The Journal of Family Practice

Evidence summary

Cohort studies demonstrate no adverse CV outcomes

A 2020 systematic review and meta-­analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.¹ The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE¹). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use. 

Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.² Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined. 

The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.³ The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability. 

A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected­ data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).⁴ Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.

Recommendations from others

In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.⁵ They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.

Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.⁶

A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.⁷ 

Editor’s takeaway

The available evidence on vaginal estrogen ­replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.

Evidence summary

Cohort studies demonstrate no adverse CV outcomes

A 2020 systematic review and meta-­analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.¹ The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE¹). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use. 

Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.² Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined. 

The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.³ The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability. 

A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected­ data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).⁴ Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.

Recommendations from others

In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.⁵ They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.

Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.⁶

A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.⁷ 

Editor’s takeaway

The available evidence on vaginal estrogen ­replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.

Evidence summary

Cohort studies demonstrate no adverse CV outcomes

A 2020 systematic review and meta-­analysis evaluated randomized controlled trials (RCTs) and observational studies to examine the association between menopausal hormone therapy and CV disease.¹ The 26 RCTs primarily evaluated oral hormone administration. The observational studies comprised 30 cohort studies, 13 case-control studies, and 5 nested case-control studies, primarily in Europe and North America; 21 reported the route of administration. The trials evaluated women ages 49 to 77 years (mean, 61 years), and follow-up ranged from 1 to 21.5 years (mean, 7 years). In subgroup analyses of the observational studies, nonoral hormone therapy was associated with a lower risk for stroke and MI compared to oral administration (see TABLE¹). Study limitations included enrollment of patients with few comorbidities, from limited geographic regions. Results in the meta-analysis were not stratified by the type of nonoral hormone therapy; only 4 studies evaluated vaginal estrogen use. 

Two large cohort studies included in the systematic review provided more specific data on vaginal estrogens. The first used data from the Women’s Health Initiative in a subset of women ages 50 to 79 years (n = 46,566) who were not already on systemic hormone therapy and who did not have prior history of breast, endometrial, or ovarian cancer.² Data were collected from self-assessment questionnaires and medical record reviews. The median duration of vaginal estrogen use was 2 years, and median follow-up duration was 7.2 years. Vaginal estrogen users had a 48% lower risk for CHD (adjusted hazard ratio [aHR] = 0.52; 95% CI, 0.31-0.85) than nonusers. Rates for all-cause mortality (aHR = 0.78; 95% CI, 0.58-1.04), stroke (aHR = 0.78; 95% CI, 0.49-1.24), and DVT/PE (aHR = 0.68; 95% CI, 0.36-1.28) were similar. In this and the other cohort studies to be discussed, outcome data for all vaginal estrogen preparations (eg, cream, ring, tablet) were combined. 

The other large cohort study in the systematic review evaluated data on postmenopausal women from the Nurses’ Health Study.³ The authors evaluated health reports on 53,797 women as they transitioned through menopause. Patients with systemic hormone therapy use, history of cancer, and self-reported CV disease were excluded. After adjusting for covariates, the authors found no statistically significant difference between users and nonusers of vaginal estrogen and risk for total MI (aHR = 0.73; 95% CI, 0.47-1.13), stroke (aHR = 0.85; 95% CI, 0.56-1.29), or DVT/PE (aHR = 1.06; 95% CI, 0.58-1.93). Study limitations included low prevalence of vaginal estrogen use (< 3%), short duration of use (mean, 37.5 months), and lack of data on the type or dose of vaginal estrogen used. The study only included health professionals, which limits generalizability. 

A Finnish cohort study (excluded from the systematic review because it used historical controls) compared rates of CHD and stroke in postmenopausal women who used vaginal estrogen against an age-matched background population. Researchers collected­ data from a nationwide prescription registry for women at least 50 years old who had purchased vaginal estrogens between 1994 and 2009 (n = 195,756).⁴ Women who purchased systemic hormone therapy at any point were excluded. After 3 to 5 years of exposure, use of vaginal estrogen was associated with a decreased risk for mortality from CHD (relative risk [RR] = 0.64; 95% CI, 0.57-0.70) and stroke (RR = 0.79; 95% CI, 0.69-0.91). However, after 10 years, these benefits were not seen (CHD: RR = 0.95; 95% CI, 0.90-1.00; stroke: RR = 0.93; 95% CI, 0.85-1.01). All confidence interval data were presented graphically. Key weaknesses of this study included use of both vaginal and systemic estrogen in the comparator background population, and the failure to collect data for other CV risk variables such as weight, tobacco exposure, and blood pressure.

Recommendations from others

In 2022, the North American Menopause Society issued a Hormone Therapy Position Statement that acknowledged the lack of clinical trials directly comparing risk for adverse CV endpoints with different estrogen administration routes.⁵ They stated nonoral routes of administration might offer advantages by bypassing first-pass hepatic metabolism.

Similarly, the 2015 Endocrine Society Clinical Practice Guideline on the Treatment of Symptoms of the Menopause also stated that the effects of low-dose vaginal estrogen therapy on CV disease or DVT/PE risk had not been adequately studied.⁶

A 2013 opinion by the American College of Obstetricians and Gynecologists stated that topical estrogen vaginal creams, tablets, and rings had low levels of systemic absorption and were not associated with an increased risk for DVT/PE.⁷ 

Editor’s takeaway

The available evidence on vaginal estrogen ­replacement reassures us of its safety. After decades spent studying hormone replacement therapy with vacillating conclusions and opinions, these cohorts—the best evidence we may ever get—along with a consensus of expert opinions, consistently demonstrate no adverse CV outcomes.

Managing first-time seizures and epilepsy often requires consultation with a neurologist or epileptologist for diagnosis and subsequent management, including when medical treatment fails or in determining whether patients may benefit from surgery. However, given the high prevalence of epilepsy and even higher incidence of a single seizure, family physicians contribute significantly to the management of these patients. The main issues are managing a first-time seizure, making the diagnosis, establishing a treatment plan, and exploring triggers and mitigating factors.

Seizure vs epilepsy

All patients with epilepsy experience seizures, but not every person who experiences a seizure has (or will develop) epilepsy. Nearly 10% of the population has one seizure during their lifetime,whereas the risk for epilepsy is just 3%.¹ Therefore, a first-time seizure may not herald epilepsy, defined as repetitive (≥ 2) unprovoked seizures more than 24 hours apart.² Seizures can be provoked (acute symptomatic) or unprovoked; a clear distinction between these 2 occurrences—as well as between single and recurrent seizures—is critical for proper management. A close look at the circumstances of a first-time seizure is imperative to define the nature of the event and the possibility of further seizures before devising a treatment plan.

Provoked seizures are due to an acute brain insult such as toxic-metabolic disorders, concussion, alcohol withdrawal, an adverse effect of a medication or its withdrawal, or photic stimulation presumably by disrupting the brain’s metabolic homeostasis or integrity. The key factor is that provoked seizures always happen in close temporal association with an acute insult. A single provoked seizure happens each year in 29 to 39 individuals per 100,000.³ While these seizures typically occur singly, there is a small risk they may recur if the triggering insult persists or repeats.¹ Therefore, more than 1 seizure per se may not indicate epilepsy.³

Unprovoked seizures reflect an underlying brain dysfunction. A single unprovoked seizure happens in 23 to 61 individuals per 100,000 per year, often in men in either younger or older age groups.³ Unprovoked seizures may occur only once or may recur (ie, evolve into epilepsy). The latter scenario happens in only about half of cases; the overall risk for a recurrent seizure within 2 years of a first seizure is estimated at 42% (24% to 65%, depending on the etiology and electroencephalogram [EEG] findings).⁴ More specifically, without treatment the relapse rate will be 36% at 1 year and 47% at 2 years.⁴ Further, a second unprovoked seizure, if untreated, would increase the risk for third and fourth seizures to 73% and 76%, respectively, within 4 years.³

Evaluating the first-time seizure

Ask the patient or observers about the circumstances of the event to differentiate provoked from unprovoked onset. For one thing, not all “spells” are seizures. The differential diagnoses may include syncope, psychogenic nonepileptic events, drug intoxication or withdrawal, migraine, panic attacks, sleep disorders (parasomnia), transient global amnesia, concussion, and transient ischemic attack. EEG, neuroimaging, and other relevant diagnostic tests often are needed (eg, electrocardiogram/echocardiogram/Holter monitoring to evaluate for syncope/cardiac arrhythmia). Clinically, syncopal episodes tend to be brief with rapid recovery and no confusion, speech problems, aura, or lateralizing signs such as hand posturing or lip smacking that are typical with focal seizures. However, cases of convulsive syncope can be challenging to assess without diagnostic tests.

Many patients have experienced prior undiagnosed seizures. Subtle prior events include episodes of deja vu, transient feelings of fear, unusual smells, and speech difficulties.

True convulsive seizures do not have the variability in clinical signs seen with psychogenic nonepileptic events (eg, alternating body parts involved or direction of movements). Transient global amnesia is a rare condition with no established diagnostic test and is considered a diagnosis of exclusion, although bitemporal hyperintensities on magnetic resonance imaging (MRI) may appear 12 to 48 hours after the clinical episode.⁵ Blood work is needed in patients with medical issues treated with multiple medications to evaluate for metabolic derangements; otherwise, routine blood work provides minimal information in stable patients.

Region-specific causes. Neurocysticercosis is common in some regions, such as Latin America; therefore, attention should be paid to this aspect of patient history.

Continue to: Is it really a first-time seizure?

Is it really a first-time seizure? A “first,” usually dramatic, generalized tonic-clonic seizure that triggers the diagnostic work-up may not be the very first seizure. Evidence suggests that many patients have experienced prior undiagnosed seizures. Subtle prior events often missed include episodes of deja vu, transient feelings of fear or unusual smells, speech difficulties, staring spells, or myoclonic jerks.¹ A routine EEG to record epileptiform discharges and a high-resolution brain MRI to rule out any intracranial pathology are indicated. However, if the EEG indicates a primary generalized (as opposed to focal-onset) epilepsy, a brain MRI may not be needed. If a routine EEG is unrevealing, long-term video-EEG monitoring may be needed to detect an abnormality.

