CASE Paranoia, ataxia
Ms. S, age 46, is admitted to the hospital for cellulitis and gait disturbance. She has been living in her car for the past week and presents to the local fire department to get help for housing. She is referred to this hospital where she was found to have cellulitis in her buttock secondary to urinary and fecal incontinence. She also was noted to have difficulty ambulating and a wide-based gait. Two weeks earlier, a hotel clerk found her on the floor, unable to get up. Ms. S was seen in a local emergency room (ER) and discharged after her glucose level was found to be normal.

At admission, she has an intact sensorium and is described as disheveled, illogical, rambling, and paranoid. Her mental status exam shows she is alert and oriented to person and time, with guarded and childlike behavior. Her affect/mood is irritable and oddly related, and her thought processes are concrete and simple with some thought-blocking and paranoid content. She denies thoughts of harming herself or others, and her insight is limited and judgment is poor.

Neurology is consulted to evaluate her gait disturbance. Ms. S has decreased muscle bulk in both calves, with brisk knee reflexes bilaterally. CT imaging shows nonspecific scattered periventricular white matter hypodensities consistent with microvascular ischemic diagnosis, but a demyelinating process could not be ruled out. Ms. S reports that the gait disturbance began in childhood, and that her grandmother had the same gait disturbance. Neurology recommends an electromyogram and MRI.

During her stay in the hospital, she is unwilling to cooperate with exams, declines to answer questions regarding her past, and appears suspicious of her acute care treatment team. The psychiatric team is consulted for evaluation of her paranoia and “seeming disorganization,” and she is transferred to the psychiatric unit. She appears to be repulsed by the fact that she was in a psychiatric ward stating, “I don’t belong here” and “I’m scared of the other people here.” She denies any psychiatric history, previous hospitalizations, or substance use, and no documentation of inpatient or outpatient care was found in the county’s computerized record system. Although she is willing to take a small dose of tranquilizer (eg, lorazepam) she refuses to take antipsychotic medications saying, “My mother told me not to take [antipsychotics]. I’m not psychotic.”

What is your diagnosis at this point?

a) normal pressure hydrocephalus
b) Charcot-Marie-Tooth disease
c) schizophrenia spectrum disorder
d) multiple sclerosis (MS)
e) vascular dementia
f) cord lesion compression

The authors’ observations

The neurology team initially suspected Charcot-Marie-Tooth disease because her clinical presentation included pes cavus, distal lower extremity weakness, and lower extremity muscle atrophy with a self-reported family history of similar gait disturbance, all of which are consistent with Charcot-Marie-Tooth disease.

Subcortical syndrome—a feature of vascular dementia—is characterized by focal motor deficits, gait disturbance, history of unsteadiness with frequent falls, urinary symptoms, personality and mood changes, and cognitive dysfunction.^1-3 Subcortical syndrome is caused by chronic ischemia and lacunar infarctions that affect cerebral nuclei and white matter pathways.¹ On imaging, subcortical vascular dementia is characterized by leukoaraiosis, which are hypointense spherical-like lesions on CT and hyperintense lesions in periventricular areas on T2 MRI.⁴

Although normal pressure hydrocephalus could be suspected given her clinical presentation of the Hakim-Adams triad (ie,“wacky, wobbly, and wet”), her head CT did not show any changes consistent with this condition.

Her clinical presentation does not align with schizophrenia spectrum disorder because of her history of higher functioning, acute later onset, and the absence of hallucinations, fixed delusions, or markedly disorganized speech. Although she is paranoid of her surroundings, her delusions were ill-formed. A cord lesion compression cannot be ruled out, and MRI is required urgently.

HISTORY High functioning

When asked, Ms. S states that she was admitted to the hospital because “someone who looked like a fake police officer [a member of the fire department] told me it was nice here.” She indicates that she initially thought it would be a nice place to live temporarily but later regretted coming after realizing that she was in a psychiatry unit. Available documentation from her recent hospitalization indicated that she was living in a motel on her own. Ms. S says that she works as an actress and has had minor roles in famous movies. She says that she studied at a well-known performance arts school and that her parents are famous musicians; however, she refuses to identify her parents or give permission to contact them—or any other collateral informant—because she is embarrassed about her current situation stating, “They would never believe it.”

During this interview, Ms. S appears confused as well as disorganized—which was a challenge to clearly delineate—disheveled, and guarded with hypoverbal and hypophonic speech. Her thought process is circumstantial, and she seems to be confabulating. She denies visual or auditory hallucinations but appears paranoid and states that she thinks we are experimenting on her. Except for the neurological exam, the rest of her physical exam is within normal limits. Urine toxicology screen and labs are negative except for a positive antinuclear antibody homogenous pattern with a titer of 1:640; B₁₂ vitamin levels are not tested.

MRI is ordered, however, she does not consent to the scan saying, “It’s creepy, I don’t want people looking at my brain.” The team makes several attempts to encourage her for consent but she refuses. Because of the clinical urgency (ie, possible cord compression) and her refusal to provide a surrogate decision maker, the team felt the situation is urgent, confirmed by 2 physicians, which led them to perform the MRI on an emergent basis. The MRI reveals multiple periventricular, juxtacortical, infratentorial, and likely cervical spinal cord T2 hyperintense lesions (Figure).

What would be your differential diagnosis at this time?

a) acute disseminated encephalomyelitis (ADEM)
b) systemic lupus erythematous
c) multiple sclerosis
d) vascular dementia
e) vitamin B deficiency

The authors’ observations

Psychosis in the presence of white matter demyelination could be associated with autoimmune, vascular, or nutritional disturbances. Deficiencies in vitamins B6, 9, and 12 (pyridoxine, folate, cobalamin) have been shown to cause neuropsychiatric symptoms and white matter lesions.⁵ Low levels of vitamins B6, 9, and 12 are associated with elevated homocysteine, which can cause small vessel ischemia leading to white matter lesions similar to changes seen in vascular dementia.⁵ The exact pathophysiology of ADEM is unclear, however, it is thought that after an infection, antiviral antibodies cross react with autoantigens on myelin causing an autoimmune demyelinating disease. Another hypothesized mechanism is that circulating immune complexes and humoral factors increase vascular permeability and inflammation thereby opening the blood–brain barrier. Once it is open, cells such as lymphocytes, phagocytes, and microglia cause gliosis and demyelination. Case reports have described ADEM associated with psychotic features.⁶

Likewise, systemic lupus erythematous has been associated with psychosis and neuropsychiatric symptoms in 14% to 75% of patients. Of these patients, 40% will experience neuropsychiatric symptoms before onset of lupus symptoms.⁷ One study found the most common MRI finding in neuropsychiatric systemic lupus erythematous was leukoaraiosis, which appeared in 57.1% of patients.⁸ 
Ms. S’s MRI results strongly suggest a diagnosis of MS.

EVALUATION Questionable story

Ms. S appears delusional and grandiose when she meets with the psychiatry team. She states that before her hospitalization, she was an actress and could ambulate, rent a motel room, and drive a car without assistance. However, during the examination, she cannot walk without 2 staff members for support, and overall her self-reported history sounds questionable. There were several pieces of evidence that corroborate portions of her story: (1) a screen actors guild card was found among personal belongings; (2) she was transported to the ER from a local motel; (3) she had recently visited another hospital and, at that time, was deemed stable enough to be discharged.

On the Montreal Cognitive Assessment (MoCA) Ms. S scored 19/30, with deficits mainly in executive/visuospatial and delayed recall memory. An alternate form of the MoCA is administered 1 day later, and she scores 20/30 with similar deficits. After obtaining medication consent, she is given risperidone, up to 2 mg/d, and becomes more cooperative with the treatment team.

The authors’ observations

Approximately 40% to 65% of MS patients experience cognitive impairment.⁹ Cognitive dysfunction in a depressed patient with MS might appear as pseudo-dementia, but other possible diagnoses include:

• true dementia
• encephalitis or infection
• medication- or substance-induced.

White matter demyelination is associated with subcortical dementia, which is characterized by slowness of information processing, forgetfulness, apathy, depression, and impaired cognition. According to meta-analyses, the most prominent neuropsychological deficits in MS are found in the areas of verbal fluency, information processing speed, working memory, and long-term memory.¹⁰ Relapsing-remitting type MS patients generally have less cognitive impairment than those with the chronic progressive type of the disease.

EVALUATION Cognitive deficits

Because of her acute condition and resistance to the evaluation, a modified screening neuropsychological battery is used. During the evaluation Ms. S is guarded and demonstrates paucity of speech; her responses are odd at times or contain word-substitution errors. Hand stiffness, tremor, and imprecision are noted during writing and drawing. Results of testing indicate average-range premorbid intellectual ability, with impairments in memory and information processing speed and a mild weakness in phonemic verbal fluency. Ms. S endorses statements reflecting paranoia and hostility on a self-report measure of emotional and personality functioning, consistent with her behavioral presentation. However, her responses on other subscales, including depression and psychotic symptoms, are within normal limits. Her cognitive deficits would be unusual if she had a psychiatric illness alone and are likely associated with her positive neuroimaging findings that suggest a demyelinating process. Overall, the results of the evaluation support a MS diagnosis.

The authors’ observations
Psychosis is found at a higher rate among MS patients (2% to 3%) than the general population (0.5% to 1%).⁹ Although rare, psychosis often can cloud the diagnosis of MS. Psychiatric symptoms that can occur in MS include:

• hallucinations and delusions (>50%)
• irritability and agitation (20%)
• grandiosity (15%)
• confusion, blunted affect, flight of ideas, depression, reduced self-care, and pressured speech (10%).¹¹

A review of 10 studies found that depression was the most prevalent symptom in MS, and that schizophrenia occurred in up to 7% of MS patients.¹² There are currently 3 theories about the relationship between psychosis and MS:

• MS and psychosis are thought to share the same pathophysiological process.
• Psychotic symptoms arise from regional demyelination simultaneously with MS.
• Psychosis is caused by medical treatment of MS.⁹

Other causes of psychiatric symptoms in MS include:

• depression associated with brain atrophy and lesions
• depression and anxiety as a result of chronic illness
• depression resulting from inflammatory changes
• corticosteroid treatment causing depression, mania, or psychosis.¹²

The link between psychosis and MS is still poorly understood and further investigation is needed.

How would you treat Ms. S?

a) haloperidol
b) risperidone
c) corticosteroids
d) selective serotonin reuptake inhibitors

Treating psychiatric symptoms in the context of MS

The literature, mainly case reports, suggests several treatment modalities for psychosis with MS. Clozapine has been shown to be beneficial in several case reports, and risperidone⁹ and ziprasidone¹³ also have been effective. Other studies recommended low-dose chlorpromazine.⁹

For MS patients with cognitive impairment, one study showed that interferon beta-1b (IFN-1b) treatment resulted in significant improvement in concentration, attention, visual learning, and recall after 1 year compared with control patients.⁹ However, there are also case reports of IFN-1b and glucocorticoid-induced psychosis in patients, which resolved after discontinuing treatment.⁹

Psychotic symptoms have been shown to resolve after corticosteroid treatment of MS.¹⁴ In another case report, mania and delusions subsided 3 days after IV methylprednisolone, whereas risperidone had no effect on psychotic features. However, it was unclear whether risperidone was discontinued when methylprednisolone was administered, therefore the specific effect of methylprednisolone is difficult to discern.¹⁵ Finally, in a case of a patient who has chronic MS for 16 years and presented with acute onset paranoid psychosis, symptoms resolved with aripiprazole, 10 to 20 mg/d.¹⁶ Because of the limited utility of case reports, there is a need for further research in medical management of psychiatric symptoms in MS.

CASE Paranoia, ataxia
Ms. S, age 46, is admitted to the hospital for cellulitis and gait disturbance. She has been living in her car for the past week and presents to the local fire department to get help for housing. She is referred to this hospital where she was found to have cellulitis in her buttock secondary to urinary and fecal incontinence. She also was noted to have difficulty ambulating and a wide-based gait. Two weeks earlier, a hotel clerk found her on the floor, unable to get up. Ms. S was seen in a local emergency room (ER) and discharged after her glucose level was found to be normal.

At admission, she has an intact sensorium and is described as disheveled, illogical, rambling, and paranoid. Her mental status exam shows she is alert and oriented to person and time, with guarded and childlike behavior. Her affect/mood is irritable and oddly related, and her thought processes are concrete and simple with some thought-blocking and paranoid content. She denies thoughts of harming herself or others, and her insight is limited and judgment is poor.

Neurology is consulted to evaluate her gait disturbance. Ms. S has decreased muscle bulk in both calves, with brisk knee reflexes bilaterally. CT imaging shows nonspecific scattered periventricular white matter hypodensities consistent with microvascular ischemic diagnosis, but a demyelinating process could not be ruled out. Ms. S reports that the gait disturbance began in childhood, and that her grandmother had the same gait disturbance. Neurology recommends an electromyogram and MRI.

During her stay in the hospital, she is unwilling to cooperate with exams, declines to answer questions regarding her past, and appears suspicious of her acute care treatment team. The psychiatric team is consulted for evaluation of her paranoia and “seeming disorganization,” and she is transferred to the psychiatric unit. She appears to be repulsed by the fact that she was in a psychiatric ward stating, “I don’t belong here” and “I’m scared of the other people here.” She denies any psychiatric history, previous hospitalizations, or substance use, and no documentation of inpatient or outpatient care was found in the county’s computerized record system. Although she is willing to take a small dose of tranquilizer (eg, lorazepam) she refuses to take antipsychotic medications saying, “My mother told me not to take [antipsychotics]. I’m not psychotic.”

What is your diagnosis at this point?

a) normal pressure hydrocephalus
b) Charcot-Marie-Tooth disease
c) schizophrenia spectrum disorder
d) multiple sclerosis (MS)
e) vascular dementia
f) cord lesion compression

The authors’ observations

The neurology team initially suspected Charcot-Marie-Tooth disease because her clinical presentation included pes cavus, distal lower extremity weakness, and lower extremity muscle atrophy with a self-reported family history of similar gait disturbance, all of which are consistent with Charcot-Marie-Tooth disease.

