires dose adjustment in patients with renal insufciency.
The dosage adjustment regimens of commonly used ASM agents in different
renal function states and after dialysis are detailed in Table4.10 [345].
452
No supplemental dosage
Glomerular
No adjustment
ltration
rate<15 Postdialysis
No supplemental dosage
No supplemental dosage
required
No adjustment
required
required
required
No adjustment
required
required
No supplemental dosage
Insufcient data, no
adjustment may be
required
Insufcient
data, no
adjustment may
required
No adjustment
required
be required
L. Zhou and Z. Chen
If postdialysis seizures
occur, 50% of the daily
dose needs to be
supplemented
50% daily dose
supplementation
No adjustment
required
Slow titration,
maximum
300mg/day
Appropriate amount
May need to be
reduced
Glomerular
Glomerular
Glomerular
Renal
Main
Protein
No adjustment
ltration rate
15–29
No adjustment
ltration rate
30–59
200–800mg, 2×/
ltration
rate>60
Trace
excretion
rate
metabolic
pathways
binding
ratio
No adjustment
required
required
No adjustment
required
required
2–3 times/day
day
<5% 150–200mg,
(element)
(CYP450)
(CYP450)
Insufcient
No adjustment
required
No adjustment
required
day, 2–3 times/
1%–3% 30–60mg/kg/
(CYP450)
data, no
data, no
day
2% 4–12mg per day Insufcient
(CYP3A4)
No adjustment
No adjustment
adjustment may
adjustment may
required
be required
No adjustment
required
be required
day
94% 20–40mg per
(CYP3A4)
No adjustment
30%–35% 100–600mg per
Liver
required
required
day
(CYP450)
60%
Slow titration,
No adjustment
40% 50–200mg, 2×/
May need to be
maximum
300mg/day
required
May need to be
day
(CYP450)
reduced
reduced
day
Zonisamide 40%–
Table 4.10 Dose adjustment regimens for commonly used ASMs in patients with different renal function states and after dialysis [257]
ASM
Valproic acid 90% Liver
Phenytoin 90% Liver
Carbamazepine 70–80% Liver
Perampanel 95% Liver
Chlorbazam 86% Liver
Lacosamide <15% Liver
Lamotrigine 50–55% Liver 10% 50–250mg, 2×/
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
50% daily dose
500–1000mg/day,
supplemented with 50%
of the daily dose after
50% daily dose
reduction
50% daily dose
reduction
dialysis
Halve regular
Halve regular
monitor blood levels
May need to be
dose at start
May need to be
dose at start
50% daily dose
Insufcient data, need to
50% daily dose
supplementation
50% daily dose
reduced
50% daily dose
reduced
supplementation
supplementation
75% daily dose
reduction
reduction
50% daily dose
reduction
reduction
453
50% daily dose
reduction
times/day
Levetiracetam <10% Hydrolysis 66% 500–1500mg, 2
No adjustment
Oxcarbazepine 40% Liver 50% 300–1200mg,
50% daily dose
May need to be
reduced
required
times/day
2×/day
25% 60–100mg, 2–3
(CYP450)
Topiramate 20% Hydrolysis 60–70% 100–200mg, 2
Phenobarbital 55% Liver
25% daily dose
reduction
reduction
per day
times/day
70–80% 1000–3000mg
the original
form
0% Excretion in
Aminohexenoic
acid
454
L. Zhou and Z. Chen
4.3.7.4 Pulmonary Encephalopathy
Denition
Pulmonary encephalopathy (PE) is a pathological state of brain dysfunction caused
by severe pulmonary disease [346]. It usually results from hypoxemia and carbon
dioxide retention due to lung diseases such as chronic obstructive pulmonary disease (COPD), pulmonary brosis, pulmonary hypertension, or pulmonary
thromboembolism.
Clinical Features andEpidemiology
The main manifestation is diffuse cerebral dysfunction, which is usually characterized by impaired consciousness, such as confusion, delirium, and even deep coma.