Accuracy of EEG and MRI. Following a first unprovoked seizure, routine EEG to detect epileptiform discharges in adults has yielded a sensitivity of 17.3% and specificity of 94.7%. In evaluating children, these values are 57.8% and 69.6%, respectively.⁶ If results are equivocal, a 24-hour EEG can increase the likelihood of detecting epileptiform discharges to 89% of patients.⁷ Brain MRI may detect an abnormality in 12% to 14% of patients with newly diagnosed epilepsy, and in up to 80% of those with recurrent seizures.⁸ In confirming hippocampus sclerosis, MRI has demonstrated a sensitivity of 93% and specificity of 86%.⁹

When to treat a first-time seizure. Available data and prediction models identify risk factors that would help determine whether to start an antiseizure medication after a first unprovoked seizure: abnormal EEG with particular epileptiform activity, abnormal neurologic exam, abnormal computerized tomography or MRI results, nocturnal seizure, focal seizure, or family history of seizures. In the absence of such risk factors, chances of further unprovoked seizures are not high enough to justify treatment with antiseizure medications. However, if a second unprovoked seizure were to occur, that would meet the definition of epilepsy, and treatment is indicated due to the high risk for further seizures.^10,11

Epilepsy diagnosis

The International League Against Epilepsy (ILAE) previously defined epilepsy as 2 unprovoked seizures more than 24 hours apart. However, a more recent ILAE task force modified this definition: even a single unprovoked seizure would be enough to diagnose epilepsy if there is high probability of further seizures—eg, in the presence of definitive epileptiform discharges on EEG or presence of a brain tumor or a remote brain insult on imaging, since such conditions induce an enduring predisposition to generate epileptic seizures. ² Also, a single unprovoked seizure is enough to diagnose epilepsy if it is part of an epileptic syndrome such as juvenile myoclonic epilepsy. Further, a time limit was added to the definition—ie, epilepsy is considered resolved if a patient remains seizure free for 10 years without use of antiseizure medications during the past 5 years. However, given the multitude of variables and evidence, the task force acknowledged the need for individualized considerations. ²

Seizure classification

Classification of seizure type is based on the site of seizure onset and its spread pattern—ie, focal, generalized, or unknown onset.

Continue to: Focal-onset seizures

Focal-onset seizures originate “within networks limited to one hemisphere,” although possibly in more than 1 region (ie, multifocal, and presence or absence of loss of awareness). ¹² Focal seizures may then be further classified into “motor onset” or “nonmotor onset” (eg, autonomic, emotional, sensory). ²

Generalized seizures are those “originating at some point within, and rapidly engaging, bilaterally distributed networks.” ¹³ Unlike focal-onset seizures, generalized seizures are not classified based on awareness, as most generalized seizures involve loss of awareness (absence) or total loss of consciousness (generalized tonic-clonic). They are instead categorized based on the presence of motor vs nonmotor features (eg, tonic-clonic, myoclonic, atonic). Epilepsy classification is quite dynamic and constantly updated based on new genetic, electroencephalographic, and neuroimaging discoveries.

Treatment of epilepsy

Antiseizure medications

Treatment with antiseizure medications (ASMs; formerly known as antiepileptic drugs ) is the mainstay of epilepsy management. Achieving efficacy (seizure freedom) and tolerability (minimal adverse effects) are the primary goals of treatment. Factors that should govern the selection of an ASM include the seizure type/epilepsy syndrome, adverse effect profile of the ASM, pharmacodynamic/pharmacokinetic considerations, and patient comorbidities.

Levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies.

The Standard and New Antiepileptic Drugs (SANAD I and II) trials provide data from direct, unblinded, and longitudinal comparisons of existing and new ASMs and their utility in different seizure types. In the SANAD I cohort of patients with generalized and unclassified epilepsies, valproate was superior to lamotrigine and topiramate for 12-month remission and treatment failure rates, respectively.¹⁴ However, valproate generally is avoided in women of childbearing age due its potential adverse effects during pregnancy. In focal epilepsies, lamotrigine was superior to carbamazepine, gabapentin, and topiramate with respect to treatment failure, and noninferior to carbamazepine for 12-month remission.¹⁵ In the SANAD II trial, levetiracetam was noninferior to valproate for incidence of adverse events in patients with generalized and unclassified epilepsies although was found to be neither more clinically effective nor more cost effective.¹⁶ For patients of childbearing potential with generalized and unclassified epilepsies, there is evidence to support the safe and effective use of levetiracetam.¹⁷In focal epilepsies, lamotrigine was superior to levetiracetam and zonisamide with respect to treatment failures and adverse events and was noninferior to zonisamide for 12-month remission.¹⁸ In summary, levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies while lamotrigine is deemed an appropriate first-line agent for focal epilepsies (TABLE 1^19-28).

Drug level monitoring. It is standard practice to periodically monitor serum levels in patients taking first-generation ASMs such as phenytoin, carbamazepine, phenobarbital, and valproic acid because of their narrow therapeutic range and the potential for overdose or interaction with other medications or foods (eg, grapefruit juice may increase carbamazepine serum level by inhibiting ­CYP3A4, the enzyme that metabolizes the drug). Patients taking newer ASMs may not require regular serum level monitoring except during titration, with hepatic or renal dosing, when concomitantly used with estrogen-based oral contraceptives (eg, lamotrigine), before or during pregnancy, or when nonadherence is suspected.

Continue to: Can antiseizure treatment be stopped?

Can antiseizure treatment be stopped?

Current evidence favors continuing ASM therapy in patients whose seizures are under control, although the decision should be tailored to an individual’s circumstances. According to the 2021 American Academy of Neurology (AAN) guidelines, adults who have been seizure free for at least 2 years and discontinue ASMs are possibly still at higher risk for seizure recurrence in the long term (24-60 months), compared with those who continue treatment.²⁹ On the other hand, for adults who have been seizure free for at least 12 months, ASM withdrawal may not increase their risk for status epilepticus, and there are insufficient data to support or refute an effect on mortality or quality of life with ASM withdrawal in this population. The decision to taper or maintain ASM therapy in seizure-free patients also should take into consideration other clinically relevant outcome measures such as the patient’s lifestyle and medication adverse effects. Therefore, this decision should be made after sufficient discussion with patients and their caregivers. (Information for patients can be found at: www.epilepsy.com/treatment/medicines/stopping-medication.)

There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

For children, the AAN guideline panel recommends discussing with family the small risk (2%) for becoming medication resistant if seizures recur during or after ASM withdrawal. ²⁹ For children who have been seizure free for 18 to 24 months, there is probably not a significant long-term (24-48 months) difference in seizure recurrence in those who taper ASMs vs those who do not. However, presence of epileptiform discharges on EEG before discontinuation of an ASM indicates increased risk for seizure recurrence. ²⁹

Intractable (refractory) epilepsy

While most patients with epilepsy attain complete seizure control with appropriate drug therapy, approximately 30% continue to experience seizures (“drug-resistant” epilepsy, also termed intractable or refractory ). ³⁰ In 2010, the ILAE defined drug-resistant epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom” (defined as cessation of seizures for at least 3 times the longest pre-intervention inter-seizure interval or 12 months, whichever is longer). ^21,31 It should be noted that drug withdrawal due to adverse effects is not counted as failure of that ASM. Recognition of drug-resistant epilepsy may prompt referral to an epileptologist who can consider rational combination drug therapy or surgical resection of the seizure focus, vagus nerve stimulation, electrical stimulation of the seizure focus, or deep brain (thalamic) stimulation.

Seizure triggers and mitigating factors

Epilepsy mostly affects patients during seizure episodes; however, the unpredictability of these events adds significantly to the burden of disease. There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

Noncompliance with antiseizure medications is a common seizure trigger affecting up to one-half of patients with epilepsy.³²

Continue to: Medications

Medications may provoke seizures in susceptible individuals (TABLE 2^33-35).

Sleep deprivation is a potential seizure trigger in people with epilepsy based on observational studies, case reports, patient surveys, and EEG-based studies, although data from randomized controlled studies are limited.³⁶ The standard best practice is to encourage appropriate sleep hygiene, which involves getting at least 7 hours of sleep per night.³⁷

Alcohol is a GABAergic substance like benzodiazepines with antiseizure effects. However, it acts as a potential precipitant of seizures in cases of withdrawal or acute intoxication, or when it leads to sleep disruption or nonadherence to antiseizure medications. Therefore, advise patients with alcohol use disorder to slowly taper consumption (best done through a support program) and avoid sudden withdrawal. However, complete abstinence from alcohol use is not often recommended except in special circumstances (eg, a history of alcohol-related seizures). Several studies have demonstrated that modest alcohol use (1-2 drinks per occasion) does not increase seizure frequency or significantly alter serum concentrations of commonly used ASMs.³⁸

Cannabis and other substances. The 2 main biologically active components of marijuana are delta-9-tetrahydrocannibinol (THC), the main psychoactive constituent, and cannabidiol (CBD). Animal and human studies have demonstrated anticonvulsant properties of THC and CBD. But THC, in high amounts, can result in adverse cognitive effects and worsening seizures.³⁹ A purified 98% oil-based CBD extract (Epidiolex) has been approved as an adjunctive treatment for certain medically refractory epilepsy syndromes in children and young adults—ie, Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex syndrome.⁴⁰ There are no reliable data on the effect of recreational use of marijuana on seizure control. Other illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

Special clinical cases

Pregnancy and epilepsy

Despite the potential adverse effects of ASMs on fetal health, the current global consensus is to continue treatment during pregnancy, given that the potential harm of convulsive seizures outweighs the potential risks associated with in-utero exposure to ASMs. There is not enough evidence to indicate significant harm to the fetus caused by focal, absence, or myoclonic seizures. Low-dose folic acid is used to minimize the risks of ASMs during pregnancy.

Continue to: As the fetus develops...

Illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

As the fetus develops, there are changes in volume of ASM distribution, renal clearance, protein binding, and hepatic metabolism, which require checking serum levels at regular intervals and making dosage adjustments.

The ongoing study evaluating Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)⁴¹ has led to multiple landmark studies guiding the choice of preferred ASMs during pregnancy in patients with epilepsy.^42,43 This has culminated in today’s use of lamotrigine and levetiracetam as the 2 preferred agents (while avoiding valproate) in pregnant patients with epilepsy.⁴⁴

Psychogenic nonepileptic seizures

Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers.