Subcortical syndrome—a feature of vascular dementia—is characterized by focal motor deficits, gait disturbance, history of unsteadiness with frequent falls, urinary symptoms, personality and mood changes, and cognitive dysfunction.^1-3 Subcortical syndrome is caused by chronic ischemia and lacunar infarctions that affect cerebral nuclei and white matter pathways.¹ On imaging, subcortical vascular dementia is characterized by leukoaraiosis, which are hypointense spherical-like lesions on CT and hyperintense lesions in periventricular areas on T2 MRI.⁴

Although normal pressure hydrocephalus could be suspected given her clinical presentation of the Hakim-Adams triad (ie,“wacky, wobbly, and wet”), her head CT did not show any changes consistent with this condition.

Her clinical presentation does not align with schizophrenia spectrum disorder because of her history of higher functioning, acute later onset, and the absence of hallucinations, fixed delusions, or markedly disorganized speech. Although she is paranoid of her surroundings, her delusions were ill-formed. A cord lesion compression cannot be ruled out, and MRI is required urgently.

HISTORY High functioning

When asked, Ms. S states that she was admitted to the hospital because “someone who looked like a fake police officer [a member of the fire department] told me it was nice here.” She indicates that she initially thought it would be a nice place to live temporarily but later regretted coming after realizing that she was in a psychiatry unit. Available documentation from her recent hospitalization indicated that she was living in a motel on her own. Ms. S says that she works as an actress and has had minor roles in famous movies. She says that she studied at a well-known performance arts school and that her parents are famous musicians; however, she refuses to identify her parents or give permission to contact them—or any other collateral informant—because she is embarrassed about her current situation stating, “They would never believe it.”

During this interview, Ms. S appears confused as well as disorganized—which was a challenge to clearly delineate—disheveled, and guarded with hypoverbal and hypophonic speech. Her thought process is circumstantial, and she seems to be confabulating. She denies visual or auditory hallucinations but appears paranoid and states that she thinks we are experimenting on her. Except for the neurological exam, the rest of her physical exam is within normal limits. Urine toxicology screen and labs are negative except for a positive antinuclear antibody homogenous pattern with a titer of 1:640; B₁₂ vitamin levels are not tested.

MRI is ordered, however, she does not consent to the scan saying, “It’s creepy, I don’t want people looking at my brain.” The team makes several attempts to encourage her for consent but she refuses. Because of the clinical urgency (ie, possible cord compression) and her refusal to provide a surrogate decision maker, the team felt the situation is urgent, confirmed by 2 physicians, which led them to perform the MRI on an emergent basis. The MRI reveals multiple periventricular, juxtacortical, infratentorial, and likely cervical spinal cord T2 hyperintense lesions (Figure).

What would be your differential diagnosis at this time?

a) acute disseminated encephalomyelitis (ADEM)
b) systemic lupus erythematous
c) multiple sclerosis
d) vascular dementia
e) vitamin B deficiency

The authors’ observations

Psychosis in the presence of white matter demyelination could be associated with autoimmune, vascular, or nutritional disturbances. Deficiencies in vitamins B6, 9, and 12 (pyridoxine, folate, cobalamin) have been shown to cause neuropsychiatric symptoms and white matter lesions.⁵ Low levels of vitamins B6, 9, and 12 are associated with elevated homocysteine, which can cause small vessel ischemia leading to white matter lesions similar to changes seen in vascular dementia.⁵ The exact pathophysiology of ADEM is unclear, however, it is thought that after an infection, antiviral antibodies cross react with autoantigens on myelin causing an autoimmune demyelinating disease. Another hypothesized mechanism is that circulating immune complexes and humoral factors increase vascular permeability and inflammation thereby opening the blood–brain barrier. Once it is open, cells such as lymphocytes, phagocytes, and microglia cause gliosis and demyelination. Case reports have described ADEM associated with psychotic features.⁶

Likewise, systemic lupus erythematous has been associated with psychosis and neuropsychiatric symptoms in 14% to 75% of patients. Of these patients, 40% will experience neuropsychiatric symptoms before onset of lupus symptoms.⁷ One study found the most common MRI finding in neuropsychiatric systemic lupus erythematous was leukoaraiosis, which appeared in 57.1% of patients.⁸ 
Ms. S’s MRI results strongly suggest a diagnosis of MS.

EVALUATION Questionable story

Ms. S appears delusional and grandiose when she meets with the psychiatry team. She states that before her hospitalization, she was an actress and could ambulate, rent a motel room, and drive a car without assistance. However, during the examination, she cannot walk without 2 staff members for support, and overall her self-reported history sounds questionable. There were several pieces of evidence that corroborate portions of her story: (1) a screen actors guild card was found among personal belongings; (2) she was transported to the ER from a local motel; (3) she had recently visited another hospital and, at that time, was deemed stable enough to be discharged.

On the Montreal Cognitive Assessment (MoCA) Ms. S scored 19/30, with deficits mainly in executive/visuospatial and delayed recall memory. An alternate form of the MoCA is administered 1 day later, and she scores 20/30 with similar deficits. After obtaining medication consent, she is given risperidone, up to 2 mg/d, and becomes more cooperative with the treatment team.

The authors’ observations

Approximately 40% to 65% of MS patients experience cognitive impairment.⁹ Cognitive dysfunction in a depressed patient with MS might appear as pseudo-dementia, but other possible diagnoses include:

• true dementia
• encephalitis or infection
• medication- or substance-induced.

White matter demyelination is associated with subcortical dementia, which is characterized by slowness of information processing, forgetfulness, apathy, depression, and impaired cognition. According to meta-analyses, the most prominent neuropsychological deficits in MS are found in the areas of verbal fluency, information processing speed, working memory, and long-term memory.¹⁰ Relapsing-remitting type MS patients generally have less cognitive impairment than those with the chronic progressive type of the disease.

EVALUATION Cognitive deficits

Because of her acute condition and resistance to the evaluation, a modified screening neuropsychological battery is used. During the evaluation Ms. S is guarded and demonstrates paucity of speech; her responses are odd at times or contain word-substitution errors. Hand stiffness, tremor, and imprecision are noted during writing and drawing. Results of testing indicate average-range premorbid intellectual ability, with impairments in memory and information processing speed and a mild weakness in phonemic verbal fluency. Ms. S endorses statements reflecting paranoia and hostility on a self-report measure of emotional and personality functioning, consistent with her behavioral presentation. However, her responses on other subscales, including depression and psychotic symptoms, are within normal limits. Her cognitive deficits would be unusual if she had a psychiatric illness alone and are likely associated with her positive neuroimaging findings that suggest a demyelinating process. Overall, the results of the evaluation support a MS diagnosis.

The authors’ observations
Psychosis is found at a higher rate among MS patients (2% to 3%) than the general population (0.5% to 1%).⁹ Although rare, psychosis often can cloud the diagnosis of MS. Psychiatric symptoms that can occur in MS include:

• hallucinations and delusions (>50%)
• irritability and agitation (20%)
• grandiosity (15%)
• confusion, blunted affect, flight of ideas, depression, reduced self-care, and pressured speech (10%).¹¹

A review of 10 studies found that depression was the most prevalent symptom in MS, and that schizophrenia occurred in up to 7% of MS patients.¹² There are currently 3 theories about the relationship between psychosis and MS:

• MS and psychosis are thought to share the same pathophysiological process.
• Psychotic symptoms arise from regional demyelination simultaneously with MS.
• Psychosis is caused by medical treatment of MS.⁹

Other causes of psychiatric symptoms in MS include:

• depression associated with brain atrophy and lesions
• depression and anxiety as a result of chronic illness
• depression resulting from inflammatory changes
• corticosteroid treatment causing depression, mania, or psychosis.¹²

The link between psychosis and MS is still poorly understood and further investigation is needed.

How would you treat Ms. S?

a) haloperidol
b) risperidone
c) corticosteroids
d) selective serotonin reuptake inhibitors

Treating psychiatric symptoms in the context of MS

The literature, mainly case reports, suggests several treatment modalities for psychosis with MS. Clozapine has been shown to be beneficial in several case reports, and risperidone⁹ and ziprasidone¹³ also have been effective. Other studies recommended low-dose chlorpromazine.⁹

For MS patients with cognitive impairment, one study showed that interferon beta-1b (IFN-1b) treatment resulted in significant improvement in concentration, attention, visual learning, and recall after 1 year compared with control patients.⁹ However, there are also case reports of IFN-1b and glucocorticoid-induced psychosis in patients, which resolved after discontinuing treatment.⁹

Psychotic symptoms have been shown to resolve after corticosteroid treatment of MS.¹⁴ In another case report, mania and delusions subsided 3 days after IV methylprednisolone, whereas risperidone had no effect on psychotic features. However, it was unclear whether risperidone was discontinued when methylprednisolone was administered, therefore the specific effect of methylprednisolone is difficult to discern.¹⁵ Finally, in a case of a patient who has chronic MS for 16 years and presented with acute onset paranoid psychosis, symptoms resolved with aripiprazole, 10 to 20 mg/d.¹⁶ Because of the limited utility of case reports, there is a need for further research in medical management of psychiatric symptoms in MS.

CASE Paranoia, ataxia
Ms. S, age 46, is admitted to the hospital for cellulitis and gait disturbance. She has been living in her car for the past week and presents to the local fire department to get help for housing. She is referred to this hospital where she was found to have cellulitis in her buttock secondary to urinary and fecal incontinence. She also was noted to have difficulty ambulating and a wide-based gait. Two weeks earlier, a hotel clerk found her on the floor, unable to get up. Ms. S was seen in a local emergency room (ER) and discharged after her glucose level was found to be normal.

At admission, she has an intact sensorium and is described as disheveled, illogical, rambling, and paranoid. Her mental status exam shows she is alert and oriented to person and time, with guarded and childlike behavior. Her affect/mood is irritable and oddly related, and her thought processes are concrete and simple with some thought-blocking and paranoid content. She denies thoughts of harming herself or others, and her insight is limited and judgment is poor.

Neurology is consulted to evaluate her gait disturbance. Ms. S has decreased muscle bulk in both calves, with brisk knee reflexes bilaterally. CT imaging shows nonspecific scattered periventricular white matter hypodensities consistent with microvascular ischemic diagnosis, but a demyelinating process could not be ruled out. Ms. S reports that the gait disturbance began in childhood, and that her grandmother had the same gait disturbance. Neurology recommends an electromyogram and MRI.

During her stay in the hospital, she is unwilling to cooperate with exams, declines to answer questions regarding her past, and appears suspicious of her acute care treatment team. The psychiatric team is consulted for evaluation of her paranoia and “seeming disorganization,” and she is transferred to the psychiatric unit. She appears to be repulsed by the fact that she was in a psychiatric ward stating, “I don’t belong here” and “I’m scared of the other people here.” She denies any psychiatric history, previous hospitalizations, or substance use, and no documentation of inpatient or outpatient care was found in the county’s computerized record system. Although she is willing to take a small dose of tranquilizer (eg, lorazepam) she refuses to take antipsychotic medications saying, “My mother told me not to take [antipsychotics]. I’m not psychotic.”

What is your diagnosis at this point?

a) normal pressure hydrocephalus
b) Charcot-Marie-Tooth disease
c) schizophrenia spectrum disorder
d) multiple sclerosis (MS)
e) vascular dementia
f) cord lesion compression

The authors’ observations

The neurology team initially suspected Charcot-Marie-Tooth disease because her clinical presentation included pes cavus, distal lower extremity weakness, and lower extremity muscle atrophy with a self-reported family history of similar gait disturbance, all of which are consistent with Charcot-Marie-Tooth disease.

Subcortical syndrome—a feature of vascular dementia—is characterized by focal motor deficits, gait disturbance, history of unsteadiness with frequent falls, urinary symptoms, personality and mood changes, and cognitive dysfunction.^1-3 Subcortical syndrome is caused by chronic ischemia and lacunar infarctions that affect cerebral nuclei and white matter pathways.¹ On imaging, subcortical vascular dementia is characterized by leukoaraiosis, which are hypointense spherical-like lesions on CT and hyperintense lesions in periventricular areas on T2 MRI.⁴

Although normal pressure hydrocephalus could be suspected given her clinical presentation of the Hakim-Adams triad (ie,“wacky, wobbly, and wet”), her head CT did not show any changes consistent with this condition.

Her clinical presentation does not align with schizophrenia spectrum disorder because of her history of higher functioning, acute later onset, and the absence of hallucinations, fixed delusions, or markedly disorganized speech. Although she is paranoid of her surroundings, her delusions were ill-formed. A cord lesion compression cannot be ruled out, and MRI is required urgently.

HISTORY High functioning

When asked, Ms. S states that she was admitted to the hospital because “someone who looked like a fake police officer [a member of the fire department] told me it was nice here.” She indicates that she initially thought it would be a nice place to live temporarily but later regretted coming after realizing that she was in a psychiatry unit. Available documentation from her recent hospitalization indicated that she was living in a motel on her own. Ms. S says that she works as an actress and has had minor roles in famous movies. She says that she studied at a well-known performance arts school and that her parents are famous musicians; however, she refuses to identify her parents or give permission to contact them—or any other collateral informant—because she is embarrassed about her current situation stating, “They would never believe it.”

During this interview, Ms. S appears confused as well as disorganized—which was a challenge to clearly delineate—disheveled, and guarded with hypoverbal and hypophonic speech. Her thought process is circumstantial, and she seems to be confabulating. She denies visual or auditory hallucinations but appears paranoid and states that she thinks we are experimenting on her. Except for the neurological exam, the rest of her physical exam is within normal limits. Urine toxicology screen and labs are negative except for a positive antinuclear antibody homogenous pattern with a titer of 1:640; B₁₂ vitamin levels are not tested.

MRI is ordered, however, she does not consent to the scan saying, “It’s creepy, I don’t want people looking at my brain.” The team makes several attempts to encourage her for consent but she refuses. Because of the clinical urgency (ie, possible cord compression) and her refusal to provide a surrogate decision maker, the team felt the situation is urgent, confirmed by 2 physicians, which led them to perform the MRI on an emergent basis. The MRI reveals multiple periventricular, juxtacortical, infratentorial, and likely cervical spinal cord T2 hyperintense lesions (Figure).