A minority of patients may have other clinical manifestations, such as seizures,
headache, or extrapyramidal symptoms [258]. However, the proportion of patients
with PE presenting with seizures has not been clearly reported. Nevertheless, there
appears to be a link between COPD and epilepsy. Large cohort studies in several
countries have revealed that COPD is a common comorbidity in patients with epilepsy [347–349]. Smoking may be a risk factor for this comorbidity, but the exact
mechanism is unclear. Prolonged chronic hypoxic states, in turn, may also increase
the risk of epilepsy [350].
Pathogenic Mechanisms
The mechanisms by which PE causes seizures may be related to the following factors [346, 351, 352]:
(1) Hypoxemia: Patients with PE suffer from insufcient oxygen supply due to
lung disease, which can cause hypoxemia. Hypoxemia can lead to neuronal
damage and metabolic abnormalities in the brain, thus promoting seizures.
(2) Acid–Base Imbalance: Patients with PE often experience respiratory acidosis
and metabolic alkalosis. An acid-base imbalance may interfere with the normal
function of neurons, leading to seizures.
(3) Chronic Carbon Dioxide Retention: Patients with PE often suffer from chronic
carbon dioxide retention, known as chronic respiratory acidosis. The accumulation of carbon dioxide can lead to cerebral vasodilation and increased blood
ow, further impairing neuronal function and contributing to the occurrence of
seizures.
(4) Inammatory Response: Lung diseases are often accompanied by an inamma-
tory response that leads to the release of inammatory mediators and cytokines.
These inammatory factors may affect the normal function of neurons through
a variety of pathways, including the regulation of neurotransmission, ion channel activity, and neuronal excitability.
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
455
Treatment
The treatment of seizures in patients with PE usually follows the conventional principles of drug selection, but care should be taken to avoid the use of benzodiazepines, which can cause respiratory depression and respiratory muscle weakness and
exacerbate hypoxia and carbon dioxide retention, leading to worsening of the condition [353].
4.3.7.5 Autoimmune-Related Encephalopathy
Hashimoto’s Encephalopathy
Denition
Hashimoto’s encephalopathy is an encephalopathic syndrome characterized by elevated levels of serum and/or cerebrospinal uid antithyroid-associated antibodies
with symptoms such as altered consciousness, psychosis, hallucinations, and seizures and, in most cases, sensitivity to glucocorticoid therapy.
Clinical Features andEpidemiology
The disease was rst described in 1966 by Lord Brain etal. [354]. To date, the disease is relatively rare, with a prevalence of approximately 2.1/100,000 adults [355].
The male-to-female ratio of patients is 1:4 [356]. It can occur in all age groups, with
a median age of onset of 12–14years for adolescents and 45–48years for adults
[355, 357]. Older adults are more vulnerable, and the overall median age of onset is
41–48years [358].
The clinical symptoms of Hashimoto’s encephalopathy can vary but are predominantly encephalopathic. In a systematic review of 251 patients described in the
literature, Charlotte Laurent etal. [359] summarized the clinical presentations as
follows: tics (n=117, 47%), confusion (n=115, 46%), speech disorders (n=91,
37%), memory impairments (n=107, 43%), gait disorders (n=67, 27%), and persecutory delusions (n=61, 25%). Of these, 28 patients (11%) had progressive memory impairment, and 26 (10%) had only isolated mental disorders.
Kothbauer-Magreiter etal. [360] classied symptoms of Hashimoto’s encephalopathy into two categories: (1) the vascular type, which is characterized by recurrent
stroke-like symptoms (e.g., hemiparesis, aphasia, and gait abnormalities) with less
severe cognitive impairment, and (2) the slowly progressive type, which is characterized by insidiously worsening dementia, impaired consciousness, psychotic disorders, hallucinations, and epileptic seizures.
Seizures are common in patients with Hashimoto’s encephalopathy, accounting
for approximately 2/3 of cases [361]. The most common type of seizure is focal to
generalized seizure [362]. In addition, it can also present as status epilepticus,
including epilepsia partialis continua (EPC) and nonconvulsive status epilepticus
456
L. Zhou and Z. Chen
(NCSE), in approximately 12% of cases [363]. Presentation with progressive myoclonic epilepsy has also been reported [364]. Therefore, patients with unexplained
focal or generalized seizures accompanied by encephalopathic symptoms should be
screened for the possibility of Hashimoto’s encephalopathy [365].