A form of conversion disorder, psychogenic nonepileptic seizures (PNES) manifests as abnormal motor or behavioral events mimicking seizures but without associated epileptiform discharges on EEG. This is observed in 10% of patients seen in epilepsy clinics and even more often in those admitted to epilepsy­ monitoring units (25%-40%).⁴⁵ Diagnosis of PNES requires EEG monitoring both for confirmation and for discernment from true epileptic seizures, in particular frontal lobe epilepsy that may clinically mimic PNES. PNES often is associated with underlying psychological tensions or comorbid conditions such as depression, anxiety, or traumatic life experiences. There is no treatment for PNES per se, and its management is focused on controlling any underlying psychological comorbidities that may not always be obvious. There is some evidence suggesting that these patients experience an innate inability to verbally express their emotions and instead subconsciously resort to psychosomatics to express them in a somatic dimension.^46,47

Status epilepticus

Defined as prolonged seizures (> 5 min) or 2 consecutive seizures without regaining aware ness in between, status epilepticus (SE) is a potentially fatal condition. Subclinical nonconvulsive SE, especially in comatose patients, can be diagnosed only via EEG monitoring. Untreated SE may manifest as a diagnostic dilemma in unresponsive or critically ill patients and can increase the risk for mortality. ⁴⁸

Febrile seizures

Febrile seizures affect 2% to 5% of children most often in the second year of life.⁴⁹ The use of preventive antiseizure medication is not recommended; instead, the key is to investigate the underlying febrile illness. Lumbar puncture is indicated if there are signs and symptoms of meningitis (25% of children with bacterial meningitis present with seizures).⁴⁹ Febrile seizures often are self-limited, but there is risk for SE in up to 15% of cases.⁵⁰ If convulsive febrile seizures last longer than 5 minutes, initiate benzodiazepines followed by the standard protocol used for the management of SE.⁵¹

Continue to: Epilepsy as a spectrum disorder

The higher prevalence of comorbid cognitive and psychiatric conditions in patients with epilepsy, affecting about half of patients, ⁵² suggests that seizures may constitute only one aspect of a multifaceted disease that otherwise should be considered a spectrum disorder. Among such conditions are memory deficits, depression, and anxiety. Conversely, epilepsy is more common in patients with depression than in those without. ⁵²

Social impact of epilepsy

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

Vehicle driving regulations. Patients with epilepsy are required to follow state law regarding driving restrictions. Different states have different rules and regulations about driving restrictions and reporting requirements (by patients or their physicians). Refer patients to the Department of Motor Vehicles (DMV) in their state of residence for up-to-date instructions.⁵³ The Epilepsy Foundation (epilepsy.com) can serve as a resource for each state’s DMV website.

Employment assistance. Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers. The Americans with Disabilities Act (ADA) and the US Equal Employment Opportunity Commission (EEOC) forbid discrimination against qualified people with disabilities, including those with epilepsy, and require reasonable accommodations in the workplace (www.eeoc.gov/laws/guidance/­epilepsy-workplace-and-ada).⁵⁴

CORRESPONDENCE
Gholam K. Motamedi, MD, Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007; [email protected]

Managing first-time seizures and epilepsy often requires consultation with a neurologist or epileptologist for diagnosis and subsequent management, including when medical treatment fails or in determining whether patients may benefit from surgery. However, given the high prevalence of epilepsy and even higher incidence of a single seizure, family physicians contribute significantly to the management of these patients. The main issues are managing a first-time seizure, making the diagnosis, establishing a treatment plan, and exploring triggers and mitigating factors.

Seizure vs epilepsy

All patients with epilepsy experience seizures, but not every person who experiences a seizure has (or will develop) epilepsy. Nearly 10% of the population has one seizure during their lifetime,whereas the risk for epilepsy is just 3%.¹ Therefore, a first-time seizure may not herald epilepsy, defined as repetitive (≥ 2) unprovoked seizures more than 24 hours apart.² Seizures can be provoked (acute symptomatic) or unprovoked; a clear distinction between these 2 occurrences—as well as between single and recurrent seizures—is critical for proper management. A close look at the circumstances of a first-time seizure is imperative to define the nature of the event and the possibility of further seizures before devising a treatment plan.

Provoked seizures are due to an acute brain insult such as toxic-metabolic disorders, concussion, alcohol withdrawal, an adverse effect of a medication or its withdrawal, or photic stimulation presumably by disrupting the brain’s metabolic homeostasis or integrity. The key factor is that provoked seizures always happen in close temporal association with an acute insult. A single provoked seizure happens each year in 29 to 39 individuals per 100,000.³ While these seizures typically occur singly, there is a small risk they may recur if the triggering insult persists or repeats.¹ Therefore, more than 1 seizure per se may not indicate epilepsy.³

Unprovoked seizures reflect an underlying brain dysfunction. A single unprovoked seizure happens in 23 to 61 individuals per 100,000 per year, often in men in either younger or older age groups.³ Unprovoked seizures may occur only once or may recur (ie, evolve into epilepsy). The latter scenario happens in only about half of cases; the overall risk for a recurrent seizure within 2 years of a first seizure is estimated at 42% (24% to 65%, depending on the etiology and electroencephalogram [EEG] findings).⁴ More specifically, without treatment the relapse rate will be 36% at 1 year and 47% at 2 years.⁴ Further, a second unprovoked seizure, if untreated, would increase the risk for third and fourth seizures to 73% and 76%, respectively, within 4 years.³

Evaluating the first-time seizure

Ask the patient or observers about the circumstances of the event to differentiate provoked from unprovoked onset. For one thing, not all “spells” are seizures. The differential diagnoses may include syncope, psychogenic nonepileptic events, drug intoxication or withdrawal, migraine, panic attacks, sleep disorders (parasomnia), transient global amnesia, concussion, and transient ischemic attack. EEG, neuroimaging, and other relevant diagnostic tests often are needed (eg, electrocardiogram/echocardiogram/Holter monitoring to evaluate for syncope/cardiac arrhythmia). Clinically, syncopal episodes tend to be brief with rapid recovery and no confusion, speech problems, aura, or lateralizing signs such as hand posturing or lip smacking that are typical with focal seizures. However, cases of convulsive syncope can be challenging to assess without diagnostic tests.

Many patients have experienced prior undiagnosed seizures. Subtle prior events include episodes of deja vu, transient feelings of fear, unusual smells, and speech difficulties.

True convulsive seizures do not have the variability in clinical signs seen with psychogenic nonepileptic events (eg, alternating body parts involved or direction of movements). Transient global amnesia is a rare condition with no established diagnostic test and is considered a diagnosis of exclusion, although bitemporal hyperintensities on magnetic resonance imaging (MRI) may appear 12 to 48 hours after the clinical episode.⁵ Blood work is needed in patients with medical issues treated with multiple medications to evaluate for metabolic derangements; otherwise, routine blood work provides minimal information in stable patients.

Region-specific causes. Neurocysticercosis is common in some regions, such as Latin America; therefore, attention should be paid to this aspect of patient history.

Continue to: Is it really a first-time seizure?

Is it really a first-time seizure? A “first,” usually dramatic, generalized tonic-clonic seizure that triggers the diagnostic work-up may not be the very first seizure. Evidence suggests that many patients have experienced prior undiagnosed seizures. Subtle prior events often missed include episodes of deja vu, transient feelings of fear or unusual smells, speech difficulties, staring spells, or myoclonic jerks.¹ A routine EEG to record epileptiform discharges and a high-resolution brain MRI to rule out any intracranial pathology are indicated. However, if the EEG indicates a primary generalized (as opposed to focal-onset) epilepsy, a brain MRI may not be needed. If a routine EEG is unrevealing, long-term video-EEG monitoring may be needed to detect an abnormality.

Accuracy of EEG and MRI. Following a first unprovoked seizure, routine EEG to detect epileptiform discharges in adults has yielded a sensitivity of 17.3% and specificity of 94.7%. In evaluating children, these values are 57.8% and 69.6%, respectively.⁶ If results are equivocal, a 24-hour EEG can increase the likelihood of detecting epileptiform discharges to 89% of patients.⁷ Brain MRI may detect an abnormality in 12% to 14% of patients with newly diagnosed epilepsy, and in up to 80% of those with recurrent seizures.⁸ In confirming hippocampus sclerosis, MRI has demonstrated a sensitivity of 93% and specificity of 86%.⁹

When to treat a first-time seizure. Available data and prediction models identify risk factors that would help determine whether to start an antiseizure medication after a first unprovoked seizure: abnormal EEG with particular epileptiform activity, abnormal neurologic exam, abnormal computerized tomography or MRI results, nocturnal seizure, focal seizure, or family history of seizures. In the absence of such risk factors, chances of further unprovoked seizures are not high enough to justify treatment with antiseizure medications. However, if a second unprovoked seizure were to occur, that would meet the definition of epilepsy, and treatment is indicated due to the high risk for further seizures.^10,11

Epilepsy diagnosis

The International League Against Epilepsy (ILAE) previously defined epilepsy as 2 unprovoked seizures more than 24 hours apart. However, a more recent ILAE task force modified this definition: even a single unprovoked seizure would be enough to diagnose epilepsy if there is high probability of further seizures—eg, in the presence of definitive epileptiform discharges on EEG or presence of a brain tumor or a remote brain insult on imaging, since such conditions induce an enduring predisposition to generate epileptic seizures. ² Also, a single unprovoked seizure is enough to diagnose epilepsy if it is part of an epileptic syndrome such as juvenile myoclonic epilepsy. Further, a time limit was added to the definition—ie, epilepsy is considered resolved if a patient remains seizure free for 10 years without use of antiseizure medications during the past 5 years. However, given the multitude of variables and evidence, the task force acknowledged the need for individualized considerations. ²

Seizure classification

Classification of seizure type is based on the site of seizure onset and its spread pattern—ie, focal, generalized, or unknown onset.

Continue to: Focal-onset seizures

Focal-onset seizures originate “within networks limited to one hemisphere,” although possibly in more than 1 region (ie, multifocal, and presence or absence of loss of awareness). ¹² Focal seizures may then be further classified into “motor onset” or “nonmotor onset” (eg, autonomic, emotional, sensory). ²

Generalized seizures are those “originating at some point within, and rapidly engaging, bilaterally distributed networks.” ¹³ Unlike focal-onset seizures, generalized seizures are not classified based on awareness, as most generalized seizures involve loss of awareness (absence) or total loss of consciousness (generalized tonic-clonic). They are instead categorized based on the presence of motor vs nonmotor features (eg, tonic-clonic, myoclonic, atonic). Epilepsy classification is quite dynamic and constantly updated based on new genetic, electroencephalographic, and neuroimaging discoveries.

Treatment of epilepsy

Antiseizure medications

Treatment with antiseizure medications (ASMs; formerly known as antiepileptic drugs ) is the mainstay of epilepsy management. Achieving efficacy (seizure freedom) and tolerability (minimal adverse effects) are the primary goals of treatment. Factors that should govern the selection of an ASM include the seizure type/epilepsy syndrome, adverse effect profile of the ASM, pharmacodynamic/pharmacokinetic considerations, and patient comorbidities.

Levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies.