What would be your differential diagnosis at this time?

a) acute disseminated encephalomyelitis (ADEM)
b) systemic lupus erythematous
c) multiple sclerosis
d) vascular dementia
e) vitamin B deficiency

The authors’ observations

Psychosis in the presence of white matter demyelination could be associated with autoimmune, vascular, or nutritional disturbances. Deficiencies in vitamins B6, 9, and 12 (pyridoxine, folate, cobalamin) have been shown to cause neuropsychiatric symptoms and white matter lesions.⁵ Low levels of vitamins B6, 9, and 12 are associated with elevated homocysteine, which can cause small vessel ischemia leading to white matter lesions similar to changes seen in vascular dementia.⁵ The exact pathophysiology of ADEM is unclear, however, it is thought that after an infection, antiviral antibodies cross react with autoantigens on myelin causing an autoimmune demyelinating disease. Another hypothesized mechanism is that circulating immune complexes and humoral factors increase vascular permeability and inflammation thereby opening the blood–brain barrier. Once it is open, cells such as lymphocytes, phagocytes, and microglia cause gliosis and demyelination. Case reports have described ADEM associated with psychotic features.⁶

Likewise, systemic lupus erythematous has been associated with psychosis and neuropsychiatric symptoms in 14% to 75% of patients. Of these patients, 40% will experience neuropsychiatric symptoms before onset of lupus symptoms.⁷ One study found the most common MRI finding in neuropsychiatric systemic lupus erythematous was leukoaraiosis, which appeared in 57.1% of patients.⁸ 
Ms. S’s MRI results strongly suggest a diagnosis of MS.

EVALUATION Questionable story

Ms. S appears delusional and grandiose when she meets with the psychiatry team. She states that before her hospitalization, she was an actress and could ambulate, rent a motel room, and drive a car without assistance. However, during the examination, she cannot walk without 2 staff members for support, and overall her self-reported history sounds questionable. There were several pieces of evidence that corroborate portions of her story: (1) a screen actors guild card was found among personal belongings; (2) she was transported to the ER from a local motel; (3) she had recently visited another hospital and, at that time, was deemed stable enough to be discharged.

On the Montreal Cognitive Assessment (MoCA) Ms. S scored 19/30, with deficits mainly in executive/visuospatial and delayed recall memory. An alternate form of the MoCA is administered 1 day later, and she scores 20/30 with similar deficits. After obtaining medication consent, she is given risperidone, up to 2 mg/d, and becomes more cooperative with the treatment team.

The authors’ observations

Approximately 40% to 65% of MS patients experience cognitive impairment.⁹ Cognitive dysfunction in a depressed patient with MS might appear as pseudo-dementia, but other possible diagnoses include:

• true dementia
• encephalitis or infection
• medication- or substance-induced.

White matter demyelination is associated with subcortical dementia, which is characterized by slowness of information processing, forgetfulness, apathy, depression, and impaired cognition. According to meta-analyses, the most prominent neuropsychological deficits in MS are found in the areas of verbal fluency, information processing speed, working memory, and long-term memory.¹⁰ Relapsing-remitting type MS patients generally have less cognitive impairment than those with the chronic progressive type of the disease.

EVALUATION Cognitive deficits

Because of her acute condition and resistance to the evaluation, a modified screening neuropsychological battery is used. During the evaluation Ms. S is guarded and demonstrates paucity of speech; her responses are odd at times or contain word-substitution errors. Hand stiffness, tremor, and imprecision are noted during writing and drawing. Results of testing indicate average-range premorbid intellectual ability, with impairments in memory and information processing speed and a mild weakness in phonemic verbal fluency. Ms. S endorses statements reflecting paranoia and hostility on a self-report measure of emotional and personality functioning, consistent with her behavioral presentation. However, her responses on other subscales, including depression and psychotic symptoms, are within normal limits. Her cognitive deficits would be unusual if she had a psychiatric illness alone and are likely associated with her positive neuroimaging findings that suggest a demyelinating process. Overall, the results of the evaluation support a MS diagnosis.

The authors’ observations
Psychosis is found at a higher rate among MS patients (2% to 3%) than the general population (0.5% to 1%).⁹ Although rare, psychosis often can cloud the diagnosis of MS. Psychiatric symptoms that can occur in MS include:

• hallucinations and delusions (>50%)
• irritability and agitation (20%)
• grandiosity (15%)
• confusion, blunted affect, flight of ideas, depression, reduced self-care, and pressured speech (10%).¹¹

A review of 10 studies found that depression was the most prevalent symptom in MS, and that schizophrenia occurred in up to 7% of MS patients.¹² There are currently 3 theories about the relationship between psychosis and MS:

• MS and psychosis are thought to share the same pathophysiological process.
• Psychotic symptoms arise from regional demyelination simultaneously with MS.
• Psychosis is caused by medical treatment of MS.⁹

Other causes of psychiatric symptoms in MS include:

• depression associated with brain atrophy and lesions
• depression and anxiety as a result of chronic illness
• depression resulting from inflammatory changes
• corticosteroid treatment causing depression, mania, or psychosis.¹²

The link between psychosis and MS is still poorly understood and further investigation is needed.

How would you treat Ms. S?

a) haloperidol
b) risperidone
c) corticosteroids
d) selective serotonin reuptake inhibitors

Treating psychiatric symptoms in the context of MS

The literature, mainly case reports, suggests several treatment modalities for psychosis with MS. Clozapine has been shown to be beneficial in several case reports, and risperidone⁹ and ziprasidone¹³ also have been effective. Other studies recommended low-dose chlorpromazine.⁹

For MS patients with cognitive impairment, one study showed that interferon beta-1b (IFN-1b) treatment resulted in significant improvement in concentration, attention, visual learning, and recall after 1 year compared with control patients.⁹ However, there are also case reports of IFN-1b and glucocorticoid-induced psychosis in patients, which resolved after discontinuing treatment.⁹

Psychotic symptoms have been shown to resolve after corticosteroid treatment of MS.¹⁴ In another case report, mania and delusions subsided 3 days after IV methylprednisolone, whereas risperidone had no effect on psychotic features. However, it was unclear whether risperidone was discontinued when methylprednisolone was administered, therefore the specific effect of methylprednisolone is difficult to discern.¹⁵ Finally, in a case of a patient who has chronic MS for 16 years and presented with acute onset paranoid psychosis, symptoms resolved with aripiprazole, 10 to 20 mg/d.¹⁶ Because of the limited utility of case reports, there is a need for further research in medical management of psychiatric symptoms in MS.

Many patients experience difficulty swallowing pills, for various reasons:

• discomfort (particularly pediatric and geriatric patients)
• postsurgical need for an alternate route of enteral intake (nasogastric tube, gastrostomy, jejunostomy)
• dysphagia due to a neurologic disorder (multiple sclerosis, impaired gag reflex, dementing processes)
• odynophagia (pain upon swallowing) due to gastroesophageal reflux or a structural abnormality
• a structural abnormality of the head or neck that impairs swallowing.¹

If these difficulties are not addressed, they can interfere with medication adherence. In those instances, using an alternative dosage form or manipulating an available formulation might be required.

Crushing guidelines

There are limited data on crushed-form products and their impact on efficacy. Therefore, when patients have difficulty taking pills, switching to liquid solution or orally disintegrating forms is recommended. However, most psychotropics are available only as tablets or capsules. Patients can crush their pills immediately before administration for easier intake. The following are some general guidelines for doing so:²

• Scored tablets typically can be crushed.
• Crushing sublingual and buccal tablets can alter their effectiveness.
• Crushing sustained-release medications can eliminate the sustained-release action.³
• Enteric-coated medications should not be crushed, because this can alter drug absorption.
• Capsules generally can be opened to administer powdered contents, unless the capsule has time-release properties or an enteric coating.

The accompanying Table, organized by drug class, indicates whether a drug can be crushed to a powdered form, which usually is mixed with food or liquid for easier intake. The Table also lists liquid and orally disintegrating forms available, and other routes, including injectable immediate and long-acting formulations. Helping patients find a medication formulation that suits their needs strengthens adherence and the therapeutic relationship.

Many patients experience difficulty swallowing pills, for various reasons:

• discomfort (particularly pediatric and geriatric patients)
• postsurgical need for an alternate route of enteral intake (nasogastric tube, gastrostomy, jejunostomy)
• dysphagia due to a neurologic disorder (multiple sclerosis, impaired gag reflex, dementing processes)
• odynophagia (pain upon swallowing) due to gastroesophageal reflux or a structural abnormality
• a structural abnormality of the head or neck that impairs swallowing.¹

If these difficulties are not addressed, they can interfere with medication adherence. In those instances, using an alternative dosage form or manipulating an available formulation might be required.

Crushing guidelines

There are limited data on crushed-form products and their impact on efficacy. Therefore, when patients have difficulty taking pills, switching to liquid solution or orally disintegrating forms is recommended. However, most psychotropics are available only as tablets or capsules. Patients can crush their pills immediately before administration for easier intake. The following are some general guidelines for doing so:²

• Scored tablets typically can be crushed.
• Crushing sublingual and buccal tablets can alter their effectiveness.
• Crushing sustained-release medications can eliminate the sustained-release action.³
• Enteric-coated medications should not be crushed, because this can alter drug absorption.
• Capsules generally can be opened to administer powdered contents, unless the capsule has time-release properties or an enteric coating.

The accompanying Table, organized by drug class, indicates whether a drug can be crushed to a powdered form, which usually is mixed with food or liquid for easier intake. The Table also lists liquid and orally disintegrating forms available, and other routes, including injectable immediate and long-acting formulations. Helping patients find a medication formulation that suits their needs strengthens adherence and the therapeutic relationship.

Many patients experience difficulty swallowing pills, for various reasons:

• discomfort (particularly pediatric and geriatric patients)
• postsurgical need for an alternate route of enteral intake (nasogastric tube, gastrostomy, jejunostomy)
• dysphagia due to a neurologic disorder (multiple sclerosis, impaired gag reflex, dementing processes)
• odynophagia (pain upon swallowing) due to gastroesophageal reflux or a structural abnormality
• a structural abnormality of the head or neck that impairs swallowing.¹

If these difficulties are not addressed, they can interfere with medication adherence. In those instances, using an alternative dosage form or manipulating an available formulation might be required.

Crushing guidelines

There are limited data on crushed-form products and their impact on efficacy. Therefore, when patients have difficulty taking pills, switching to liquid solution or orally disintegrating forms is recommended. However, most psychotropics are available only as tablets or capsules. Patients can crush their pills immediately before administration for easier intake. The following are some general guidelines for doing so:²

• Scored tablets typically can be crushed.
• Crushing sublingual and buccal tablets can alter their effectiveness.
• Crushing sustained-release medications can eliminate the sustained-release action.³
• Enteric-coated medications should not be crushed, because this can alter drug absorption.
• Capsules generally can be opened to administer powdered contents, unless the capsule has time-release properties or an enteric coating.

The accompanying Table, organized by drug class, indicates whether a drug can be crushed to a powdered form, which usually is mixed with food or liquid for easier intake. The Table also lists liquid and orally disintegrating forms available, and other routes, including injectable immediate and long-acting formulations. Helping patients find a medication formulation that suits their needs strengthens adherence and the therapeutic relationship.

CASE › Stacey, a 12-year-old girl with mild persistent asthma, presents to her family physician (FP) with her mother for her annual well visit. Stacey reports no complaints, but has visited twice recently for acute exacerbations of her asthma, which had previously been well-controlled. When reviewing her social history, Stacey reports that she started her second year of middle school 3 months ago. When asked if she enjoys school, Stacey looks down and says, “School is fine.” Her mother quickly adds that Stacey has quit the school cheerleading team—much to the coach’s dismay—and is having difficulty in her math class, a class in which she normally excels. Stacey appears embarrassed that her mother has brought these things up. Her mother says that at the beginning of the year, 2 girls began picking on Stacey, calling her names and making fun of her on social media and in front of other students.

For many years, bullying was trivialized. Some viewed it as a universal childhood experience; others considered it a rite of passage.^1,2 It was not examined as a public health issue until the 1970s. In fact, no legislation addressing bullying or “peer abuse” existed in the United States until the mass shooting at Columbine High School in Littleton, Colo, in 1999. Within 3 years of the Columbine tragedy, the number of state laws that mentioned bullying went from zero to 15; within 10 years of Columbine, 41 states had laws addressing bullying,¹ and by 2015, every state, the District of Columbia, and some territories had a bullying law in place.³

Ask patients, "Are you being bullied?" and then follow that with, "How often are you bullied?" and, "Does it happen at school? Online?" These details can help guide interventions.As research and advocacy regarding bullying has grown, its impact on the health of children, adolescents, and even adults has become more apparent. In a 2001 study of school-associated violent deaths in the United States between 1994 and 1999, the Centers for Disease Control and Prevention (CDC) found that among students, homicide perpetrators were more than twice as likely as homicide victims to have been bullied by peers.⁴ Given that homicide is the third leading cause of death in people ages 15 to 24,⁵ past exposure to bullying may be a significant contributing factor to mortality in this age group.⁴

In addition to a correlation with homicidal behavior, those involved in bullying—whether as the bully or victim—are at risk for a wide range of symptoms, conditions, and problems including poor psychosocial adjustment, depression, anxiety, suicide (the second leading cause of death in the 10-14 and 15-24 age groups⁵), academic decline, psychosomatic manifestations, fighting, alcohol use, smoking, and difficulty with the management of chronic diseases.^6-10 Not only does being a victim of bullying have a direct impact on a child’s current mental and physical well-being, but it can have lasting psychological and behavioral effects that can follow children well into adulthood.⁷ The significant impact of bullying on individuals and society as a whole mandates a multifaceted approach that begins in your exam room. What follows is practical advice on screening, counseling, and working with schools and the community at large to curb the bullying epidemic.

IMAGE: © ALICIA BUELOW

Clarifying the problem: The CDC’s definition

Recognizing that varying definitions of bullying were being used in research studies that looked at violent or aggressive behaviors in youth, the CDC published a consensus statement in 2014 that proposed the following definition for bullying:¹¹ any unwanted aggressive behavior by another youth or group of youths who are not siblings or current dating partners that involves an observed or perceived power imbalance and is repeated multiple times or is highly likely to be repeated. This expanded on an earlier definition by Olweus^12,13 that also identified a longitudinal nature and power imbalance as key features.