Imaging in patients with Hashimoto’s encephalopathy is usually normal, or these
patients present with nonspecic changes, such as ischemic foci, white matter
demyelination, and focal vasogenic edema [366]. More than 90–98% of patients
present with nonspecic EEG abnormalities, usually characterized by background
slowing, and other abnormalities, such as focal spikes or sharp waves, biphasic or
triphasic waves, frontal intermittent rhythmic delta activity (FIRDA), and periodic
synchronous discharge (PSD) [361, 367]. Nonspecic EEG abnormalities are not
associated with the diagnosis of Hashimoto’s encephalopathy but can improve rapidly after hormone therapy, which may play a role in monitoring the response to
treatment [368]. Mild abnormalities of the cerebrospinal uid are observed in
approximately 80% of patients, mainly presenting as mild protein level elevation
and an elevated lymphocyte ratio [369]. Elevated levels of serum thyroid-associated
antibodies, such as thyroperoxidase antibody (TPOAb) and thyroglobulin antibody
(TgAb), are essential for diagnosis, and TPOAb levels, in particular, may be markedly elevated, but their titers are not necessarily related to the severity of the disease [369].
Pathogenic Mechanisms
The pathogenesis of Hashimoto’s encephalopathy and its relationship to Hashimoto’s
thyroiditis and thyroid-associated antibodies are not clear. Currently, there are two
possible pathogenic mechanisms:
(1) Autoimmune vasculitis in the central nervous system (CNS).
Autoimmune vasculitis in the central nervous system mainly presents with
perivascular lymphoid inltration of small and medium vessels, with or without
immune complex deposits. The inltrating immune cells are mainly T lymphocytes [370]. The inltration involves the areas around small veins and arterioles
of the entire brain, including the perichondrium, cortex, white matter, basal
ganglia, and brainstem [371]. Nolte etal. [372] described the case of a patient
with Hashimoto’s encephalopathy who died of heart failure, whose vasculitis
only occurred in the veins and small veins of the brainstem, suggesting that
there may be some specic brain regions in which this vasculitis is prevalent.
Vasculitis can cause cerebral microcirculatory disorders, decreased cerebral
perfusion, and inammatory edema, resulting in cerebral neuronal dysfunction
and excitation/inhibition imbalance, which in turn may cause corresponding
neurologic decits and seizures.
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
457
(2) Autoimmune response to antigens of both the thyroid gland and the central
nervous system.
The main support for this hypothesis lies in the presence of thyroid-related
antibodies in the cerebrospinal uid or brain tissue of some patients with
Hashimoto’s encephalopathy. It is possible that thyroid-related antibodies produced outside the brain can enter the CNS through the blood–brain barrier and
attack the target tissue of the brain. For example, Moodley etal. [373] conrmed the presence of thyroid-related antibody targets in the brain by analyzing
brain tissues from ve adult patients who died after trauma, with thyrotropin
receptor antibody targets located on cortical neurons and soft meningeal blood
vessels, whereas thyroglobulin antibody targets localized only in vascular
smooth muscle in the brain. Interestingly, however, Ferracci et al. [369]
described the presence of thyroid antibodies in the cerebrospinal uid of ve
patients, but their blood–brain barrier was intact, suggesting possible intrathecal synthesis. Attack by relevant antibodies can directly cause neuronal dysfunction, leading to encephalopathy.
Treatment
The application of ASMs alone, such as valproic acid, levetiracetam, carbamazepine, and oxcarbazepine, may be ineffective for treating seizures in these patients,
and only by effective immunotherapy can the seizures be fully controlled [374].