The Standard and New Antiepileptic Drugs (SANAD I and II) trials provide data from direct, unblinded, and longitudinal comparisons of existing and new ASMs and their utility in different seizure types. In the SANAD I cohort of patients with generalized and unclassified epilepsies, valproate was superior to lamotrigine and topiramate for 12-month remission and treatment failure rates, respectively.¹⁴ However, valproate generally is avoided in women of childbearing age due its potential adverse effects during pregnancy. In focal epilepsies, lamotrigine was superior to carbamazepine, gabapentin, and topiramate with respect to treatment failure, and noninferior to carbamazepine for 12-month remission.¹⁵ In the SANAD II trial, levetiracetam was noninferior to valproate for incidence of adverse events in patients with generalized and unclassified epilepsies although was found to be neither more clinically effective nor more cost effective.¹⁶ For patients of childbearing potential with generalized and unclassified epilepsies, there is evidence to support the safe and effective use of levetiracetam.¹⁷In focal epilepsies, lamotrigine was superior to levetiracetam and zonisamide with respect to treatment failures and adverse events and was noninferior to zonisamide for 12-month remission.¹⁸ In summary, levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies while lamotrigine is deemed an appropriate first-line agent for focal epilepsies (TABLE 1^19-28).

Drug level monitoring. It is standard practice to periodically monitor serum levels in patients taking first-generation ASMs such as phenytoin, carbamazepine, phenobarbital, and valproic acid because of their narrow therapeutic range and the potential for overdose or interaction with other medications or foods (eg, grapefruit juice may increase carbamazepine serum level by inhibiting ­CYP3A4, the enzyme that metabolizes the drug). Patients taking newer ASMs may not require regular serum level monitoring except during titration, with hepatic or renal dosing, when concomitantly used with estrogen-based oral contraceptives (eg, lamotrigine), before or during pregnancy, or when nonadherence is suspected.

Continue to: Can antiseizure treatment be stopped?

Can antiseizure treatment be stopped?

Current evidence favors continuing ASM therapy in patients whose seizures are under control, although the decision should be tailored to an individual’s circumstances. According to the 2021 American Academy of Neurology (AAN) guidelines, adults who have been seizure free for at least 2 years and discontinue ASMs are possibly still at higher risk for seizure recurrence in the long term (24-60 months), compared with those who continue treatment.²⁹ On the other hand, for adults who have been seizure free for at least 12 months, ASM withdrawal may not increase their risk for status epilepticus, and there are insufficient data to support or refute an effect on mortality or quality of life with ASM withdrawal in this population. The decision to taper or maintain ASM therapy in seizure-free patients also should take into consideration other clinically relevant outcome measures such as the patient’s lifestyle and medication adverse effects. Therefore, this decision should be made after sufficient discussion with patients and their caregivers. (Information for patients can be found at: www.epilepsy.com/treatment/medicines/stopping-medication.)

There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

For children, the AAN guideline panel recommends discussing with family the small risk (2%) for becoming medication resistant if seizures recur during or after ASM withdrawal. ²⁹ For children who have been seizure free for 18 to 24 months, there is probably not a significant long-term (24-48 months) difference in seizure recurrence in those who taper ASMs vs those who do not. However, presence of epileptiform discharges on EEG before discontinuation of an ASM indicates increased risk for seizure recurrence. ²⁹

Intractable (refractory) epilepsy

While most patients with epilepsy attain complete seizure control with appropriate drug therapy, approximately 30% continue to experience seizures (“drug-resistant” epilepsy, also termed intractable or refractory ). ³⁰ In 2010, the ILAE defined drug-resistant epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom” (defined as cessation of seizures for at least 3 times the longest pre-intervention inter-seizure interval or 12 months, whichever is longer). ^21,31 It should be noted that drug withdrawal due to adverse effects is not counted as failure of that ASM. Recognition of drug-resistant epilepsy may prompt referral to an epileptologist who can consider rational combination drug therapy or surgical resection of the seizure focus, vagus nerve stimulation, electrical stimulation of the seizure focus, or deep brain (thalamic) stimulation.

Seizure triggers and mitigating factors

Epilepsy mostly affects patients during seizure episodes; however, the unpredictability of these events adds significantly to the burden of disease. There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

Noncompliance with antiseizure medications is a common seizure trigger affecting up to one-half of patients with epilepsy.³²

Continue to: Medications

Medications may provoke seizures in susceptible individuals (TABLE 2^33-35).

Sleep deprivation is a potential seizure trigger in people with epilepsy based on observational studies, case reports, patient surveys, and EEG-based studies, although data from randomized controlled studies are limited.³⁶ The standard best practice is to encourage appropriate sleep hygiene, which involves getting at least 7 hours of sleep per night.³⁷

Alcohol is a GABAergic substance like benzodiazepines with antiseizure effects. However, it acts as a potential precipitant of seizures in cases of withdrawal or acute intoxication, or when it leads to sleep disruption or nonadherence to antiseizure medications. Therefore, advise patients with alcohol use disorder to slowly taper consumption (best done through a support program) and avoid sudden withdrawal. However, complete abstinence from alcohol use is not often recommended except in special circumstances (eg, a history of alcohol-related seizures). Several studies have demonstrated that modest alcohol use (1-2 drinks per occasion) does not increase seizure frequency or significantly alter serum concentrations of commonly used ASMs.³⁸

Cannabis and other substances. The 2 main biologically active components of marijuana are delta-9-tetrahydrocannibinol (THC), the main psychoactive constituent, and cannabidiol (CBD). Animal and human studies have demonstrated anticonvulsant properties of THC and CBD. But THC, in high amounts, can result in adverse cognitive effects and worsening seizures.³⁹ A purified 98% oil-based CBD extract (Epidiolex) has been approved as an adjunctive treatment for certain medically refractory epilepsy syndromes in children and young adults—ie, Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex syndrome.⁴⁰ There are no reliable data on the effect of recreational use of marijuana on seizure control. Other illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

Special clinical cases

Pregnancy and epilepsy

Despite the potential adverse effects of ASMs on fetal health, the current global consensus is to continue treatment during pregnancy, given that the potential harm of convulsive seizures outweighs the potential risks associated with in-utero exposure to ASMs. There is not enough evidence to indicate significant harm to the fetus caused by focal, absence, or myoclonic seizures. Low-dose folic acid is used to minimize the risks of ASMs during pregnancy.

Continue to: As the fetus develops...

Illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

As the fetus develops, there are changes in volume of ASM distribution, renal clearance, protein binding, and hepatic metabolism, which require checking serum levels at regular intervals and making dosage adjustments.

The ongoing study evaluating Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)⁴¹ has led to multiple landmark studies guiding the choice of preferred ASMs during pregnancy in patients with epilepsy.^42,43 This has culminated in today’s use of lamotrigine and levetiracetam as the 2 preferred agents (while avoiding valproate) in pregnant patients with epilepsy.⁴⁴

Psychogenic nonepileptic seizures

Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers.

A form of conversion disorder, psychogenic nonepileptic seizures (PNES) manifests as abnormal motor or behavioral events mimicking seizures but without associated epileptiform discharges on EEG. This is observed in 10% of patients seen in epilepsy clinics and even more often in those admitted to epilepsy­ monitoring units (25%-40%).⁴⁵ Diagnosis of PNES requires EEG monitoring both for confirmation and for discernment from true epileptic seizures, in particular frontal lobe epilepsy that may clinically mimic PNES. PNES often is associated with underlying psychological tensions or comorbid conditions such as depression, anxiety, or traumatic life experiences. There is no treatment for PNES per se, and its management is focused on controlling any underlying psychological comorbidities that may not always be obvious. There is some evidence suggesting that these patients experience an innate inability to verbally express their emotions and instead subconsciously resort to psychosomatics to express them in a somatic dimension.^46,47

Status epilepticus

Defined as prolonged seizures (> 5 min) or 2 consecutive seizures without regaining aware ness in between, status epilepticus (SE) is a potentially fatal condition. Subclinical nonconvulsive SE, especially in comatose patients, can be diagnosed only via EEG monitoring. Untreated SE may manifest as a diagnostic dilemma in unresponsive or critically ill patients and can increase the risk for mortality. ⁴⁸

Febrile seizures

Febrile seizures affect 2% to 5% of children most often in the second year of life.⁴⁹ The use of preventive antiseizure medication is not recommended; instead, the key is to investigate the underlying febrile illness. Lumbar puncture is indicated if there are signs and symptoms of meningitis (25% of children with bacterial meningitis present with seizures).⁴⁹ Febrile seizures often are self-limited, but there is risk for SE in up to 15% of cases.⁵⁰ If convulsive febrile seizures last longer than 5 minutes, initiate benzodiazepines followed by the standard protocol used for the management of SE.⁵¹

Continue to: Epilepsy as a spectrum disorder

The higher prevalence of comorbid cognitive and psychiatric conditions in patients with epilepsy, affecting about half of patients, ⁵² suggests that seizures may constitute only one aspect of a multifaceted disease that otherwise should be considered a spectrum disorder. Among such conditions are memory deficits, depression, and anxiety. Conversely, epilepsy is more common in patients with depression than in those without. ⁵²

Social impact of epilepsy

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

Vehicle driving regulations. Patients with epilepsy are required to follow state law regarding driving restrictions. Different states have different rules and regulations about driving restrictions and reporting requirements (by patients or their physicians). Refer patients to the Department of Motor Vehicles (DMV) in their state of residence for up-to-date instructions.⁵³ The Epilepsy Foundation (epilepsy.com) can serve as a resource for each state’s DMV website.

Employment assistance. Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers. The Americans with Disabilities Act (ADA) and the US Equal Employment Opportunity Commission (EEOC) forbid discrimination against qualified people with disabilities, including those with epilepsy, and require reasonable accommodations in the workplace (www.eeoc.gov/laws/guidance/­epilepsy-workplace-and-ada).⁵⁴

CORRESPONDENCE
Gholam K. Motamedi, MD, Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007; [email protected]

Managing first-time seizures and epilepsy often requires consultation with a neurologist or epileptologist for diagnosis and subsequent management, including when medical treatment fails or in determining whether patients may benefit from surgery. However, given the high prevalence of epilepsy and even higher incidence of a single seizure, family physicians contribute significantly to the management of these patients. The main issues are managing a first-time seizure, making the diagnosis, establishing a treatment plan, and exploring triggers and mitigating factors.

Seizure vs epilepsy

All patients with epilepsy experience seizures, but not every person who experiences a seizure has (or will develop) epilepsy. Nearly 10% of the population has one seizure during their lifetime,whereas the risk for epilepsy is just 3%.¹ Therefore, a first-time seizure may not herald epilepsy, defined as repetitive (≥ 2) unprovoked seizures more than 24 hours apart.² Seizures can be provoked (acute symptomatic) or unprovoked; a clear distinction between these 2 occurrences—as well as between single and recurrent seizures—is critical for proper management. A close look at the circumstances of a first-time seizure is imperative to define the nature of the event and the possibility of further seizures before devising a treatment plan.