Types of bullying. Direct bullying entails blatant attacks on a targeted young person, while indirect bullying involves communication with others about the targeted individual (eg, spreading harmful rumors). Bullying may be physical, verbal, or relational (eg, excluding someone from their usual social circle, denying friendship, the silent treatment, writing mean letters, eye rolling, etc.) and may involve damage to property. Boys tend toward more direct bullying behaviors, while girls more often engage in indirect bullying, which may be more challenging for both adults and other students to recognize.^12,13 With increased use of technology and social media by adolescents, cyberbullying has become increasingly more prevalent, with its effects on adolescent health and academics being every bit as profound as those of traditional bullying.¹⁴

About 1 in 4/5 students suffer. The prevalence of bullying ranges by country and culture. The vast majority of early bullying research was conducted in Norway, which found that approximately 15% of students in elementary and secondary schools were involved in bullying in some capacity.¹² In a study involving over 200,000 adolescents from 40 European countries, 26% of adolescents reported being involved in bullying, ranging from 8.6% to 45.2% for boys and 4.8% to 35.8% for girls.¹⁵ Variations in prevalence may be due to cultural differences in the acts of bullying or differences in interpretation of the term “bullying.”^1,15

Among students, homicide perpetrators are more than twice as likely as homicide victims to have been bullied by their peers.In the United States, a 2001 survey of more than 15,000 students in public and private schools (grades 6-10) asked the students about their involvement in bullying: 13% said they'd been a bully, 10.6% a victim, and 6.3% said they'd been both.⁶ There was no significant difference in the frequency of self-reported bullying among urban, suburban, or rural settings.

Despite efforts to educate the public about bullying and work with schools to intervene and prevent bullying, incidence remains largely unchanged. In 2013, the National Crime Victimization Survey reported that approximately 22% of adolescents ages 12 through 18 were victims of bullying.¹⁶ Similarly, the CDC's 2015 Youth Risk Behavior Surveillance System reported that 20.2% of high school students experienced bullying on school property.¹⁷

Screening: Best practices

The FP’s role begins with screening children at risk for bullying (TABLE 1^18-22) or those whose complaints suggest that they may be victims of bullying.

Start screening when children enter elementary school

Given that providers’ time is limited for every patient visit, it is important to address bullying at times that are most likely to yield impactful results. The American Academy of Pediatrics recommends that the topic of bullying be introduced at the 6-year-old well-child visit (a typical age for entry to elementary school).⁷ Views in the literature are inconsistent regarding when and how to address bullying at other time points. One approach is to pre-screen those with risk factors associated with bullying (TABLE 1^18-22), and to focus screening on those with warning signs of bullying, which include mood disorders, psychosomatic or behavioral symptoms, substance abuse, self-harm behaviors, suicidal ideation or a suicide attempt, a decline in academic performance, and reports of school truancy. Parental concerns, such as when a child suddenly needs more money for lunch, is having aggressive outbursts, or is exhibiting unexplained physical injuries, should also be regarded as cues to screen.⁹

Screen patients in high-risk groups

A number of groups of children are at high risk for bullying and warrant targeted screening efforts.

• Children with special health needs. Research has shown that children with special health needs are at increased risk for being bullied.¹⁸ In fact, the presence of a chronic disease may increase the risk for bullying, and bullying often negatively impacts chronic disease management. As a result, it’s important to have a high index of suspicion with patients who have a chronic disease and who are not responding as expected to medical management or who experience deterioration after being previously well-controlled.¹⁸
• Children who are under- or overweight. Similarly, bullying based on a child's weight is a phenomenon that has been recognized to have a significant impact on children’s emotional health.¹⁹
• Youth who identify as lesbian, gay, bisexual, transgender, or queer/questioning (LGBTQ+) are more likely than non-LGBTQ+ peers to attempt suicide when exposed to a hostile social environment, such as that created by bullying.²⁰

Screening need not be complicated

One screening approach is simply to ask patients, “Are you being bullied?” followed by such questions as, “How often are you bullied?” or “How long have you been bullied?” Asking about the setting of the bullying (Does it happen at school? Traveling to/from school? Online?) and other details may help guide interventions and the provision of resources.⁹ Another approach is to provide patients with some type of written survey (see TABLE 2²³ for an example) to encourage responses that patients might be reluctant to disclose verbally.^23,24 (See “Barriers to screening.")

Provider and parental interventions

Interventions often entail counseling the patient and the family about bullying and its effects, empowering victims and their caregivers, and screening for bullying comorbidities and correlates.² Refer patients to behavioral health specialists when there is evidence of pervasive effects on mood, behavior, or social development, but keep in mind that counseling can begin in your own exam room.

Effective discussion starters. Affirming the problem and its unacceptability, talking about the different types of bullying and where bullying may occur, and asking about patient perceptions of bullying can be effective discussion starters. FPs should help patients identify bullying, open lines of communication between children and their parents and between parents and other caregivers, and demonstrate respect and kindness in their approach to discussing the topic. Encourage children to speak with trusted adults when exposed to bullying. Talk to them about standing up to bullies (saying “stop” confidently or walking away from difficult situations) and staying safe by staying near adults or groups of peers when bullies are present (TABLE 3²⁵).

Empowering caregivers. Encourage parents to spend time each day talking with their child about the child’s time away from home (TABLE 3²⁵). Counsel parents/caregivers to expand their role. Knowing a child’s friends, encouraging the child academically, and increasing communication are all associated with lower risks of bullying.²⁶ Similarly, parental oversight of Internet and social media use is associated with decreased participation in cyberbullying.²⁷

In addition, the Positive Parenting telephone-based parenting education curriculum has been shown to decrease bullying, physical fighting, physical injuries, and victimization of children.²⁸ The research-based, family strengthening program emphasizes 3 core elements of authoritative parenting: nurturance, discipline, and respect or granting of psychologic autonomy. The program entails 15- to 30-minute weekly phone conversations between parents and educators, as well as videos and a manual.

Are community programs in place—or are they needed?

Many schools have robust, state-mandated programs in place to identify bullying and provide support for students who are victims of bullying. (See “NJ’s harassment and bullying protocol: A case in point.”) Explaining this to victims and their families may help them come forward and seek assistance. FPs who want to advocate for their patients should start with local schools to support such programs and link students at risk with school counselors.

If programs are lacking in your community, there is much you can do to educate yourself about successful programs and advise local community organizations and schools about them. Among the most successful and well-studied interventions for thwarting the bullying epidemic have been school-based community ones. The most studied of these is the Olweus Bullying Prevention Program (OBPP), which is based on 4 principles:^1,29

1. Adults both at home and at school should take a positive and encouraging interest in students.
2. Unacceptable behavior should have strict and well-known limits.
3. Sanctions should be applied consistently and should be non-hostile in nature.
4. Adults both at home and in the educational environment should act as authorities.

In short, the program focuses on greater awareness and involvement on the part of adults, and employing measures at the school level (eg, surveys, better supervision during break and lunch times), the class level (eg, rules against bullying, regular class meetings with students), and the individual level (eg, serious talks with bullies, victims, parents of involved students).

Research has shown that the OBPP reduces bullying behaviors by as much as 50%, reduces vandalism and truancy, and reduces the number of new victims.¹² Limits to the more widespread implementation of the OBPP have consisted mainly of the inability to appropriately train adults, including teachers and other school personnel in educational settings. Despite these limitations, the OBPP has been praised and endorsed by numerous groups, including the US Department of Justice.³⁰

Encourage children who are bullied to stay safe by standing near adults or groups of peers when bullies are present.Other non-curricular, school-based programs exist, such as the School-Wide Positive Behavioral Interventions and Supports (SWPBIS). This program is a school-wide prevention strategy aimed at: 1) reducing behavior problems that lead to office discipline referrals and suspensions, and 2) changing perceptions of school safety. (For more information, see https://www.crimesolutions.gov/ProgramDetails.aspx?ID=385 and https://www.pbis.org/school/swpbis-for-beginners.)³¹

The research-based Second Step: Student Success Through Prevention (SS-SSTP) Middle School Program (http://www.cfchildren.org/second-step/middle-school)³² focuses on the often difficult middle school years. The program helps schools teach and model essential communication, coping, and decision-making skills to help adolescents navigate around common pitfalls such as peer pressure, substance abuse, and bullying (both in-person and online). The program aims to reduce aggression and provide support for a more inclusive environment that helps students stay in school, make good choices, and experience social and academic success.

The Positive Action Program (https://www.positiveaction.net/research/primer),³³ which is predicated on the notion that we feel good about ourselves when we do positive things, features scripted lessons and kits of materials (eg, posters, games, worksheets, puzzles) appropriate for each grade level.

CASE › Stacey’s visit to her FP’s office has presented several clues that she may be a victim of bullying. Her mild persistent asthma appears to no longer be as well controlled as it was in the past. Direct questioning has revealed that 2 girls at school have been making fun of Stacey when she uses her inhaled corticosteroid in the morning before class, so she has stopped using it. These same students are on her cheerleading team, so she quit the team to avoid them. Her school-related anxiety is so great that she no longer pays attention in math class and is constantly worried that something is being posted about her online.

Stacy’s FP responds to this information with a multifaceted approach. In the exam room, he screens Stacy for depression. While she is negative and denies any suicidal ideation, Stacy is clearly having anxiety, so the FP refers Stacey to a counselor at a local mental health clinic. With Stacy’s permission, the FP discusses the issue with her mother and they decide together with Stacy that she should talk to a teacher at school about the ongoing bullying. Because this was not the first time that the FP has heard this from a child in the community, the FP plans to attend an upcoming school board meeting to advocate for an evidence-based bullying prevention program to help curb the ongoing problem facing his patients.

CORRESPONDENCE
Robert McClowry, MD, Department of Family and Community Medicine, Jefferson Family Medicine Associates, 833 Chestnut East, 3rd Floor, Suite 301, Philadelphia, PA, 19107-4414; Robert.McClowry@Jefferson.edu.

CASE › Stacey, a 12-year-old girl with mild persistent asthma, presents to her family physician (FP) with her mother for her annual well visit. Stacey reports no complaints, but has visited twice recently for acute exacerbations of her asthma, which had previously been well-controlled. When reviewing her social history, Stacey reports that she started her second year of middle school 3 months ago. When asked if she enjoys school, Stacey looks down and says, “School is fine.” Her mother quickly adds that Stacey has quit the school cheerleading team—much to the coach’s dismay—and is having difficulty in her math class, a class in which she normally excels. Stacey appears embarrassed that her mother has brought these things up. Her mother says that at the beginning of the year, 2 girls began picking on Stacey, calling her names and making fun of her on social media and in front of other students.

For many years, bullying was trivialized. Some viewed it as a universal childhood experience; others considered it a rite of passage.^1,2 It was not examined as a public health issue until the 1970s. In fact, no legislation addressing bullying or “peer abuse” existed in the United States until the mass shooting at Columbine High School in Littleton, Colo, in 1999. Within 3 years of the Columbine tragedy, the number of state laws that mentioned bullying went from zero to 15; within 10 years of Columbine, 41 states had laws addressing bullying,¹ and by 2015, every state, the District of Columbia, and some territories had a bullying law in place.³

Ask patients, "Are you being bullied?" and then follow that with, "How often are you bullied?" and, "Does it happen at school? Online?" These details can help guide interventions.As research and advocacy regarding bullying has grown, its impact on the health of children, adolescents, and even adults has become more apparent. In a 2001 study of school-associated violent deaths in the United States between 1994 and 1999, the Centers for Disease Control and Prevention (CDC) found that among students, homicide perpetrators were more than twice as likely as homicide victims to have been bullied by peers.⁴ Given that homicide is the third leading cause of death in people ages 15 to 24,⁵ past exposure to bullying may be a significant contributing factor to mortality in this age group.⁴

In addition to a correlation with homicidal behavior, those involved in bullying—whether as the bully or victim—are at risk for a wide range of symptoms, conditions, and problems including poor psychosocial adjustment, depression, anxiety, suicide (the second leading cause of death in the 10-14 and 15-24 age groups⁵), academic decline, psychosomatic manifestations, fighting, alcohol use, smoking, and difficulty with the management of chronic diseases.^6-10 Not only does being a victim of bullying have a direct impact on a child’s current mental and physical well-being, but it can have lasting psychological and behavioral effects that can follow children well into adulthood.⁷ The significant impact of bullying on individuals and society as a whole mandates a multifaceted approach that begins in your exam room. What follows is practical advice on screening, counseling, and working with schools and the community at large to curb the bullying epidemic.

IMAGE: © ALICIA BUELOW

Clarifying the problem: The CDC’s definition

Recognizing that varying definitions of bullying were being used in research studies that looked at violent or aggressive behaviors in youth, the CDC published a consensus statement in 2014 that proposed the following definition for bullying:¹¹ any unwanted aggressive behavior by another youth or group of youths who are not siblings or current dating partners that involves an observed or perceived power imbalance and is repeated multiple times or is highly likely to be repeated. This expanded on an earlier definition by Olweus^12,13 that also identified a longitudinal nature and power imbalance as key features.

Types of bullying. Direct bullying entails blatant attacks on a targeted young person, while indirect bullying involves communication with others about the targeted individual (eg, spreading harmful rumors). Bullying may be physical, verbal, or relational (eg, excluding someone from their usual social circle, denying friendship, the silent treatment, writing mean letters, eye rolling, etc.) and may involve damage to property. Boys tend toward more direct bullying behaviors, while girls more often engage in indirect bullying, which may be more challenging for both adults and other students to recognize.^12,13 With increased use of technology and social media by adolescents, cyberbullying has become increasingly more prevalent, with its effects on adolescent health and academics being every bit as profound as those of traditional bullying.¹⁴

About 1 in 4/5 students suffer. The prevalence of bullying ranges by country and culture. The vast majority of early bullying research was conducted in Norway, which found that approximately 15% of students in elementary and secondary schools were involved in bullying in some capacity.¹² In a study involving over 200,000 adolescents from 40 European countries, 26% of adolescents reported being involved in bullying, ranging from 8.6% to 45.2% for boys and 4.8% to 35.8% for girls.¹⁵ Variations in prevalence may be due to cultural differences in the acts of bullying or differences in interpretation of the term “bullying.”^1,15

Among students, homicide perpetrators are more than twice as likely as homicide victims to have been bullied by their peers.In the United States, a 2001 survey of more than 15,000 students in public and private schools (grades 6-10) asked the students about their involvement in bullying: 13% said they'd been a bully, 10.6% a victim, and 6.3% said they'd been both.⁶ There was no significant difference in the frequency of self-reported bullying among urban, suburban, or rural settings.