Once the disease is diagnosed or suspected, early initiation of glucocorticoid
therapy is usually recommended. There is no standardized dose or course for this
therapy. A common regimen for adult patients is intravenous injection of
500–1000mg/day methylprednisolone for 5days, with a sequential oral dosage of
60mg/day and a reduction of 10mg every 2weeks, followed by maintenance at the
lowest dose for 1–2years [375]. More than 90% of patients experience complete or
partial remission with hormone therapy [359]. Because of its sensitivity to glucocorticoids, this disease has been named steroid-responsive encephalopathy associated with autoimmune thyroiditis (SREAT). However, glucocorticoid therapy is not
effective in all patients. In the acute phase, if glucocorticoid therapy is not effective,
immunoglobulin therapy (a total dosage of 2g/kg) [376] or plasma exchange therapy [377] may be therapeutic options.
Other immunomodulators, such as azathioprine, methotrexate, cyclophosphamide, mycophenolate mofetil, hydroxychloroquine sulfate, and rituximab, may be
given if glucocorticoid monotherapy fails or glucocorticoid-related side effects need
to be prevented [378].
Hashimoto’s encephalopathy relapse occurs in approximately 16% of patients,
especially those who are comatose at onset. However, TgAb(+) alone without other
antibody positivity is associated with a favorable outcome [359].
458
L. Zhou and Z. Chen
Lupus Encephalopathy
Denition
Lupus encephalopathy (LE) refers to a series of brain dysfunctions caused by systemic lupus erythematosus (SLE) involving the central nervous system and is a relatively serious complication of SLE.
Clinical Features andEpidemiology
In 1999, the American College of Rheumatology listed 19 complications of SLE
involving the nervous system and categorized them as neuropsychiatric systemic
lupus erythematosus (NPSLE) [379], including 12 CNS symptoms and 7 peripheral
nervous system (PNS) symptoms, as shown in Table4.11.
Approximately 37–95% of patients present with at least one symptom of NPSLE
[380]. The prevalence of different symptoms varies, with the most common being
headache, mild cognitive dysfunction and mood disorders. Seizures, stroke, and
anxiety disorders are also prevalent, as shown in Table4.12 [381].
Seizures in patients with SLE can include generalized tonic–clonic seizures or
partial seizures (complex partial seizures or simple partial seizures). Most seizures
are isolated, but recurrences can occur in 12–43% of patients, especially within the
rst year after onset [382]. Seizures may result from the direct toxic effects of
Table 4.11 Neurologic complications of SLE
Symptoms
CNS Aseptic meningitis
Cerebrovascular disease
Demyelination syndrome (medicine)
Headache (including migraine and benign intracranial pressure elevation)
Movement disorders (chorea)
Myelopathy
Seizures
Delirium
Neurosis
Cognitive impairment
Emotional disorder
Mental disorder
PNS Acute inammatory demyelinating polyneuropathy/neuropathy (Guillain–Barre
syndrome)
Autonomic disorder
Mononeuritis simplex/multiple mononeuritis
Myasthenia gravis
Cranial neuropathy
Plexopathy
Polyneuropathy
4 Clinical Application ofAnti-seizure Medication asDrug Therapy
459
Table 4.12
Frequency Symptoms
Common,
>10–20%
Frequent,
5–10%
Uncommon,
3–5%
Rare, <1–2% Chorea, movement disorders, myelopathy, aseptic meningitis, cranial
Frequency of different symptoms of NPSLE
Headaches, mild cognitive dysfunction, mood disorders
Seizures, stroke, anxiety
Psychosis, peripheral neuropathy, delirium, severe cognitive impairment
neuropathy, mononeuropathy, demyelination syndrome, Guillain–Barre
syndrome, autonomic disorders, myasthenia gravis, plexopathy
autoantibodies related to SLE or may be a symptom of other complications associated with the disease, such as cerebral infarction/hemorrhage, posterior reversible
encephalopathy syndrome (PRES), cerebral venous sinus thrombosis, and meningeal hemosiderin deposits. Usually, seizures are more common in adolescents [382].
Approximately 25% of patients with SLE show abnormalities in brain imaging,
mainly cerebral atrophy, ischemic/hemorrhagic lesions, and demyelinating
lesions [383].