Provoked seizures are due to an acute brain insult such as toxic-metabolic disorders, concussion, alcohol withdrawal, an adverse effect of a medication or its withdrawal, or photic stimulation presumably by disrupting the brain’s metabolic homeostasis or integrity. The key factor is that provoked seizures always happen in close temporal association with an acute insult. A single provoked seizure happens each year in 29 to 39 individuals per 100,000.³ While these seizures typically occur singly, there is a small risk they may recur if the triggering insult persists or repeats.¹ Therefore, more than 1 seizure per se may not indicate epilepsy.³

Unprovoked seizures reflect an underlying brain dysfunction. A single unprovoked seizure happens in 23 to 61 individuals per 100,000 per year, often in men in either younger or older age groups.³ Unprovoked seizures may occur only once or may recur (ie, evolve into epilepsy). The latter scenario happens in only about half of cases; the overall risk for a recurrent seizure within 2 years of a first seizure is estimated at 42% (24% to 65%, depending on the etiology and electroencephalogram [EEG] findings).⁴ More specifically, without treatment the relapse rate will be 36% at 1 year and 47% at 2 years.⁴ Further, a second unprovoked seizure, if untreated, would increase the risk for third and fourth seizures to 73% and 76%, respectively, within 4 years.³

Evaluating the first-time seizure

Ask the patient or observers about the circumstances of the event to differentiate provoked from unprovoked onset. For one thing, not all “spells” are seizures. The differential diagnoses may include syncope, psychogenic nonepileptic events, drug intoxication or withdrawal, migraine, panic attacks, sleep disorders (parasomnia), transient global amnesia, concussion, and transient ischemic attack. EEG, neuroimaging, and other relevant diagnostic tests often are needed (eg, electrocardiogram/echocardiogram/Holter monitoring to evaluate for syncope/cardiac arrhythmia). Clinically, syncopal episodes tend to be brief with rapid recovery and no confusion, speech problems, aura, or lateralizing signs such as hand posturing or lip smacking that are typical with focal seizures. However, cases of convulsive syncope can be challenging to assess without diagnostic tests.

Many patients have experienced prior undiagnosed seizures. Subtle prior events include episodes of deja vu, transient feelings of fear, unusual smells, and speech difficulties.

True convulsive seizures do not have the variability in clinical signs seen with psychogenic nonepileptic events (eg, alternating body parts involved or direction of movements). Transient global amnesia is a rare condition with no established diagnostic test and is considered a diagnosis of exclusion, although bitemporal hyperintensities on magnetic resonance imaging (MRI) may appear 12 to 48 hours after the clinical episode.⁵ Blood work is needed in patients with medical issues treated with multiple medications to evaluate for metabolic derangements; otherwise, routine blood work provides minimal information in stable patients.

Region-specific causes. Neurocysticercosis is common in some regions, such as Latin America; therefore, attention should be paid to this aspect of patient history.

Continue to: Is it really a first-time seizure?

Is it really a first-time seizure? A “first,” usually dramatic, generalized tonic-clonic seizure that triggers the diagnostic work-up may not be the very first seizure. Evidence suggests that many patients have experienced prior undiagnosed seizures. Subtle prior events often missed include episodes of deja vu, transient feelings of fear or unusual smells, speech difficulties, staring spells, or myoclonic jerks.¹ A routine EEG to record epileptiform discharges and a high-resolution brain MRI to rule out any intracranial pathology are indicated. However, if the EEG indicates a primary generalized (as opposed to focal-onset) epilepsy, a brain MRI may not be needed. If a routine EEG is unrevealing, long-term video-EEG monitoring may be needed to detect an abnormality.

Accuracy of EEG and MRI. Following a first unprovoked seizure, routine EEG to detect epileptiform discharges in adults has yielded a sensitivity of 17.3% and specificity of 94.7%. In evaluating children, these values are 57.8% and 69.6%, respectively.⁶ If results are equivocal, a 24-hour EEG can increase the likelihood of detecting epileptiform discharges to 89% of patients.⁷ Brain MRI may detect an abnormality in 12% to 14% of patients with newly diagnosed epilepsy, and in up to 80% of those with recurrent seizures.⁸ In confirming hippocampus sclerosis, MRI has demonstrated a sensitivity of 93% and specificity of 86%.⁹

When to treat a first-time seizure. Available data and prediction models identify risk factors that would help determine whether to start an antiseizure medication after a first unprovoked seizure: abnormal EEG with particular epileptiform activity, abnormal neurologic exam, abnormal computerized tomography or MRI results, nocturnal seizure, focal seizure, or family history of seizures. In the absence of such risk factors, chances of further unprovoked seizures are not high enough to justify treatment with antiseizure medications. However, if a second unprovoked seizure were to occur, that would meet the definition of epilepsy, and treatment is indicated due to the high risk for further seizures.^10,11

Epilepsy diagnosis

The International League Against Epilepsy (ILAE) previously defined epilepsy as 2 unprovoked seizures more than 24 hours apart. However, a more recent ILAE task force modified this definition: even a single unprovoked seizure would be enough to diagnose epilepsy if there is high probability of further seizures—eg, in the presence of definitive epileptiform discharges on EEG or presence of a brain tumor or a remote brain insult on imaging, since such conditions induce an enduring predisposition to generate epileptic seizures. ² Also, a single unprovoked seizure is enough to diagnose epilepsy if it is part of an epileptic syndrome such as juvenile myoclonic epilepsy. Further, a time limit was added to the definition—ie, epilepsy is considered resolved if a patient remains seizure free for 10 years without use of antiseizure medications during the past 5 years. However, given the multitude of variables and evidence, the task force acknowledged the need for individualized considerations. ²

Seizure classification

Classification of seizure type is based on the site of seizure onset and its spread pattern—ie, focal, generalized, or unknown onset.

Continue to: Focal-onset seizures

Focal-onset seizures originate “within networks limited to one hemisphere,” although possibly in more than 1 region (ie, multifocal, and presence or absence of loss of awareness). ¹² Focal seizures may then be further classified into “motor onset” or “nonmotor onset” (eg, autonomic, emotional, sensory). ²

Generalized seizures are those “originating at some point within, and rapidly engaging, bilaterally distributed networks.” ¹³ Unlike focal-onset seizures, generalized seizures are not classified based on awareness, as most generalized seizures involve loss of awareness (absence) or total loss of consciousness (generalized tonic-clonic). They are instead categorized based on the presence of motor vs nonmotor features (eg, tonic-clonic, myoclonic, atonic). Epilepsy classification is quite dynamic and constantly updated based on new genetic, electroencephalographic, and neuroimaging discoveries.

Treatment of epilepsy

Antiseizure medications

Treatment with antiseizure medications (ASMs; formerly known as antiepileptic drugs ) is the mainstay of epilepsy management. Achieving efficacy (seizure freedom) and tolerability (minimal adverse effects) are the primary goals of treatment. Factors that should govern the selection of an ASM include the seizure type/epilepsy syndrome, adverse effect profile of the ASM, pharmacodynamic/pharmacokinetic considerations, and patient comorbidities.

Levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies.

The Standard and New Antiepileptic Drugs (SANAD I and II) trials provide data from direct, unblinded, and longitudinal comparisons of existing and new ASMs and their utility in different seizure types. In the SANAD I cohort of patients with generalized and unclassified epilepsies, valproate was superior to lamotrigine and topiramate for 12-month remission and treatment failure rates, respectively.¹⁴ However, valproate generally is avoided in women of childbearing age due its potential adverse effects during pregnancy. In focal epilepsies, lamotrigine was superior to carbamazepine, gabapentin, and topiramate with respect to treatment failure, and noninferior to carbamazepine for 12-month remission.¹⁵ In the SANAD II trial, levetiracetam was noninferior to valproate for incidence of adverse events in patients with generalized and unclassified epilepsies although was found to be neither more clinically effective nor more cost effective.¹⁶ For patients of childbearing potential with generalized and unclassified epilepsies, there is evidence to support the safe and effective use of levetiracetam.¹⁷In focal epilepsies, lamotrigine was superior to levetiracetam and zonisamide with respect to treatment failures and adverse events and was noninferior to zonisamide for 12-month remission.¹⁸ In summary, levetiracetam and valproate (not to be used in women of childbearing potential) are considered appropriate first-line agents for generalized and unclassified epilepsies while lamotrigine is deemed an appropriate first-line agent for focal epilepsies (TABLE 1^19-28).

Drug level monitoring. It is standard practice to periodically monitor serum levels in patients taking first-generation ASMs such as phenytoin, carbamazepine, phenobarbital, and valproic acid because of their narrow therapeutic range and the potential for overdose or interaction with other medications or foods (eg, grapefruit juice may increase carbamazepine serum level by inhibiting ­CYP3A4, the enzyme that metabolizes the drug). Patients taking newer ASMs may not require regular serum level monitoring except during titration, with hepatic or renal dosing, when concomitantly used with estrogen-based oral contraceptives (eg, lamotrigine), before or during pregnancy, or when nonadherence is suspected.

Continue to: Can antiseizure treatment be stopped?

Can antiseizure treatment be stopped?

Current evidence favors continuing ASM therapy in patients whose seizures are under control, although the decision should be tailored to an individual’s circumstances. According to the 2021 American Academy of Neurology (AAN) guidelines, adults who have been seizure free for at least 2 years and discontinue ASMs are possibly still at higher risk for seizure recurrence in the long term (24-60 months), compared with those who continue treatment.²⁹ On the other hand, for adults who have been seizure free for at least 12 months, ASM withdrawal may not increase their risk for status epilepticus, and there are insufficient data to support or refute an effect on mortality or quality of life with ASM withdrawal in this population. The decision to taper or maintain ASM therapy in seizure-free patients also should take into consideration other clinically relevant outcome measures such as the patient’s lifestyle and medication adverse effects. Therefore, this decision should be made after sufficient discussion with patients and their caregivers. (Information for patients can be found at: www.epilepsy.com/treatment/medicines/stopping-medication.)

There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

For children, the AAN guideline panel recommends discussing with family the small risk (2%) for becoming medication resistant if seizures recur during or after ASM withdrawal. ²⁹ For children who have been seizure free for 18 to 24 months, there is probably not a significant long-term (24-48 months) difference in seizure recurrence in those who taper ASMs vs those who do not. However, presence of epileptiform discharges on EEG before discontinuation of an ASM indicates increased risk for seizure recurrence. ²⁹

Intractable (refractory) epilepsy

While most patients with epilepsy attain complete seizure control with appropriate drug therapy, approximately 30% continue to experience seizures (“drug-resistant” epilepsy, also termed intractable or refractory ). ³⁰ In 2010, the ILAE defined drug-resistant epilepsy as “failure of adequate trials of two tolerated, appropriately chosen and used anti-epileptic drug schedules (whether as monotherapy or in combination) to achieve sustained seizure freedom” (defined as cessation of seizures for at least 3 times the longest pre-intervention inter-seizure interval or 12 months, whichever is longer). ^21,31 It should be noted that drug withdrawal due to adverse effects is not counted as failure of that ASM. Recognition of drug-resistant epilepsy may prompt referral to an epileptologist who can consider rational combination drug therapy or surgical resection of the seizure focus, vagus nerve stimulation, electrical stimulation of the seizure focus, or deep brain (thalamic) stimulation.