Despite efforts to educate the public about bullying and work with schools to intervene and prevent bullying, incidence remains largely unchanged. In 2013, the National Crime Victimization Survey reported that approximately 22% of adolescents ages 12 through 18 were victims of bullying.¹⁶ Similarly, the CDC's 2015 Youth Risk Behavior Surveillance System reported that 20.2% of high school students experienced bullying on school property.¹⁷

Screening: Best practices

The FP’s role begins with screening children at risk for bullying (TABLE 1^18-22) or those whose complaints suggest that they may be victims of bullying.

Start screening when children enter elementary school

Given that providers’ time is limited for every patient visit, it is important to address bullying at times that are most likely to yield impactful results. The American Academy of Pediatrics recommends that the topic of bullying be introduced at the 6-year-old well-child visit (a typical age for entry to elementary school).⁷ Views in the literature are inconsistent regarding when and how to address bullying at other time points. One approach is to pre-screen those with risk factors associated with bullying (TABLE 1^18-22), and to focus screening on those with warning signs of bullying, which include mood disorders, psychosomatic or behavioral symptoms, substance abuse, self-harm behaviors, suicidal ideation or a suicide attempt, a decline in academic performance, and reports of school truancy. Parental concerns, such as when a child suddenly needs more money for lunch, is having aggressive outbursts, or is exhibiting unexplained physical injuries, should also be regarded as cues to screen.⁹

Screen patients in high-risk groups

A number of groups of children are at high risk for bullying and warrant targeted screening efforts.

• Children with special health needs. Research has shown that children with special health needs are at increased risk for being bullied.¹⁸ In fact, the presence of a chronic disease may increase the risk for bullying, and bullying often negatively impacts chronic disease management. As a result, it’s important to have a high index of suspicion with patients who have a chronic disease and who are not responding as expected to medical management or who experience deterioration after being previously well-controlled.¹⁸
• Children who are under- or overweight. Similarly, bullying based on a child's weight is a phenomenon that has been recognized to have a significant impact on children’s emotional health.¹⁹
• Youth who identify as lesbian, gay, bisexual, transgender, or queer/questioning (LGBTQ+) are more likely than non-LGBTQ+ peers to attempt suicide when exposed to a hostile social environment, such as that created by bullying.²⁰

Screening need not be complicated

One screening approach is simply to ask patients, “Are you being bullied?” followed by such questions as, “How often are you bullied?” or “How long have you been bullied?” Asking about the setting of the bullying (Does it happen at school? Traveling to/from school? Online?) and other details may help guide interventions and the provision of resources.⁹ Another approach is to provide patients with some type of written survey (see TABLE 2²³ for an example) to encourage responses that patients might be reluctant to disclose verbally.^23,24 (See “Barriers to screening.")

Provider and parental interventions

Interventions often entail counseling the patient and the family about bullying and its effects, empowering victims and their caregivers, and screening for bullying comorbidities and correlates.² Refer patients to behavioral health specialists when there is evidence of pervasive effects on mood, behavior, or social development, but keep in mind that counseling can begin in your own exam room.

Effective discussion starters. Affirming the problem and its unacceptability, talking about the different types of bullying and where bullying may occur, and asking about patient perceptions of bullying can be effective discussion starters. FPs should help patients identify bullying, open lines of communication between children and their parents and between parents and other caregivers, and demonstrate respect and kindness in their approach to discussing the topic. Encourage children to speak with trusted adults when exposed to bullying. Talk to them about standing up to bullies (saying “stop” confidently or walking away from difficult situations) and staying safe by staying near adults or groups of peers when bullies are present (TABLE 3²⁵).

Empowering caregivers. Encourage parents to spend time each day talking with their child about the child’s time away from home (TABLE 3²⁵). Counsel parents/caregivers to expand their role. Knowing a child’s friends, encouraging the child academically, and increasing communication are all associated with lower risks of bullying.²⁶ Similarly, parental oversight of Internet and social media use is associated with decreased participation in cyberbullying.²⁷

In addition, the Positive Parenting telephone-based parenting education curriculum has been shown to decrease bullying, physical fighting, physical injuries, and victimization of children.²⁸ The research-based, family strengthening program emphasizes 3 core elements of authoritative parenting: nurturance, discipline, and respect or granting of psychologic autonomy. The program entails 15- to 30-minute weekly phone conversations between parents and educators, as well as videos and a manual.

Are community programs in place—or are they needed?

Many schools have robust, state-mandated programs in place to identify bullying and provide support for students who are victims of bullying. (See “NJ’s harassment and bullying protocol: A case in point.”) Explaining this to victims and their families may help them come forward and seek assistance. FPs who want to advocate for their patients should start with local schools to support such programs and link students at risk with school counselors.

If programs are lacking in your community, there is much you can do to educate yourself about successful programs and advise local community organizations and schools about them. Among the most successful and well-studied interventions for thwarting the bullying epidemic have been school-based community ones. The most studied of these is the Olweus Bullying Prevention Program (OBPP), which is based on 4 principles:^1,29

1. Adults both at home and at school should take a positive and encouraging interest in students.
2. Unacceptable behavior should have strict and well-known limits.
3. Sanctions should be applied consistently and should be non-hostile in nature.
4. Adults both at home and in the educational environment should act as authorities.

In short, the program focuses on greater awareness and involvement on the part of adults, and employing measures at the school level (eg, surveys, better supervision during break and lunch times), the class level (eg, rules against bullying, regular class meetings with students), and the individual level (eg, serious talks with bullies, victims, parents of involved students).

Research has shown that the OBPP reduces bullying behaviors by as much as 50%, reduces vandalism and truancy, and reduces the number of new victims.¹² Limits to the more widespread implementation of the OBPP have consisted mainly of the inability to appropriately train adults, including teachers and other school personnel in educational settings. Despite these limitations, the OBPP has been praised and endorsed by numerous groups, including the US Department of Justice.³⁰

Encourage children who are bullied to stay safe by standing near adults or groups of peers when bullies are present.Other non-curricular, school-based programs exist, such as the School-Wide Positive Behavioral Interventions and Supports (SWPBIS). This program is a school-wide prevention strategy aimed at: 1) reducing behavior problems that lead to office discipline referrals and suspensions, and 2) changing perceptions of school safety. (For more information, see https://www.crimesolutions.gov/ProgramDetails.aspx?ID=385 and https://www.pbis.org/school/swpbis-for-beginners.)³¹

The research-based Second Step: Student Success Through Prevention (SS-SSTP) Middle School Program (http://www.cfchildren.org/second-step/middle-school)³² focuses on the often difficult middle school years. The program helps schools teach and model essential communication, coping, and decision-making skills to help adolescents navigate around common pitfalls such as peer pressure, substance abuse, and bullying (both in-person and online). The program aims to reduce aggression and provide support for a more inclusive environment that helps students stay in school, make good choices, and experience social and academic success.

The Positive Action Program (https://www.positiveaction.net/research/primer),³³ which is predicated on the notion that we feel good about ourselves when we do positive things, features scripted lessons and kits of materials (eg, posters, games, worksheets, puzzles) appropriate for each grade level.

CASE › Stacey’s visit to her FP’s office has presented several clues that she may be a victim of bullying. Her mild persistent asthma appears to no longer be as well controlled as it was in the past. Direct questioning has revealed that 2 girls at school have been making fun of Stacey when she uses her inhaled corticosteroid in the morning before class, so she has stopped using it. These same students are on her cheerleading team, so she quit the team to avoid them. Her school-related anxiety is so great that she no longer pays attention in math class and is constantly worried that something is being posted about her online.

Stacy’s FP responds to this information with a multifaceted approach. In the exam room, he screens Stacy for depression. While she is negative and denies any suicidal ideation, Stacy is clearly having anxiety, so the FP refers Stacey to a counselor at a local mental health clinic. With Stacy’s permission, the FP discusses the issue with her mother and they decide together with Stacy that she should talk to a teacher at school about the ongoing bullying. Because this was not the first time that the FP has heard this from a child in the community, the FP plans to attend an upcoming school board meeting to advocate for an evidence-based bullying prevention program to help curb the ongoing problem facing his patients.

CORRESPONDENCE
Robert McClowry, MD, Department of Family and Community Medicine, Jefferson Family Medicine Associates, 833 Chestnut East, 3rd Floor, Suite 301, Philadelphia, PA, 19107-4414; Robert.McClowry@Jefferson.edu.

CASE › Stacey, a 12-year-old girl with mild persistent asthma, presents to her family physician (FP) with her mother for her annual well visit. Stacey reports no complaints, but has visited twice recently for acute exacerbations of her asthma, which had previously been well-controlled. When reviewing her social history, Stacey reports that she started her second year of middle school 3 months ago. When asked if she enjoys school, Stacey looks down and says, “School is fine.” Her mother quickly adds that Stacey has quit the school cheerleading team—much to the coach’s dismay—and is having difficulty in her math class, a class in which she normally excels. Stacey appears embarrassed that her mother has brought these things up. Her mother says that at the beginning of the year, 2 girls began picking on Stacey, calling her names and making fun of her on social media and in front of other students.

For many years, bullying was trivialized. Some viewed it as a universal childhood experience; others considered it a rite of passage.^1,2 It was not examined as a public health issue until the 1970s. In fact, no legislation addressing bullying or “peer abuse” existed in the United States until the mass shooting at Columbine High School in Littleton, Colo, in 1999. Within 3 years of the Columbine tragedy, the number of state laws that mentioned bullying went from zero to 15; within 10 years of Columbine, 41 states had laws addressing bullying,¹ and by 2015, every state, the District of Columbia, and some territories had a bullying law in place.³

Ask patients, "Are you being bullied?" and then follow that with, "How often are you bullied?" and, "Does it happen at school? Online?" These details can help guide interventions.As research and advocacy regarding bullying has grown, its impact on the health of children, adolescents, and even adults has become more apparent. In a 2001 study of school-associated violent deaths in the United States between 1994 and 1999, the Centers for Disease Control and Prevention (CDC) found that among students, homicide perpetrators were more than twice as likely as homicide victims to have been bullied by peers.⁴ Given that homicide is the third leading cause of death in people ages 15 to 24,⁵ past exposure to bullying may be a significant contributing factor to mortality in this age group.⁴

In addition to a correlation with homicidal behavior, those involved in bullying—whether as the bully or victim—are at risk for a wide range of symptoms, conditions, and problems including poor psychosocial adjustment, depression, anxiety, suicide (the second leading cause of death in the 10-14 and 15-24 age groups⁵), academic decline, psychosomatic manifestations, fighting, alcohol use, smoking, and difficulty with the management of chronic diseases.^6-10 Not only does being a victim of bullying have a direct impact on a child’s current mental and physical well-being, but it can have lasting psychological and behavioral effects that can follow children well into adulthood.⁷ The significant impact of bullying on individuals and society as a whole mandates a multifaceted approach that begins in your exam room. What follows is practical advice on screening, counseling, and working with schools and the community at large to curb the bullying epidemic.

IMAGE: © ALICIA BUELOW

Clarifying the problem: The CDC’s definition

Recognizing that varying definitions of bullying were being used in research studies that looked at violent or aggressive behaviors in youth, the CDC published a consensus statement in 2014 that proposed the following definition for bullying:¹¹ any unwanted aggressive behavior by another youth or group of youths who are not siblings or current dating partners that involves an observed or perceived power imbalance and is repeated multiple times or is highly likely to be repeated. This expanded on an earlier definition by Olweus^12,13 that also identified a longitudinal nature and power imbalance as key features.

Types of bullying. Direct bullying entails blatant attacks on a targeted young person, while indirect bullying involves communication with others about the targeted individual (eg, spreading harmful rumors). Bullying may be physical, verbal, or relational (eg, excluding someone from their usual social circle, denying friendship, the silent treatment, writing mean letters, eye rolling, etc.) and may involve damage to property. Boys tend toward more direct bullying behaviors, while girls more often engage in indirect bullying, which may be more challenging for both adults and other students to recognize.^12,13 With increased use of technology and social media by adolescents, cyberbullying has become increasingly more prevalent, with its effects on adolescent health and academics being every bit as profound as those of traditional bullying.¹⁴

About 1 in 4/5 students suffer. The prevalence of bullying ranges by country and culture. The vast majority of early bullying research was conducted in Norway, which found that approximately 15% of students in elementary and secondary schools were involved in bullying in some capacity.¹² In a study involving over 200,000 adolescents from 40 European countries, 26% of adolescents reported being involved in bullying, ranging from 8.6% to 45.2% for boys and 4.8% to 35.8% for girls.¹⁵ Variations in prevalence may be due to cultural differences in the acts of bullying or differences in interpretation of the term “bullying.”^1,15

Among students, homicide perpetrators are more than twice as likely as homicide victims to have been bullied by their peers.In the United States, a 2001 survey of more than 15,000 students in public and private schools (grades 6-10) asked the students about their involvement in bullying: 13% said they'd been a bully, 10.6% a victim, and 6.3% said they'd been both.⁶ There was no significant difference in the frequency of self-reported bullying among urban, suburban, or rural settings.

Despite efforts to educate the public about bullying and work with schools to intervene and prevent bullying, incidence remains largely unchanged. In 2013, the National Crime Victimization Survey reported that approximately 22% of adolescents ages 12 through 18 were victims of bullying.¹⁶ Similarly, the CDC's 2015 Youth Risk Behavior Surveillance System reported that 20.2% of high school students experienced bullying on school property.¹⁷

Screening: Best practices

The FP’s role begins with screening children at risk for bullying (TABLE 1^18-22) or those whose complaints suggest that they may be victims of bullying.

Start screening when children enter elementary school

Given that providers’ time is limited for every patient visit, it is important to address bullying at times that are most likely to yield impactful results. The American Academy of Pediatrics recommends that the topic of bullying be introduced at the 6-year-old well-child visit (a typical age for entry to elementary school).⁷ Views in the literature are inconsistent regarding when and how to address bullying at other time points. One approach is to pre-screen those with risk factors associated with bullying (TABLE 1^18-22), and to focus screening on those with warning signs of bullying, which include mood disorders, psychosomatic or behavioral symptoms, substance abuse, self-harm behaviors, suicidal ideation or a suicide attempt, a decline in academic performance, and reports of school truancy. Parental concerns, such as when a child suddenly needs more money for lunch, is having aggressive outbursts, or is exhibiting unexplained physical injuries, should also be regarded as cues to screen.⁹

Screen patients in high-risk groups

A number of groups of children are at high risk for bullying and warrant targeted screening efforts.