Pathogenic Mechanisms
The pathogenic and epileptogenic mechanisms of NPSLE are complex and involve
multiple mechanisms and interactions.
(1) Genetic susceptibility: To date, several genes associated with SLE, including
HLADRB1, IRF5, STAT4, BLK, TNFAIP3, TNIP1, FCGR2B, and TNFSF13,
have been identied. A Japanese study revealed that the greater the number of
gene variants one carries that are related to SLE, the greater the probability of
developing NPSLE [384]. In addition, variants in TREX1, the causative gene
for Aicardi-Goutieres syndrome, have also been found to be associated with
SLE, and variants in TREX1 are especially common in patients with manifestations of CNS involvement, such as seizures [385].
(2) Autoantibodies: Antiphospholipid (aPL) antibody levels are elevated in the
majority of SLE patients with seizures, strokes, and headaches [386]. However,
in epilepsy patients without SLE, those patients who had seizures for the past
month were more likely to be aPL antibody-positive than those who were seizure free for the past year [387]. This can be explained by the fact that aPL
antibodies themselves are neuropathogenic in nature and can cause seizures
through direct neurotoxic effects [388]. Anti-ribosomal protein (anti-Rib-P)
antibodies are also common in patients with SLE, and a large cohort study
revealed that patients with elevated levels of this antibody early in the course of
the disease had a signicantly greater risk of developing lupus psychosis during
the next 3years of follow-up [389]. Anti-glutamate receptor (anti-NMDA or
anti-NR2) antibodies can be found in 30–40% of patients with SLE, and they
460
L. Zhou and Z. Chen
are double-stranded DNA antibodies. The NMDA receptor is widely distributed
in the brain, especially in the amygdala and hippocampus, and is strongly correlated with memory and affective functions [390]. Elevated levels of this antibody can be used as a marker to distinguish lupus encephalopathy from lupus
peripheral neuropathy [391].
(3) Vasculopathy: Deposition of lupus-associated immune complexes in the vascu-
lar wall can cause vascular damage, resulting in multiple small vessel inammatory lesions, microemboli, microinfarcts, and microhemorrhages [392].
Antiphospholipid antibodies may cause hypercoagulability and contribute to
the formation of cerebral thrombi.
(4) Inammatory factors: The expression of several cytokines and chemokines is
upregulated during the active period of disease and downregulated after effective treatment [393]. These cytokines and inammatory mediators disrupt the
blood–brain barrier, causing neuroinammation and interfering with the normal functioning of neurons.
Treatment
There is no uniform expert consensus on the treatment of seizures in patients with
NPSLE.The European League Against Rheumatism (EULAR) does not recommend the use of ASMs in patients with only a single seizure and a low risk of recurrence, but treatment should be initiated promptly if there is a high risk of seizure
recurrence (i.e., recurrent seizures, the presence of an abnormal brain lesion, or
abnormal epileptiform discharges on the EEG) [394]. The selection of ASMs is usually based on the seizure type (generalized or partial). In most patients, seizures are
easily controlled, and medications can be successfully tapered [389].
Two large cohort studies suggested that antimalarial drugs, such as hydroxychloroquine, had a protective role in preventing seizures in patients with SLE [389, 394],
but the exact mechanism is unclear. In addition, because hydroxychloroquine has
antithrombotic effects, it may be used in combination with aspirin to treat seizures
caused by thrombotic events due to aPL antibodies [395]. If aPL antibody levels are
markedly elevated (moderate to high titers) or accompanied by a hypercoagulable
state, anticoagulative therapy may be considered [393].
If the seizures, or sometimes status epilepticus, are due to an acute inammatory
response, immunotherapy should be initiated in addition to ASMs [381]. In 2010,
the EULAR recommended the use of glucocorticoids as a rst-line treatment, and if
this treatment is not effective, the addition of another immunosuppressive agent,
such as intravenous cyclophosphamide therapy, may be considered [396]. It was
reported that in some patients with refractory epilepsy, the combination of intravenous high-dose methylprednisolone and cyclophosphamide is effective in reducing
the frequency of seizures [397].