Seizure triggers and mitigating factors

Epilepsy mostly affects patients during seizure episodes; however, the unpredictability of these events adds significantly to the burden of disease. There are no reliable methods for predicting seizure other than knowing of the several potential risks and recognizing and avoiding these triggers.

Noncompliance with antiseizure medications is a common seizure trigger affecting up to one-half of patients with epilepsy.³²

Continue to: Medications

Medications may provoke seizures in susceptible individuals (TABLE 2^33-35).

Sleep deprivation is a potential seizure trigger in people with epilepsy based on observational studies, case reports, patient surveys, and EEG-based studies, although data from randomized controlled studies are limited.³⁶ The standard best practice is to encourage appropriate sleep hygiene, which involves getting at least 7 hours of sleep per night.³⁷

Alcohol is a GABAergic substance like benzodiazepines with antiseizure effects. However, it acts as a potential precipitant of seizures in cases of withdrawal or acute intoxication, or when it leads to sleep disruption or nonadherence to antiseizure medications. Therefore, advise patients with alcohol use disorder to slowly taper consumption (best done through a support program) and avoid sudden withdrawal. However, complete abstinence from alcohol use is not often recommended except in special circumstances (eg, a history of alcohol-related seizures). Several studies have demonstrated that modest alcohol use (1-2 drinks per occasion) does not increase seizure frequency or significantly alter serum concentrations of commonly used ASMs.³⁸

Cannabis and other substances. The 2 main biologically active components of marijuana are delta-9-tetrahydrocannibinol (THC), the main psychoactive constituent, and cannabidiol (CBD). Animal and human studies have demonstrated anticonvulsant properties of THC and CBD. But THC, in high amounts, can result in adverse cognitive effects and worsening seizures.³⁹ A purified 98% oil-based CBD extract (Epidiolex) has been approved as an adjunctive treatment for certain medically refractory epilepsy syndromes in children and young adults—ie, Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis complex syndrome.⁴⁰ There are no reliable data on the effect of recreational use of marijuana on seizure control. Other illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

Special clinical cases

Pregnancy and epilepsy

Despite the potential adverse effects of ASMs on fetal health, the current global consensus is to continue treatment during pregnancy, given that the potential harm of convulsive seizures outweighs the potential risks associated with in-utero exposure to ASMs. There is not enough evidence to indicate significant harm to the fetus caused by focal, absence, or myoclonic seizures. Low-dose folic acid is used to minimize the risks of ASMs during pregnancy.

Continue to: As the fetus develops...

Illicit substances such as cocaine may lower seizure threshold by their stimulatory and disruptive effects on sleep, diet, and healthy routines.

As the fetus develops, there are changes in volume of ASM distribution, renal clearance, protein binding, and hepatic metabolism, which require checking serum levels at regular intervals and making dosage adjustments.

The ongoing study evaluating Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD)⁴¹ has led to multiple landmark studies guiding the choice of preferred ASMs during pregnancy in patients with epilepsy.^42,43 This has culminated in today’s use of lamotrigine and levetiracetam as the 2 preferred agents (while avoiding valproate) in pregnant patients with epilepsy.⁴⁴

Psychogenic nonepileptic seizures

Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers.

A form of conversion disorder, psychogenic nonepileptic seizures (PNES) manifests as abnormal motor or behavioral events mimicking seizures but without associated epileptiform discharges on EEG. This is observed in 10% of patients seen in epilepsy clinics and even more often in those admitted to epilepsy­ monitoring units (25%-40%).⁴⁵ Diagnosis of PNES requires EEG monitoring both for confirmation and for discernment from true epileptic seizures, in particular frontal lobe epilepsy that may clinically mimic PNES. PNES often is associated with underlying psychological tensions or comorbid conditions such as depression, anxiety, or traumatic life experiences. There is no treatment for PNES per se, and its management is focused on controlling any underlying psychological comorbidities that may not always be obvious. There is some evidence suggesting that these patients experience an innate inability to verbally express their emotions and instead subconsciously resort to psychosomatics to express them in a somatic dimension.^46,47

Status epilepticus

Defined as prolonged seizures (> 5 min) or 2 consecutive seizures without regaining aware ness in between, status epilepticus (SE) is a potentially fatal condition. Subclinical nonconvulsive SE, especially in comatose patients, can be diagnosed only via EEG monitoring. Untreated SE may manifest as a diagnostic dilemma in unresponsive or critically ill patients and can increase the risk for mortality. ⁴⁸

Febrile seizures

Febrile seizures affect 2% to 5% of children most often in the second year of life.⁴⁹ The use of preventive antiseizure medication is not recommended; instead, the key is to investigate the underlying febrile illness. Lumbar puncture is indicated if there are signs and symptoms of meningitis (25% of children with bacterial meningitis present with seizures).⁴⁹ Febrile seizures often are self-limited, but there is risk for SE in up to 15% of cases.⁵⁰ If convulsive febrile seizures last longer than 5 minutes, initiate benzodiazepines followed by the standard protocol used for the management of SE.⁵¹

Continue to: Epilepsy as a spectrum disorder

The higher prevalence of comorbid cognitive and psychiatric conditions in patients with epilepsy, affecting about half of patients, ⁵² suggests that seizures may constitute only one aspect of a multifaceted disease that otherwise should be considered a spectrum disorder. Among such conditions are memory deficits, depression, and anxiety. Conversely, epilepsy is more common in patients with depression than in those without. ⁵²

Social impact of epilepsy

De-escalation of treatment offers an equivalent, resource-sparing alternative to traditional treatment of pediatric torus fractures of the distal radius.

Vehicle driving regulations. Patients with epilepsy are required to follow state law regarding driving restrictions. Different states have different rules and regulations about driving restrictions and reporting requirements (by patients or their physicians). Refer patients to the Department of Motor Vehicles (DMV) in their state of residence for up-to-date instructions.⁵³ The Epilepsy Foundation (epilepsy.com) can serve as a resource for each state’s DMV website.

Employment assistance. Having epilepsy should not preclude patients from seeking employment and pursuing meaningful careers. The Americans with Disabilities Act (ADA) and the US Equal Employment Opportunity Commission (EEOC) forbid discrimination against qualified people with disabilities, including those with epilepsy, and require reasonable accommodations in the workplace (www.eeoc.gov/laws/guidance/­epilepsy-workplace-and-ada).⁵⁴

CORRESPONDENCE
Gholam K. Motamedi, MD, Department of Neurology, PHC 7, Georgetown University Hospital, 3800 Reservoir Road, NW, Washington, DC 20007; [email protected]

The dream of family practice began more than 6 decades ago with a movement toward personal physicians who have “… the feeling of warm personal regard and concern of doctor for patient, the feeling that the doctor treats people, not illnesses ….” The personal family physician helps patients “… not because of the interesting medical problems they may present but because they are human beings in need of help.”¹ One of the most influential founders of family medicine, Dr. Gayle Stephens, expounded on this idea in a series of essays that tapped into the intellectual, philosophical, historical, and moral underpinnings of our discipline.²

Following the dream and the birth of family medicine—like any organization—its lifecycle can be envisioned as proceeding through the rest of the 7 stages of organizational life (TABLE).³ Now allow me to give you some numbers. There are more than 118,000 family physicians in the United States, 784 family medicine residencies filled by 4530 medical school graduates, more than 150 departments of family medicine, multiple national family medicine organizations, and even a World Organization of Family Doctors.^4,5 The American Board of Family Medicine is the second largest medical specialty board in the country. Family doctors make up nearly 40% of our total primary care workforce.⁶ We launched the venture, got organized, made it. We are an institution.

This final issue of The Journal of Family Practice marks the end of an era of nearly 50 years of publication.

The threat at the institution stage is that we are on the precipice of “closing in.” Many factors are driving this stage: commoditization in health care, market influences and competition for patients, alternative primary care models, erosion of the patient-physician relationship (partly driven by technology), narrowing scope of care, clinician burnout, and the challenges of implementing value-based care, to name a few. You see what comes next in the TABLE.³ The good news is that there is an alternative to the “natural” progression to the ending stage: the path of renewal.³

In the lifecycle of an organization, the path of renewal starts the cycle anew, with dreaming the dream. I recently had the opportunity to visit Singapore to learn about their health system. Singapore is one of the wealthiest countries in the world. I was impressed with their many innovations, including technological ones, as well as new models of care. However, I was most impressed that the country is betting big on family medicine. Their Ministry of Health has launched an initiative they are calling Healthier SG.⁷ The goal is for “all Singaporeans to have a trusted and lifelong relationship with [their] family doctor.” Their dream is to bring personal doctoring to everyone in the country to make Singapore healthier.

While their path of renewal is occurring halfway around the world, here at home, our path of renewal has been ignited over the past several years by the work of the Robert Graham Center; the Keystone Conferences; the American Board of Family Medicine; and the National Academies of Science, Engineering, and Medicine, among others.^8-11 These organizations are aligning around re-centering on ­patient-clinician relationships, measuring what is important, care by interprofessional teams, payment reform, professionalism, health equity, improved information technology, and adherence to the best available evidence. We are working toward the solution shop as opposed to the production line.¹² We are indeed dreaming a new dream.

While I write about this renewal, I close with an ending. This is the final issue of The Journal of Family Practice. It marks the end of an era of nearly 50 years of publication. The Journal of Family Practice has left a lasting mark, providing generations of clinicians with evidence-based, practical guidance to help care for patients as well as serving as an important venue for scholarly work by the family medicine community. Although I have had the privilege of serving the discipline as an editor-in-chief for only a brief time, I am grateful I had the opportunity. Most of all, I appreciate being on the journey of family medicine with you, renewing the dream together.

The references for this Editorial are available in the online version of the article at www.mdedge.com/familymedicine.

The dream of family practice began more than 6 decades ago with a movement toward personal physicians who have “… the feeling of warm personal regard and concern of doctor for patient, the feeling that the doctor treats people, not illnesses ….” The personal family physician helps patients “… not because of the interesting medical problems they may present but because they are human beings in need of help.”¹ One of the most influential founders of family medicine, Dr. Gayle Stephens, expounded on this idea in a series of essays that tapped into the intellectual, philosophical, historical, and moral underpinnings of our discipline.²

Following the dream and the birth of family medicine—like any organization—its lifecycle can be envisioned as proceeding through the rest of the 7 stages of organizational life (TABLE).³ Now allow me to give you some numbers. There are more than 118,000 family physicians in the United States, 784 family medicine residencies filled by 4530 medical school graduates, more than 150 departments of family medicine, multiple national family medicine organizations, and even a World Organization of Family Doctors.^4,5 The American Board of Family Medicine is the second largest medical specialty board in the country. Family doctors make up nearly 40% of our total primary care workforce.⁶ We launched the venture, got organized, made it. We are an institution.