• Children with special health needs. Research has shown that children with special health needs are at increased risk for being bullied.¹⁸ In fact, the presence of a chronic disease may increase the risk for bullying, and bullying often negatively impacts chronic disease management. As a result, it’s important to have a high index of suspicion with patients who have a chronic disease and who are not responding as expected to medical management or who experience deterioration after being previously well-controlled.¹⁸
• Children who are under- or overweight. Similarly, bullying based on a child's weight is a phenomenon that has been recognized to have a significant impact on children’s emotional health.¹⁹
• Youth who identify as lesbian, gay, bisexual, transgender, or queer/questioning (LGBTQ+) are more likely than non-LGBTQ+ peers to attempt suicide when exposed to a hostile social environment, such as that created by bullying.²⁰

Screening need not be complicated

One screening approach is simply to ask patients, “Are you being bullied?” followed by such questions as, “How often are you bullied?” or “How long have you been bullied?” Asking about the setting of the bullying (Does it happen at school? Traveling to/from school? Online?) and other details may help guide interventions and the provision of resources.⁹ Another approach is to provide patients with some type of written survey (see TABLE 2²³ for an example) to encourage responses that patients might be reluctant to disclose verbally.^23,24 (See “Barriers to screening.")

Provider and parental interventions

Interventions often entail counseling the patient and the family about bullying and its effects, empowering victims and their caregivers, and screening for bullying comorbidities and correlates.² Refer patients to behavioral health specialists when there is evidence of pervasive effects on mood, behavior, or social development, but keep in mind that counseling can begin in your own exam room.

Effective discussion starters. Affirming the problem and its unacceptability, talking about the different types of bullying and where bullying may occur, and asking about patient perceptions of bullying can be effective discussion starters. FPs should help patients identify bullying, open lines of communication between children and their parents and between parents and other caregivers, and demonstrate respect and kindness in their approach to discussing the topic. Encourage children to speak with trusted adults when exposed to bullying. Talk to them about standing up to bullies (saying “stop” confidently or walking away from difficult situations) and staying safe by staying near adults or groups of peers when bullies are present (TABLE 3²⁵).

Empowering caregivers. Encourage parents to spend time each day talking with their child about the child’s time away from home (TABLE 3²⁵). Counsel parents/caregivers to expand their role. Knowing a child’s friends, encouraging the child academically, and increasing communication are all associated with lower risks of bullying.²⁶ Similarly, parental oversight of Internet and social media use is associated with decreased participation in cyberbullying.²⁷

In addition, the Positive Parenting telephone-based parenting education curriculum has been shown to decrease bullying, physical fighting, physical injuries, and victimization of children.²⁸ The research-based, family strengthening program emphasizes 3 core elements of authoritative parenting: nurturance, discipline, and respect or granting of psychologic autonomy. The program entails 15- to 30-minute weekly phone conversations between parents and educators, as well as videos and a manual.

Are community programs in place—or are they needed?

Many schools have robust, state-mandated programs in place to identify bullying and provide support for students who are victims of bullying. (See “NJ’s harassment and bullying protocol: A case in point.”) Explaining this to victims and their families may help them come forward and seek assistance. FPs who want to advocate for their patients should start with local schools to support such programs and link students at risk with school counselors.

If programs are lacking in your community, there is much you can do to educate yourself about successful programs and advise local community organizations and schools about them. Among the most successful and well-studied interventions for thwarting the bullying epidemic have been school-based community ones. The most studied of these is the Olweus Bullying Prevention Program (OBPP), which is based on 4 principles:^1,29

1. Adults both at home and at school should take a positive and encouraging interest in students.
2. Unacceptable behavior should have strict and well-known limits.
3. Sanctions should be applied consistently and should be non-hostile in nature.
4. Adults both at home and in the educational environment should act as authorities.

In short, the program focuses on greater awareness and involvement on the part of adults, and employing measures at the school level (eg, surveys, better supervision during break and lunch times), the class level (eg, rules against bullying, regular class meetings with students), and the individual level (eg, serious talks with bullies, victims, parents of involved students).

Research has shown that the OBPP reduces bullying behaviors by as much as 50%, reduces vandalism and truancy, and reduces the number of new victims.¹² Limits to the more widespread implementation of the OBPP have consisted mainly of the inability to appropriately train adults, including teachers and other school personnel in educational settings. Despite these limitations, the OBPP has been praised and endorsed by numerous groups, including the US Department of Justice.³⁰

Encourage children who are bullied to stay safe by standing near adults or groups of peers when bullies are present.Other non-curricular, school-based programs exist, such as the School-Wide Positive Behavioral Interventions and Supports (SWPBIS). This program is a school-wide prevention strategy aimed at: 1) reducing behavior problems that lead to office discipline referrals and suspensions, and 2) changing perceptions of school safety. (For more information, see https://www.crimesolutions.gov/ProgramDetails.aspx?ID=385 and https://www.pbis.org/school/swpbis-for-beginners.)³¹

The research-based Second Step: Student Success Through Prevention (SS-SSTP) Middle School Program (http://www.cfchildren.org/second-step/middle-school)³² focuses on the often difficult middle school years. The program helps schools teach and model essential communication, coping, and decision-making skills to help adolescents navigate around common pitfalls such as peer pressure, substance abuse, and bullying (both in-person and online). The program aims to reduce aggression and provide support for a more inclusive environment that helps students stay in school, make good choices, and experience social and academic success.

The Positive Action Program (https://www.positiveaction.net/research/primer),³³ which is predicated on the notion that we feel good about ourselves when we do positive things, features scripted lessons and kits of materials (eg, posters, games, worksheets, puzzles) appropriate for each grade level.

CASE › Stacey’s visit to her FP’s office has presented several clues that she may be a victim of bullying. Her mild persistent asthma appears to no longer be as well controlled as it was in the past. Direct questioning has revealed that 2 girls at school have been making fun of Stacey when she uses her inhaled corticosteroid in the morning before class, so she has stopped using it. These same students are on her cheerleading team, so she quit the team to avoid them. Her school-related anxiety is so great that she no longer pays attention in math class and is constantly worried that something is being posted about her online.

Stacy’s FP responds to this information with a multifaceted approach. In the exam room, he screens Stacy for depression. While she is negative and denies any suicidal ideation, Stacy is clearly having anxiety, so the FP refers Stacey to a counselor at a local mental health clinic. With Stacy’s permission, the FP discusses the issue with her mother and they decide together with Stacy that she should talk to a teacher at school about the ongoing bullying. Because this was not the first time that the FP has heard this from a child in the community, the FP plans to attend an upcoming school board meeting to advocate for an evidence-based bullying prevention program to help curb the ongoing problem facing his patients.

CORRESPONDENCE
Robert McClowry, MD, Department of Family and Community Medicine, Jefferson Family Medicine Associates, 833 Chestnut East, 3rd Floor, Suite 301, Philadelphia, PA, 19107-4414; Robert.McClowry@Jefferson.edu.

CE/CME No: CR-1702

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Define bipolar disorder according to the DSM-5 criteria.
• Recognize how patients with bipolar disorder can present to their primary care provider.
• Discuss how to perform a clinical and psychiatric evaluation on patients with suspected bipolar disorder.
• Describe the therapeutic options for a patient with bipolar disease in a primary care setting.

FACULTY
Jean Covino is a clinical professor at Pace University-Lenox Hill Hospital in New York City, and she practices at the Medemerge Family Practice Center in Green Brook, New Jersey. Jennifer Hofmann is an Associate Clinical Professor at Pace University-Lenox Hill Hospital in New York City.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of February 2017.

Article begins on next page >>

Primary care clinicians are often the first point of contact for persons with bipolar disorder. Unfortunately, delays in diagnosis are common, as many of these patients are misdiagnosed with unipolar depression on initial presentation. Since an early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes, clinicians should be able to recognize its symptoms and initiate treatment of this deceptive disorder.

Bipolar disorder is a chronic mental illness characterized by fluctuations in mood and energy that manifests as recurrent episodes of manic or depressive symptoms. It is estimated that between 10% and 38% of patients with bipolar disorder receive all their mental health care in a primary care setting.¹ Although patients with bipolar disorder often initially pre­sent to their primary care provider, they frequently go undiagnosed because of the complexity of the disorder’s symptomatology and a low index of suspicion among primary care providers.² Comorbid medical conditions and psychiatric issues can also lead to misdiagnoses.

Because primary care providers are often the first point of contact for patients with bipolar disorder, they are well positioned to recognize bipolar symptoms early in the course of the illness. The pure subtypes of bipolar disorder include bipolar I and bipolar II. Clinicians who work in a primary care or emergency department setting should be able to recognize and initiate treatment for these two subtypes while the patient is waiting for a psychiatric evaluation. Accurate early diagnosis of this disabling disorder can reduce morbidity and improve outcomes by allowing for appropriate referral, pharmacotherapy, and psychotherapy.

DEFINITION

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), bipolar disorder is a mood disorder defined by episodes of mania, hypomania, and major depression.³ Patients with bipolar I disorder experience manic episodes and almost always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode (MDE), and the absence of manic episodes.³ A manic episode is at least one week of abnormally and continually elevated, expansive, or irritable mood and increased activity or energy accompanied by at least three of the following symptoms (or four if mood is only irritable): inflated self-esteem, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, marked distractibility, increased goal-directed activity or agitation, and excessive involvement in dangerous or high-risk activities (eg, reckless spending or increased sexuality). To be considered a manic episode, the mood disturbance must cause marked impairment in social or occupational functioning, result in hospitalization, or involve psychotic features, and the symptoms cannot be attributable to the effects of drugs or medications or another medical condition.³

In a hypomanic episode, the period of elevated or irritable mood lasts for a shorter duration (at least four days); is associated with a clear, uncharacteristic change in functioning; and is observable by others but does not cause marked impairment, need for hospitalization, or psychosis. MDE is defined by the presence of at least five of nine symptoms for a minimum duration of two weeks and a change from previous functioning: depressed mood, markedly decreased interest or pleasure in activities, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, decreased ability to think or concentrate or indecisiveness, and recurrent thoughts of death or suicidality (at least one symptom must be depressed mood or loss of interest or pleasure).³

EPIDEMIOLOGY

Bipolar disorder affects men and women equally. It can occur at any age but is seen most commonly in persons younger than 25.⁴ The mean age at the first manic/hypomanic or major depressive episode was determined to be 18.2 in bipolar I and 20.3 in bipolar II.⁵ The lifetime prevalence of bipolar disorder in the United States is around 4%, with one study finding prevalence estimates of 1.0% for bipolar I disorder and 1.1% for bipolar II disorder.⁵

Bipolar disorder is common among primary care patients with depression. Two studies that explored the risk for bipolar disorder among depressed outpatients in primary care settings found that between 20% and 30% of these patients screened positive for bipolar disorder on the Mood Disorders Questionnaire (MDQ), indicating that a more thorough evaluation for bipolar disorder was needed.^6,7 A systematic review of the literature found similar rates of positive results on the MDQ screening measure among primary care patients with depression, a trauma exposure, medically unexplained symptoms, or a psychiatric complaint; bipolar disorder was diagnosed with a structured clinical interview in 3% to 9% of these patients.⁸ Children of parents with bipolar disorder have a 4% to 15% risk for also being affected.⁴

CLINICAL PRESENTATION IN PRIMARY CARE

Bipolar patients are often depressed or euthymic for a majority of their lives but can also present in a manic or hypomanic state. In primary care settings, these patients often present with depression (including postpartum depression), which can obscure the diagnosis. Misdiagnosis of bipolar disorder as recurrent unipolar depression occurs in 60% of patients seeking treatment for depression.⁹

Patients with bipolar disorder who pre­sent to primary care usually demonstrate a wide range of mood symptomatology other than depression, including mood swings, anxiety, fatigue, sleep disturbances, and the inability to focus or concentrate. Patients can also present in mixed states. These are characterized by elements of irritability, increased energy, and sleeplessness with depressive features.

Several clues that can assist in detecting bipolar disorder relate to age at onset, family history, mood shifts, seasonality, and atypical depressive symptoms  (eg, sleep dysregulation and appetite changes). Although the diagnosis of bipolar disorder is commonly delayed by many years, patients often report significant mood symptoms in their early 20s. In a study that used a self-administered questionnaire to assess the experience of persons living with bipolar disorder, 33% of the respondents were younger than 15 when their symptoms first started, 27% were between 15 and 19, and 39% were 20 or older.⁹ Parental and family history of bipolar disorder increases risk for the disorder in offspring, so a thorough family history is essential when the disorder is suspected.

Aside from the classic presentation defined by the DSM-5 criteria, patients with bipolar disorder can also exhibit other effects of their illness, such as alcohol-related problems and sexually transmitted or drug-related infections. In patients with bipolar disorder, rates of alcohol use range from 21.4% in adults to 54.5% in adolescents and young adults.¹⁰ Social history may reveal relationship and marital issues, financial problems, difficulties keeping a job, and legal problems.^9,11 Suicide attempts and completed suicides are significantly more common among persons with bipolar disorder than among the general population.^12,13

Comorbidity with at least one other disorder is common in bipolar disorder.⁵ The most common comorbid personality disorder associated with bipolar disorder is borderline personality disorder, which is characterized by ongoing instability in moods and behavior. Persons with this disorder can experience intense episodes of anger, depression, and anxiety that may last from hours to days. The high prevalence of persistent symptoms despite treatment in bipolar disorder and the unstable and partly remitting course of borderline personality make it difficult to distinguish between the two disorders.¹⁴ The frequent mood changes that occur with borderline personality disorder may appear to overlap with the mood swings characterizing bipolar disorder, but the mood episodes in borderline personality disorder are of shorter duration than those in bipolar disorder. Other common comorbid disorders seen in patients with bipolar disorder include substance abuse disorders, anxiety disorders (especially panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder), and attention-deficit/hyperactivity disorder.⁵

Primary care providers should be aware of other common comorbidities that may be present in patients with bipolar disorder. These patients commonly experience medical problems such as diabetes, obesity, and metabolic syndrome, which all lead to increased cardiovascular risk.^15-17

CLINICAL EVALUATION

The initial clinical evaluation of the patient should include a thorough medical, social, family, and psychiatric history. Medical conditions that may mimic bipolar disorder include neurologic conditions (eg, partial seizures, neoplasm, strokes, dementia, delirium) and endocrine disorders (eg, Cushing disease, hyperthyroidism/hypothyroidism), as well as vitamin deficiencies (B₁₂, folate, niacin, thiamine) and drug and substance use/misuse (alcohol, drugs including antidepressants and stimulants).⁴ All patients should have a baseline complete physical examination, including neurologic and mental status examinations. Diagnostic tests to assess for potential differential diagnoses and evaluate baseline levels include the following:

• Basic metabolic panel, including fasting glucose, to evaluate electrolytes and risk for diabetes or Cushing disease, and to assess baseline renal function
• Thyroid function tests
• Complete blood count to assess status prior to anticonvulsant treatment (eg, carbamazepine)
• Pregnancy test if applicable (prior to use of medications)
• Liver function tests to assess baseline measurements prior to use of medications
• Electrocardiography in patients older than 40 to establish baseline and assess QTc interval, especially with use of antipsychotics and carbamazepine
• Urine toxicology screen (to rule out substance abuse).