This final issue of The Journal of Family Practice marks the end of an era of nearly 50 years of publication.

The threat at the institution stage is that we are on the precipice of “closing in.” Many factors are driving this stage: commoditization in health care, market influences and competition for patients, alternative primary care models, erosion of the patient-physician relationship (partly driven by technology), narrowing scope of care, clinician burnout, and the challenges of implementing value-based care, to name a few. You see what comes next in the TABLE.³ The good news is that there is an alternative to the “natural” progression to the ending stage: the path of renewal.³

In the lifecycle of an organization, the path of renewal starts the cycle anew, with dreaming the dream. I recently had the opportunity to visit Singapore to learn about their health system. Singapore is one of the wealthiest countries in the world. I was impressed with their many innovations, including technological ones, as well as new models of care. However, I was most impressed that the country is betting big on family medicine. Their Ministry of Health has launched an initiative they are calling Healthier SG.⁷ The goal is for “all Singaporeans to have a trusted and lifelong relationship with [their] family doctor.” Their dream is to bring personal doctoring to everyone in the country to make Singapore healthier.

While their path of renewal is occurring halfway around the world, here at home, our path of renewal has been ignited over the past several years by the work of the Robert Graham Center; the Keystone Conferences; the American Board of Family Medicine; and the National Academies of Science, Engineering, and Medicine, among others.^8-11 These organizations are aligning around re-centering on ­patient-clinician relationships, measuring what is important, care by interprofessional teams, payment reform, professionalism, health equity, improved information technology, and adherence to the best available evidence. We are working toward the solution shop as opposed to the production line.¹² We are indeed dreaming a new dream.

While I write about this renewal, I close with an ending. This is the final issue of The Journal of Family Practice. It marks the end of an era of nearly 50 years of publication. The Journal of Family Practice has left a lasting mark, providing generations of clinicians with evidence-based, practical guidance to help care for patients as well as serving as an important venue for scholarly work by the family medicine community. Although I have had the privilege of serving the discipline as an editor-in-chief for only a brief time, I am grateful I had the opportunity. Most of all, I appreciate being on the journey of family medicine with you, renewing the dream together.

The references for this Editorial are available in the online version of the article at www.mdedge.com/familymedicine.

The dream of family practice began more than 6 decades ago with a movement toward personal physicians who have “… the feeling of warm personal regard and concern of doctor for patient, the feeling that the doctor treats people, not illnesses ….” The personal family physician helps patients “… not because of the interesting medical problems they may present but because they are human beings in need of help.”¹ One of the most influential founders of family medicine, Dr. Gayle Stephens, expounded on this idea in a series of essays that tapped into the intellectual, philosophical, historical, and moral underpinnings of our discipline.²

Following the dream and the birth of family medicine—like any organization—its lifecycle can be envisioned as proceeding through the rest of the 7 stages of organizational life (TABLE).³ Now allow me to give you some numbers. There are more than 118,000 family physicians in the United States, 784 family medicine residencies filled by 4530 medical school graduates, more than 150 departments of family medicine, multiple national family medicine organizations, and even a World Organization of Family Doctors.^4,5 The American Board of Family Medicine is the second largest medical specialty board in the country. Family doctors make up nearly 40% of our total primary care workforce.⁶ We launched the venture, got organized, made it. We are an institution.

This final issue of The Journal of Family Practice marks the end of an era of nearly 50 years of publication.

The threat at the institution stage is that we are on the precipice of “closing in.” Many factors are driving this stage: commoditization in health care, market influences and competition for patients, alternative primary care models, erosion of the patient-physician relationship (partly driven by technology), narrowing scope of care, clinician burnout, and the challenges of implementing value-based care, to name a few. You see what comes next in the TABLE.³ The good news is that there is an alternative to the “natural” progression to the ending stage: the path of renewal.³

In the lifecycle of an organization, the path of renewal starts the cycle anew, with dreaming the dream. I recently had the opportunity to visit Singapore to learn about their health system. Singapore is one of the wealthiest countries in the world. I was impressed with their many innovations, including technological ones, as well as new models of care. However, I was most impressed that the country is betting big on family medicine. Their Ministry of Health has launched an initiative they are calling Healthier SG.⁷ The goal is for “all Singaporeans to have a trusted and lifelong relationship with [their] family doctor.” Their dream is to bring personal doctoring to everyone in the country to make Singapore healthier.

While their path of renewal is occurring halfway around the world, here at home, our path of renewal has been ignited over the past several years by the work of the Robert Graham Center; the Keystone Conferences; the American Board of Family Medicine; and the National Academies of Science, Engineering, and Medicine, among others.^8-11 These organizations are aligning around re-centering on ­patient-clinician relationships, measuring what is important, care by interprofessional teams, payment reform, professionalism, health equity, improved information technology, and adherence to the best available evidence. We are working toward the solution shop as opposed to the production line.¹² We are indeed dreaming a new dream.

While I write about this renewal, I close with an ending. This is the final issue of The Journal of Family Practice. It marks the end of an era of nearly 50 years of publication. The Journal of Family Practice has left a lasting mark, providing generations of clinicians with evidence-based, practical guidance to help care for patients as well as serving as an important venue for scholarly work by the family medicine community. Although I have had the privilege of serving the discipline as an editor-in-chief for only a brief time, I am grateful I had the opportunity. Most of all, I appreciate being on the journey of family medicine with you, renewing the dream together.

The references for this Editorial are available in the online version of the article at www.mdedge.com/familymedicine.

THE CASE

A 55-year-old woman developed subacute progression of myalgias and subjective weakness in her proximal extremities after starting a new exercise regimen. The patient had a history of unilateral renal agenesis, type 2 diabetes, and hyperlipidemia, for which she had taken atorvastatin 40 mg/d for several years before discontinuing it 2 years earlier for unknown reasons. She had been evaluated multiple times in the primary care clinic and emergency department over the previous month. Each time, her strength was minimally reduced in the upper extremities on examination, her renal function and electrolytes were normal, and her creatine kinase (CK) level was elevated (16,000-20,000 U/L; normal range, 26-192 U/L). She was managed conservatively with fluids and given return precautions each time.

After her myalgias and weakness increased in severity, she presented to the emergency department with a muscle strength score of 4/5 in both shoulders, triceps, hip flexors, hip extensors, abductors, and adductors. Her laboratory results were significant for the presence of blood without red blood cells on her urine dipstick test and a CK level of 25,070 U/L. She was admitted for further evaluation of progressive myopathy and given aggressive IV fluid hydration to prevent renal injury based on her history of unilateral renal agenesis.

Infectious disease testing, which included a respiratory virus panel, acute hepatitis panel, HIV screening, Lyme antibody testing, cytomegalovirus DNA detection by polymerase chain reaction, Epstein-Barr virus capsid immunoglobulin M, and anti-­streptolysin O, were negative. Electrolytes, inflammatory markers, and kidney function were normal. However, high-­sensitivity troponin-T levels were elevated, with a peak value of 216.3 ng/L (normal range, 0-19 ng/L). The patient denied having any chest pain, and her electrocardiogram and transthoracic echocardiogram were normal. By hospital Day 4, her myalgias and weakness had improved, CK had stabilized (19,000-21,000 U/L), cardiac enzymes had improved, and urinalysis had normalized. She was discharged with a referral to a rheumatologist.

However, 10 days later—before she could see a rheumatologist—she was readmitted to a community hospital for recurrence of severe myalgias, progressive weakness, positive blood on urine dipstick testing, and a rising CK level (to 24,580 U/L) found during a follow-up appointment with her primary care physician. At this point, Neurology and Rheumatology were consulted and myositis-specific and ­myositis-associated autoantibody tests were sent out. Magnetic resonance imaging (MRI) of her thighs was performed and showed diffusely increased T2 signal and short tau inversion recovery in multiple proximal muscles (FIGURE).

DIAGNOSIS

Given her symmetrical proximal muscle weakness (which was refractory to IV fluid resuscitation), MRI findings, and the exclusion of infection and metabolic derangements, the patient was given a working diagnosis of myositis and treated with 1-g IV methylprednisolone followed by a 4-month steroid taper, methotrexate 20 mg weekly, and physical therapy. This working diagnosis was later confirmed with the results of her autoantibody tests.

At her 1-month follow-up visit, the ­patient reported minimal improvement in her strength, new neck weakness, and ­dysphagia with solids. Testing revealed ­anti–3-hydroxy-3-methylglutaryl-coenzyme A reductase ­(anti-HMGCR) antibody levels of more than 200 U/L (negative < 20 U/L; positive > 59 U/L), which pointed to a more refined diagnosis of anti-HMGCR immune-mediated necrotizing myositis.

DISCUSSION

Myositis should be in the differential diagnosis for patients with symmetrical proximal muscle weakness. Bohan and Peter devised a 5-part set of criteria to help diagnose myositis, shown in the TABLE.^1,2 This simple framework broadens the differential and guides diagnostic testing. Our patient’s presentation was fairly typical for anti-HMGCR myositis, a subset of immune-mediated necrotizing myositis,³ with a pretest probability of 62% per the European League Against Rheumatism/American College of Rheumatology classification criteria.² Probability of this diagnosis was further increased by the high-titer anti-HMGCR, so biopsy and electromyography (EMG), as noted by Bohan and Peter, were not pursued.

Continue to: Autoimmune myopathies...

Two-thirds of patients with anti-HMGCR myositis report current or prior statin use, and this increases to more than 90% in those age 50 years or older.

Autoimmune myopathies occur in 9 to 14 per 100,000 people,⁴ with6% of patients having anti-HMGCR auto-antibodies.⁵ Anti-HMGCR myositis is more prevalent in older women, patients with type 2 diabetes, and those with a history of atorvastatin use.^3,6 Two-thirds of patients with anti-HMGCR myositis report current or prior statin use, and this increases to more than 90% in those age 50 years or older.⁵ Anti-HMGCR myositis causes significant muscle weakness that does not resolve with discontinuation of the statin and can occur years after the initiation or discontinuation of statin treatment.⁶ Cardiac involvement is rare⁴ but dysphagia is relatively common.^7,8 Anti-HMGCR myositis also has a weak association with cancer, most commonly gastrointestinal and lung cancers.^4,7

Distinguishing statin-induced myalgias from statin-induced myositis guides management. Statin-induced myalgias are associated with normal or slightly increased CK levels (typically < 1000 U/L) and resolve with discontinuation of the statin; the patient can often tolerate re-challenge with a statin.⁶ In contrast, CK elevation in patients with statin-induced myositis is typically more than 10,000 U/L⁶ and requires aggressive treatment with immunomodulatory medications to prevent permanent muscle damage.