PSYCHIATRIC EVALUATION

Psychiatric evaluation should focus on age at onset of symptoms, the presence of hypomanic or manic symptoms, prior response to antidepressants, course of the disease including history and duration of depression or manic/hypomanic episodes, and sleep disturbances (increased during depressive episodes and significantly decreased during manic episodes). It is important to assess for a history of self-harm, suicidal ideation, suicide attempts, hospitalizations, legal issues, multiple career shifts, marriage and relationship issues, and smoking and alcohol/substance misuse. Patients with severe manic or depressive episodes may experience psychotic features such as grandiose or paranoid delusions and hallucinations. A history of symptoms from close family members or friends can assist in the diagnosis of bipolar patients.

The use of DSM-5 criteria, as summarized earlier, improves the accuracy of bipolar diagnosis.³ In addition, validated tools are available to help clinicians screen for bipolar disorder, although it is important to remember that a positive screening result is not sufficient to establish a bipolar disorder diagnosis. A widely used instrument that has been validated for screening for bipolar disorder is the MDQ (available at www.dbsalliance.org/pdfs/MDQ.pdf). This self-report questionnaire consists of 15 questions that assess hypomanic or manic symptoms and functional impairment. The first 13 questions of the MDQ screen for a lifetime history of DSM-based hypomanic or manic symptoms. The last two questions ask whether these symptoms occurred at the same time and whether they caused dysfunction in various domains, such as work and family life. The MDQ is considered positive if a patient endorses at least seven of the symptom items, indicates that symptoms have occurred at the same time, and rates their dysfunction in life domains as “moderate” or “serious.” As a screening tool, the MDQ has a reported sensitivity of 73% and a specificity of 90% for bipolar disorder.¹¹ This questionnaire can and should be used by primary care providers to help determine if their patient is at risk and requires a comprehensive evaluation for bipolar disorder.

Notably, even after a clinician has properly diagnosed bipolar disorder, patients and family members are often reluctant to commence treatment due to the stigma associated with mental health disorders.¹⁸ To help offset the effects of stigma, patients should be referred for psychologic counseling, including family counseling.

MANAGEMENT

Management of bipolar disorder in the primary care setting includes psychiatric and psychologic counseling referrals. Primary care providers must know the medications used to treat bipolar disorder and their related adverse effects, toxicities, warnings, and drug interactions, as they may treat bipolar patients for other medical conditions. Early diagnosis and treatment/referral can improve prognosis and reduce the risk for relapse and subsequent disability.¹⁹ Inpatient management is generally recommended for severe manic episodes, psychotic episodes, patients who present a danger to themselves or others, and patients with suicidal or homicidal ideations/actions.

Medications are the primary treatment for all stages of bipolar disorder, and choice of medications is based on stage, previous response, and adverse effect profiles (see Table 1).^2,4,20 Generally, antidepressants (serotonin and norepinephrine reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]) should be avoided or should be used with an effective antimanic/mood stabilizer. Many patients with severe bipolar symptoms require more than two medications, and it is imperative that all primary care providers understand that often one drug alone is not sufficient treatment for patients with bipolar disorder. For less severe manic or hypomanic states, monotherapy with antipsychotics may be effective.

Medications for severe acute manic episodes generally include the mood stabilizers lithium, valproate, or carbamazepine in conjunction with an antipsychotic, such as haloperidol, or an atypical antipsychotic, such as asenapine, aripiprazole, olanza­pine, quetiapine, or risperidone.² The goal of initial therapy in patients with acute mania is rapid resolution of symptoms and restoration of adequate sleep. Lithium has a slower onset of action than valproate and carbamazepine and requires titration and monitoring. Valproate and carbamazepine have a faster onset of action but are less effective than lithium.² Atypical antipsychotics have a more rapid onset of action than mood stabilizers and are effective in controlling acute manic symptoms, psychosis, and sleep disturbances. Patients with severe acute mania may require hospital admission for stabilization, for their safety and the safety of others.

Acute bipolar depressive episodes can be treated with several different medication options, including combination olanzapine and fluoxetine; the atypical antipsychotic quetiapine; and recently lurasidone, alone or in combination with lithium or valproate. Lamotrigine is more effective for maintenance and prevention of depressive episodes than for treatment of acute episodes, and it is also indicated for treatment of bipolar II. Valproate is more effective than lithium for mixed states and can be titrated more rapidly for faster antimanic effects.⁴

Generally, due to the high rate of recurrence, maintenance medications should be continued indefinitely. Maintenance medications include the mood stabilizers, lamotrigine, and many of the antipsychotics, including olanzapine.⁴ Adherence to medications is essential in management of bipolar disorder and can decrease the risk for relapses and destabilization. Poor adherence to medications is common, however, with rates reported at approximately 50%.²¹ Patient and family education, as well as psychotherapy, can improve adherence rates.² Primary care providers should educate patients and family members about medication options and adverse effects and must stress the need for adherence to prevent relapse. Providers should also understand the safety profile of mood stabilizers and antipsychotics and the required monitoring of laboratory tests for patients on these medications.

Psychosocial treatments are an elemental component of management. Patients should be referred early for psychologic treatments including, but not limited to, family therapy, group therapy, cognitive-behavioral therapy, and psychotherapy, which have been shown to improve daily functioning, recognition of recurrences, and medication adherence.² The rate of relapse is significantly lower in patients receiving combination psychotherapy and pharmacotherapy.²²

Clinical pearls that every primary care provider should know about bipolar disorder are summarized in Table 2.

CONCLUSION

Given the substantial impact of bipolar disorder on patients and the community, primary care clinicians must maintain a high index of suspicion for this disorder. An early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes. However, diagnosing and treating patients with bipolar disorder is challenging for primary care and specialty clinicians alike. In particular, establishing a diagnosis can be difficult, even for the most seasoned clinician, due to the diversity of symptoms. Nonetheless, diagnosing bipolar disorder, initiating treatment, and monitoring and referring patients when necessary are certainly within the purview of the primary care provider.

CE/CME No: CR-1702

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Define bipolar disorder according to the DSM-5 criteria.
• Recognize how patients with bipolar disorder can present to their primary care provider.
• Discuss how to perform a clinical and psychiatric evaluation on patients with suspected bipolar disorder.
• Describe the therapeutic options for a patient with bipolar disease in a primary care setting.

FACULTY
Jean Covino is a clinical professor at Pace University-Lenox Hill Hospital in New York City, and she practices at the Medemerge Family Practice Center in Green Brook, New Jersey. Jennifer Hofmann is an Associate Clinical Professor at Pace University-Lenox Hill Hospital in New York City.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of February 2017.

Article begins on next page >>

Primary care clinicians are often the first point of contact for persons with bipolar disorder. Unfortunately, delays in diagnosis are common, as many of these patients are misdiagnosed with unipolar depression on initial presentation. Since an early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes, clinicians should be able to recognize its symptoms and initiate treatment of this deceptive disorder.

Bipolar disorder is a chronic mental illness characterized by fluctuations in mood and energy that manifests as recurrent episodes of manic or depressive symptoms. It is estimated that between 10% and 38% of patients with bipolar disorder receive all their mental health care in a primary care setting.¹ Although patients with bipolar disorder often initially pre­sent to their primary care provider, they frequently go undiagnosed because of the complexity of the disorder’s symptomatology and a low index of suspicion among primary care providers.² Comorbid medical conditions and psychiatric issues can also lead to misdiagnoses.

Because primary care providers are often the first point of contact for patients with bipolar disorder, they are well positioned to recognize bipolar symptoms early in the course of the illness. The pure subtypes of bipolar disorder include bipolar I and bipolar II. Clinicians who work in a primary care or emergency department setting should be able to recognize and initiate treatment for these two subtypes while the patient is waiting for a psychiatric evaluation. Accurate early diagnosis of this disabling disorder can reduce morbidity and improve outcomes by allowing for appropriate referral, pharmacotherapy, and psychotherapy.

DEFINITION

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), bipolar disorder is a mood disorder defined by episodes of mania, hypomania, and major depression.³ Patients with bipolar I disorder experience manic episodes and almost always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode (MDE), and the absence of manic episodes.³ A manic episode is at least one week of abnormally and continually elevated, expansive, or irritable mood and increased activity or energy accompanied by at least three of the following symptoms (or four if mood is only irritable): inflated self-esteem, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, marked distractibility, increased goal-directed activity or agitation, and excessive involvement in dangerous or high-risk activities (eg, reckless spending or increased sexuality). To be considered a manic episode, the mood disturbance must cause marked impairment in social or occupational functioning, result in hospitalization, or involve psychotic features, and the symptoms cannot be attributable to the effects of drugs or medications or another medical condition.³

In a hypomanic episode, the period of elevated or irritable mood lasts for a shorter duration (at least four days); is associated with a clear, uncharacteristic change in functioning; and is observable by others but does not cause marked impairment, need for hospitalization, or psychosis. MDE is defined by the presence of at least five of nine symptoms for a minimum duration of two weeks and a change from previous functioning: depressed mood, markedly decreased interest or pleasure in activities, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, decreased ability to think or concentrate or indecisiveness, and recurrent thoughts of death or suicidality (at least one symptom must be depressed mood or loss of interest or pleasure).³

EPIDEMIOLOGY

Bipolar disorder affects men and women equally. It can occur at any age but is seen most commonly in persons younger than 25.⁴ The mean age at the first manic/hypomanic or major depressive episode was determined to be 18.2 in bipolar I and 20.3 in bipolar II.⁵ The lifetime prevalence of bipolar disorder in the United States is around 4%, with one study finding prevalence estimates of 1.0% for bipolar I disorder and 1.1% for bipolar II disorder.⁵

Bipolar disorder is common among primary care patients with depression. Two studies that explored the risk for bipolar disorder among depressed outpatients in primary care settings found that between 20% and 30% of these patients screened positive for bipolar disorder on the Mood Disorders Questionnaire (MDQ), indicating that a more thorough evaluation for bipolar disorder was needed.^6,7 A systematic review of the literature found similar rates of positive results on the MDQ screening measure among primary care patients with depression, a trauma exposure, medically unexplained symptoms, or a psychiatric complaint; bipolar disorder was diagnosed with a structured clinical interview in 3% to 9% of these patients.⁸ Children of parents with bipolar disorder have a 4% to 15% risk for also being affected.⁴

CLINICAL PRESENTATION IN PRIMARY CARE

Bipolar patients are often depressed or euthymic for a majority of their lives but can also present in a manic or hypomanic state. In primary care settings, these patients often present with depression (including postpartum depression), which can obscure the diagnosis. Misdiagnosis of bipolar disorder as recurrent unipolar depression occurs in 60% of patients seeking treatment for depression.⁹

Patients with bipolar disorder who pre­sent to primary care usually demonstrate a wide range of mood symptomatology other than depression, including mood swings, anxiety, fatigue, sleep disturbances, and the inability to focus or concentrate. Patients can also present in mixed states. These are characterized by elements of irritability, increased energy, and sleeplessness with depressive features.

Several clues that can assist in detecting bipolar disorder relate to age at onset, family history, mood shifts, seasonality, and atypical depressive symptoms  (eg, sleep dysregulation and appetite changes). Although the diagnosis of bipolar disorder is commonly delayed by many years, patients often report significant mood symptoms in their early 20s. In a study that used a self-administered questionnaire to assess the experience of persons living with bipolar disorder, 33% of the respondents were younger than 15 when their symptoms first started, 27% were between 15 and 19, and 39% were 20 or older.⁹ Parental and family history of bipolar disorder increases risk for the disorder in offspring, so a thorough family history is essential when the disorder is suspected.