Treatment recommendations are supported only by case series, observational studies, and expert opinion. Typical first-line treatment includes induction with high-dose corticosteroids followed by prolonged taper plus a conventional synthetic disease-­modifying antirheumatic drug (csDMARD) such as methotrexate, azathioprine, or mycophenolate.⁴ Maintenance therapy often is achieved with csDMARD therapy for 2 years.⁴ Severe cases frequently are treated with combination csDMARD therapy (eg, methotrexate and azathioprine or methotrexate and mycophenolate).⁴ Rituximab and IV immunoglobulin (IVIG) are typically reserved for refractory cases.⁶ Usual monitoring for relapse includes muscle strength testing on examination and evaluation of trending CK levels.⁸

Our patient received monthly 2-g/kg IVIG infusions, which led to slow, consistent improvement in her strength and normalization of her CK levels to 181 U/L after 6 months.

THE TAKEAWAY

Anti-HMGCR myositis should be suspected in any patient currently or previously treated with a statin who presents with proximal muscle weakness, myalgias, or an elevated CK level. We suggest early subspecialty consultation to discuss whether antibody testing, EMG, or muscle biopsy are warranted. If anti-HMGCR myositis is confirmed, it is advisable to rule out comorbid malignancy and initiate early combination treatment to minimize relapses and permanent muscle damage.

CORRESPONDENCE
Daniel T. Schoenherr, MD, Family Medicine Residency, National Capital Consortium–Alexander T. Augusta Military Medical Center, 9300 DeWitt Loop, Fort Belvoir, VA 22060; [email protected]

THE CASE

A 55-year-old woman developed subacute progression of myalgias and subjective weakness in her proximal extremities after starting a new exercise regimen. The patient had a history of unilateral renal agenesis, type 2 diabetes, and hyperlipidemia, for which she had taken atorvastatin 40 mg/d for several years before discontinuing it 2 years earlier for unknown reasons. She had been evaluated multiple times in the primary care clinic and emergency department over the previous month. Each time, her strength was minimally reduced in the upper extremities on examination, her renal function and electrolytes were normal, and her creatine kinase (CK) level was elevated (16,000-20,000 U/L; normal range, 26-192 U/L). She was managed conservatively with fluids and given return precautions each time.

After her myalgias and weakness increased in severity, she presented to the emergency department with a muscle strength score of 4/5 in both shoulders, triceps, hip flexors, hip extensors, abductors, and adductors. Her laboratory results were significant for the presence of blood without red blood cells on her urine dipstick test and a CK level of 25,070 U/L. She was admitted for further evaluation of progressive myopathy and given aggressive IV fluid hydration to prevent renal injury based on her history of unilateral renal agenesis.

Infectious disease testing, which included a respiratory virus panel, acute hepatitis panel, HIV screening, Lyme antibody testing, cytomegalovirus DNA detection by polymerase chain reaction, Epstein-Barr virus capsid immunoglobulin M, and anti-­streptolysin O, were negative. Electrolytes, inflammatory markers, and kidney function were normal. However, high-­sensitivity troponin-T levels were elevated, with a peak value of 216.3 ng/L (normal range, 0-19 ng/L). The patient denied having any chest pain, and her electrocardiogram and transthoracic echocardiogram were normal. By hospital Day 4, her myalgias and weakness had improved, CK had stabilized (19,000-21,000 U/L), cardiac enzymes had improved, and urinalysis had normalized. She was discharged with a referral to a rheumatologist.

However, 10 days later—before she could see a rheumatologist—she was readmitted to a community hospital for recurrence of severe myalgias, progressive weakness, positive blood on urine dipstick testing, and a rising CK level (to 24,580 U/L) found during a follow-up appointment with her primary care physician. At this point, Neurology and Rheumatology were consulted and myositis-specific and ­myositis-associated autoantibody tests were sent out. Magnetic resonance imaging (MRI) of her thighs was performed and showed diffusely increased T2 signal and short tau inversion recovery in multiple proximal muscles (FIGURE).

DIAGNOSIS

Given her symmetrical proximal muscle weakness (which was refractory to IV fluid resuscitation), MRI findings, and the exclusion of infection and metabolic derangements, the patient was given a working diagnosis of myositis and treated with 1-g IV methylprednisolone followed by a 4-month steroid taper, methotrexate 20 mg weekly, and physical therapy. This working diagnosis was later confirmed with the results of her autoantibody tests.

At her 1-month follow-up visit, the ­patient reported minimal improvement in her strength, new neck weakness, and ­dysphagia with solids. Testing revealed ­anti–3-hydroxy-3-methylglutaryl-coenzyme A reductase ­(anti-HMGCR) antibody levels of more than 200 U/L (negative < 20 U/L; positive > 59 U/L), which pointed to a more refined diagnosis of anti-HMGCR immune-mediated necrotizing myositis.

DISCUSSION

Myositis should be in the differential diagnosis for patients with symmetrical proximal muscle weakness. Bohan and Peter devised a 5-part set of criteria to help diagnose myositis, shown in the TABLE.^1,2 This simple framework broadens the differential and guides diagnostic testing. Our patient’s presentation was fairly typical for anti-HMGCR myositis, a subset of immune-mediated necrotizing myositis,³ with a pretest probability of 62% per the European League Against Rheumatism/American College of Rheumatology classification criteria.² Probability of this diagnosis was further increased by the high-titer anti-HMGCR, so biopsy and electromyography (EMG), as noted by Bohan and Peter, were not pursued.

Continue to: Autoimmune myopathies...

Two-thirds of patients with anti-HMGCR myositis report current or prior statin use, and this increases to more than 90% in those age 50 years or older.

Autoimmune myopathies occur in 9 to 14 per 100,000 people,⁴ with6% of patients having anti-HMGCR auto-antibodies.⁵ Anti-HMGCR myositis is more prevalent in older women, patients with type 2 diabetes, and those with a history of atorvastatin use.^3,6 Two-thirds of patients with anti-HMGCR myositis report current or prior statin use, and this increases to more than 90% in those age 50 years or older.⁵ Anti-HMGCR myositis causes significant muscle weakness that does not resolve with discontinuation of the statin and can occur years after the initiation or discontinuation of statin treatment.⁶ Cardiac involvement is rare⁴ but dysphagia is relatively common.^7,8 Anti-HMGCR myositis also has a weak association with cancer, most commonly gastrointestinal and lung cancers.^4,7

Distinguishing statin-induced myalgias from statin-induced myositis guides management. Statin-induced myalgias are associated with normal or slightly increased CK levels (typically < 1000 U/L) and resolve with discontinuation of the statin; the patient can often tolerate re-challenge with a statin.⁶ In contrast, CK elevation in patients with statin-induced myositis is typically more than 10,000 U/L⁶ and requires aggressive treatment with immunomodulatory medications to prevent permanent muscle damage.

Treatment recommendations are supported only by case series, observational studies, and expert opinion. Typical first-line treatment includes induction with high-dose corticosteroids followed by prolonged taper plus a conventional synthetic disease-­modifying antirheumatic drug (csDMARD) such as methotrexate, azathioprine, or mycophenolate.⁴ Maintenance therapy often is achieved with csDMARD therapy for 2 years.⁴ Severe cases frequently are treated with combination csDMARD therapy (eg, methotrexate and azathioprine or methotrexate and mycophenolate).⁴ Rituximab and IV immunoglobulin (IVIG) are typically reserved for refractory cases.⁶ Usual monitoring for relapse includes muscle strength testing on examination and evaluation of trending CK levels.⁸

Our patient received monthly 2-g/kg IVIG infusions, which led to slow, consistent improvement in her strength and normalization of her CK levels to 181 U/L after 6 months.

THE TAKEAWAY

Anti-HMGCR myositis should be suspected in any patient currently or previously treated with a statin who presents with proximal muscle weakness, myalgias, or an elevated CK level. We suggest early subspecialty consultation to discuss whether antibody testing, EMG, or muscle biopsy are warranted. If anti-HMGCR myositis is confirmed, it is advisable to rule out comorbid malignancy and initiate early combination treatment to minimize relapses and permanent muscle damage.

CORRESPONDENCE
Daniel T. Schoenherr, MD, Family Medicine Residency, National Capital Consortium–Alexander T. Augusta Military Medical Center, 9300 DeWitt Loop, Fort Belvoir, VA 22060; [email protected]

THE CASE

A 55-year-old woman developed subacute progression of myalgias and subjective weakness in her proximal extremities after starting a new exercise regimen. The patient had a history of unilateral renal agenesis, type 2 diabetes, and hyperlipidemia, for which she had taken atorvastatin 40 mg/d for several years before discontinuing it 2 years earlier for unknown reasons. She had been evaluated multiple times in the primary care clinic and emergency department over the previous month. Each time, her strength was minimally reduced in the upper extremities on examination, her renal function and electrolytes were normal, and her creatine kinase (CK) level was elevated (16,000-20,000 U/L; normal range, 26-192 U/L). She was managed conservatively with fluids and given return precautions each time.

After her myalgias and weakness increased in severity, she presented to the emergency department with a muscle strength score of 4/5 in both shoulders, triceps, hip flexors, hip extensors, abductors, and adductors. Her laboratory results were significant for the presence of blood without red blood cells on her urine dipstick test and a CK level of 25,070 U/L. She was admitted for further evaluation of progressive myopathy and given aggressive IV fluid hydration to prevent renal injury based on her history of unilateral renal agenesis.

Infectious disease testing, which included a respiratory virus panel, acute hepatitis panel, HIV screening, Lyme antibody testing, cytomegalovirus DNA detection by polymerase chain reaction, Epstein-Barr virus capsid immunoglobulin M, and anti-­streptolysin O, were negative. Electrolytes, inflammatory markers, and kidney function were normal. However, high-­sensitivity troponin-T levels were elevated, with a peak value of 216.3 ng/L (normal range, 0-19 ng/L). The patient denied having any chest pain, and her electrocardiogram and transthoracic echocardiogram were normal. By hospital Day 4, her myalgias and weakness had improved, CK had stabilized (19,000-21,000 U/L), cardiac enzymes had improved, and urinalysis had normalized. She was discharged with a referral to a rheumatologist.

However, 10 days later—before she could see a rheumatologist—she was readmitted to a community hospital for recurrence of severe myalgias, progressive weakness, positive blood on urine dipstick testing, and a rising CK level (to 24,580 U/L) found during a follow-up appointment with her primary care physician. At this point, Neurology and Rheumatology were consulted and myositis-specific and ­myositis-associated autoantibody tests were sent out. Magnetic resonance imaging (MRI) of her thighs was performed and showed diffusely increased T2 signal and short tau inversion recovery in multiple proximal muscles (FIGURE).