Aside from the classic presentation defined by the DSM-5 criteria, patients with bipolar disorder can also exhibit other effects of their illness, such as alcohol-related problems and sexually transmitted or drug-related infections. In patients with bipolar disorder, rates of alcohol use range from 21.4% in adults to 54.5% in adolescents and young adults.¹⁰ Social history may reveal relationship and marital issues, financial problems, difficulties keeping a job, and legal problems.^9,11 Suicide attempts and completed suicides are significantly more common among persons with bipolar disorder than among the general population.^12,13

Comorbidity with at least one other disorder is common in bipolar disorder.⁵ The most common comorbid personality disorder associated with bipolar disorder is borderline personality disorder, which is characterized by ongoing instability in moods and behavior. Persons with this disorder can experience intense episodes of anger, depression, and anxiety that may last from hours to days. The high prevalence of persistent symptoms despite treatment in bipolar disorder and the unstable and partly remitting course of borderline personality make it difficult to distinguish between the two disorders.¹⁴ The frequent mood changes that occur with borderline personality disorder may appear to overlap with the mood swings characterizing bipolar disorder, but the mood episodes in borderline personality disorder are of shorter duration than those in bipolar disorder. Other common comorbid disorders seen in patients with bipolar disorder include substance abuse disorders, anxiety disorders (especially panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder), and attention-deficit/hyperactivity disorder.⁵

Primary care providers should be aware of other common comorbidities that may be present in patients with bipolar disorder. These patients commonly experience medical problems such as diabetes, obesity, and metabolic syndrome, which all lead to increased cardiovascular risk.^15-17

CLINICAL EVALUATION

The initial clinical evaluation of the patient should include a thorough medical, social, family, and psychiatric history. Medical conditions that may mimic bipolar disorder include neurologic conditions (eg, partial seizures, neoplasm, strokes, dementia, delirium) and endocrine disorders (eg, Cushing disease, hyperthyroidism/hypothyroidism), as well as vitamin deficiencies (B₁₂, folate, niacin, thiamine) and drug and substance use/misuse (alcohol, drugs including antidepressants and stimulants).⁴ All patients should have a baseline complete physical examination, including neurologic and mental status examinations. Diagnostic tests to assess for potential differential diagnoses and evaluate baseline levels include the following:

• Basic metabolic panel, including fasting glucose, to evaluate electrolytes and risk for diabetes or Cushing disease, and to assess baseline renal function
• Thyroid function tests
• Complete blood count to assess status prior to anticonvulsant treatment (eg, carbamazepine)
• Pregnancy test if applicable (prior to use of medications)
• Liver function tests to assess baseline measurements prior to use of medications
• Electrocardiography in patients older than 40 to establish baseline and assess QTc interval, especially with use of antipsychotics and carbamazepine
• Urine toxicology screen (to rule out substance abuse).

PSYCHIATRIC EVALUATION

Psychiatric evaluation should focus on age at onset of symptoms, the presence of hypomanic or manic symptoms, prior response to antidepressants, course of the disease including history and duration of depression or manic/hypomanic episodes, and sleep disturbances (increased during depressive episodes and significantly decreased during manic episodes). It is important to assess for a history of self-harm, suicidal ideation, suicide attempts, hospitalizations, legal issues, multiple career shifts, marriage and relationship issues, and smoking and alcohol/substance misuse. Patients with severe manic or depressive episodes may experience psychotic features such as grandiose or paranoid delusions and hallucinations. A history of symptoms from close family members or friends can assist in the diagnosis of bipolar patients.

The use of DSM-5 criteria, as summarized earlier, improves the accuracy of bipolar diagnosis.³ In addition, validated tools are available to help clinicians screen for bipolar disorder, although it is important to remember that a positive screening result is not sufficient to establish a bipolar disorder diagnosis. A widely used instrument that has been validated for screening for bipolar disorder is the MDQ (available at www.dbsalliance.org/pdfs/MDQ.pdf). This self-report questionnaire consists of 15 questions that assess hypomanic or manic symptoms and functional impairment. The first 13 questions of the MDQ screen for a lifetime history of DSM-based hypomanic or manic symptoms. The last two questions ask whether these symptoms occurred at the same time and whether they caused dysfunction in various domains, such as work and family life. The MDQ is considered positive if a patient endorses at least seven of the symptom items, indicates that symptoms have occurred at the same time, and rates their dysfunction in life domains as “moderate” or “serious.” As a screening tool, the MDQ has a reported sensitivity of 73% and a specificity of 90% for bipolar disorder.¹¹ This questionnaire can and should be used by primary care providers to help determine if their patient is at risk and requires a comprehensive evaluation for bipolar disorder.

Notably, even after a clinician has properly diagnosed bipolar disorder, patients and family members are often reluctant to commence treatment due to the stigma associated with mental health disorders.¹⁸ To help offset the effects of stigma, patients should be referred for psychologic counseling, including family counseling.

MANAGEMENT

Management of bipolar disorder in the primary care setting includes psychiatric and psychologic counseling referrals. Primary care providers must know the medications used to treat bipolar disorder and their related adverse effects, toxicities, warnings, and drug interactions, as they may treat bipolar patients for other medical conditions. Early diagnosis and treatment/referral can improve prognosis and reduce the risk for relapse and subsequent disability.¹⁹ Inpatient management is generally recommended for severe manic episodes, psychotic episodes, patients who present a danger to themselves or others, and patients with suicidal or homicidal ideations/actions.

Medications are the primary treatment for all stages of bipolar disorder, and choice of medications is based on stage, previous response, and adverse effect profiles (see Table 1).^2,4,20 Generally, antidepressants (serotonin and norepinephrine reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]) should be avoided or should be used with an effective antimanic/mood stabilizer. Many patients with severe bipolar symptoms require more than two medications, and it is imperative that all primary care providers understand that often one drug alone is not sufficient treatment for patients with bipolar disorder. For less severe manic or hypomanic states, monotherapy with antipsychotics may be effective.

Medications for severe acute manic episodes generally include the mood stabilizers lithium, valproate, or carbamazepine in conjunction with an antipsychotic, such as haloperidol, or an atypical antipsychotic, such as asenapine, aripiprazole, olanza­pine, quetiapine, or risperidone.² The goal of initial therapy in patients with acute mania is rapid resolution of symptoms and restoration of adequate sleep. Lithium has a slower onset of action than valproate and carbamazepine and requires titration and monitoring. Valproate and carbamazepine have a faster onset of action but are less effective than lithium.² Atypical antipsychotics have a more rapid onset of action than mood stabilizers and are effective in controlling acute manic symptoms, psychosis, and sleep disturbances. Patients with severe acute mania may require hospital admission for stabilization, for their safety and the safety of others.

Acute bipolar depressive episodes can be treated with several different medication options, including combination olanzapine and fluoxetine; the atypical antipsychotic quetiapine; and recently lurasidone, alone or in combination with lithium or valproate. Lamotrigine is more effective for maintenance and prevention of depressive episodes than for treatment of acute episodes, and it is also indicated for treatment of bipolar II. Valproate is more effective than lithium for mixed states and can be titrated more rapidly for faster antimanic effects.⁴

Generally, due to the high rate of recurrence, maintenance medications should be continued indefinitely. Maintenance medications include the mood stabilizers, lamotrigine, and many of the antipsychotics, including olanzapine.⁴ Adherence to medications is essential in management of bipolar disorder and can decrease the risk for relapses and destabilization. Poor adherence to medications is common, however, with rates reported at approximately 50%.²¹ Patient and family education, as well as psychotherapy, can improve adherence rates.² Primary care providers should educate patients and family members about medication options and adverse effects and must stress the need for adherence to prevent relapse. Providers should also understand the safety profile of mood stabilizers and antipsychotics and the required monitoring of laboratory tests for patients on these medications.

Psychosocial treatments are an elemental component of management. Patients should be referred early for psychologic treatments including, but not limited to, family therapy, group therapy, cognitive-behavioral therapy, and psychotherapy, which have been shown to improve daily functioning, recognition of recurrences, and medication adherence.² The rate of relapse is significantly lower in patients receiving combination psychotherapy and pharmacotherapy.²²

Clinical pearls that every primary care provider should know about bipolar disorder are summarized in Table 2.

CONCLUSION

Given the substantial impact of bipolar disorder on patients and the community, primary care clinicians must maintain a high index of suspicion for this disorder. An early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes. However, diagnosing and treating patients with bipolar disorder is challenging for primary care and specialty clinicians alike. In particular, establishing a diagnosis can be difficult, even for the most seasoned clinician, due to the diversity of symptoms. Nonetheless, diagnosing bipolar disorder, initiating treatment, and monitoring and referring patients when necessary are certainly within the purview of the primary care provider.

CE/CME No: CR-1702

PROGRAM OVERVIEW
Earn credit by reading this article and successfully completing the posttest and evaluation. Successful completion is defined as a cumulative score of at least 70% correct.

EDUCATIONAL OBJECTIVES
• Define bipolar disorder according to the DSM-5 criteria.
• Recognize how patients with bipolar disorder can present to their primary care provider.
• Discuss how to perform a clinical and psychiatric evaluation on patients with suspected bipolar disorder.
• Describe the therapeutic options for a patient with bipolar disease in a primary care setting.

FACULTY
Jean Covino is a clinical professor at Pace University-Lenox Hill Hospital in New York City, and she practices at the Medemerge Family Practice Center in Green Brook, New Jersey. Jennifer Hofmann is an Associate Clinical Professor at Pace University-Lenox Hill Hospital in New York City.

The authors have no financial relationships to disclose.

ACCREDITATION STATEMENT

This program has been reviewed and is approved for a maximum of 1.0 hour of American Academy of Physician Assistants (AAPA) Category 1 CME credit by the Physician Assistant Review Panel. [NPs: Both ANCC and the AANP Certification Program recognize AAPA as an approved provider of Category 1 credit.] Approval is valid for one year from the issue date of February 2017.

Article begins on next page >>

Primary care clinicians are often the first point of contact for persons with bipolar disorder. Unfortunately, delays in diagnosis are common, as many of these patients are misdiagnosed with unipolar depression on initial presentation. Since an early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes, clinicians should be able to recognize its symptoms and initiate treatment of this deceptive disorder.

Bipolar disorder is a chronic mental illness characterized by fluctuations in mood and energy that manifests as recurrent episodes of manic or depressive symptoms. It is estimated that between 10% and 38% of patients with bipolar disorder receive all their mental health care in a primary care setting.¹ Although patients with bipolar disorder often initially pre­sent to their primary care provider, they frequently go undiagnosed because of the complexity of the disorder’s symptomatology and a low index of suspicion among primary care providers.² Comorbid medical conditions and psychiatric issues can also lead to misdiagnoses.

Because primary care providers are often the first point of contact for patients with bipolar disorder, they are well positioned to recognize bipolar symptoms early in the course of the illness. The pure subtypes of bipolar disorder include bipolar I and bipolar II. Clinicians who work in a primary care or emergency department setting should be able to recognize and initiate treatment for these two subtypes while the patient is waiting for a psychiatric evaluation. Accurate early diagnosis of this disabling disorder can reduce morbidity and improve outcomes by allowing for appropriate referral, pharmacotherapy, and psychotherapy.

DEFINITION

According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders (DSM-5), bipolar disorder is a mood disorder defined by episodes of mania, hypomania, and major depression.³ Patients with bipolar I disorder experience manic episodes and almost always experience major depressive and hypomanic episodes. Bipolar II disorder is marked by at least one hypomanic episode, at least one major depressive episode (MDE), and the absence of manic episodes.³ A manic episode is at least one week of abnormally and continually elevated, expansive, or irritable mood and increased activity or energy accompanied by at least three of the following symptoms (or four if mood is only irritable): inflated self-esteem, decreased need for sleep, increased talkativeness, flight of ideas or racing thoughts, marked distractibility, increased goal-directed activity or agitation, and excessive involvement in dangerous or high-risk activities (eg, reckless spending or increased sexuality). To be considered a manic episode, the mood disturbance must cause marked impairment in social or occupational functioning, result in hospitalization, or involve psychotic features, and the symptoms cannot be attributable to the effects of drugs or medications or another medical condition.³

In a hypomanic episode, the period of elevated or irritable mood lasts for a shorter duration (at least four days); is associated with a clear, uncharacteristic change in functioning; and is observable by others but does not cause marked impairment, need for hospitalization, or psychosis. MDE is defined by the presence of at least five of nine symptoms for a minimum duration of two weeks and a change from previous functioning: depressed mood, markedly decreased interest or pleasure in activities, significant change in weight or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, fatigue or loss of energy, feelings of worthlessness or excessive guilt, decreased ability to think or concentrate or indecisiveness, and recurrent thoughts of death or suicidality (at least one symptom must be depressed mood or loss of interest or pleasure).³

EPIDEMIOLOGY

Bipolar disorder affects men and women equally. It can occur at any age but is seen most commonly in persons younger than 25.⁴ The mean age at the first manic/hypomanic or major depressive episode was determined to be 18.2 in bipolar I and 20.3 in bipolar II.⁵ The lifetime prevalence of bipolar disorder in the United States is around 4%, with one study finding prevalence estimates of 1.0% for bipolar I disorder and 1.1% for bipolar II disorder.⁵

Bipolar disorder is common among primary care patients with depression. Two studies that explored the risk for bipolar disorder among depressed outpatients in primary care settings found that between 20% and 30% of these patients screened positive for bipolar disorder on the Mood Disorders Questionnaire (MDQ), indicating that a more thorough evaluation for bipolar disorder was needed.^6,7 A systematic review of the literature found similar rates of positive results on the MDQ screening measure among primary care patients with depression, a trauma exposure, medically unexplained symptoms, or a psychiatric complaint; bipolar disorder was diagnosed with a structured clinical interview in 3% to 9% of these patients.⁸ Children of parents with bipolar disorder have a 4% to 15% risk for also being affected.⁴

CLINICAL PRESENTATION IN PRIMARY CARE

Bipolar patients are often depressed or euthymic for a majority of their lives but can also present in a manic or hypomanic state. In primary care settings, these patients often present with depression (including postpartum depression), which can obscure the diagnosis. Misdiagnosis of bipolar disorder as recurrent unipolar depression occurs in 60% of patients seeking treatment for depression.⁹

Patients with bipolar disorder who pre­sent to primary care usually demonstrate a wide range of mood symptomatology other than depression, including mood swings, anxiety, fatigue, sleep disturbances, and the inability to focus or concentrate. Patients can also present in mixed states. These are characterized by elements of irritability, increased energy, and sleeplessness with depressive features.

Several clues that can assist in detecting bipolar disorder relate to age at onset, family history, mood shifts, seasonality, and atypical depressive symptoms  (eg, sleep dysregulation and appetite changes). Although the diagnosis of bipolar disorder is commonly delayed by many years, patients often report significant mood symptoms in their early 20s. In a study that used a self-administered questionnaire to assess the experience of persons living with bipolar disorder, 33% of the respondents were younger than 15 when their symptoms first started, 27% were between 15 and 19, and 39% were 20 or older.⁹ Parental and family history of bipolar disorder increases risk for the disorder in offspring, so a thorough family history is essential when the disorder is suspected.

Aside from the classic presentation defined by the DSM-5 criteria, patients with bipolar disorder can also exhibit other effects of their illness, such as alcohol-related problems and sexually transmitted or drug-related infections. In patients with bipolar disorder, rates of alcohol use range from 21.4% in adults to 54.5% in adolescents and young adults.¹⁰ Social history may reveal relationship and marital issues, financial problems, difficulties keeping a job, and legal problems.^9,11 Suicide attempts and completed suicides are significantly more common among persons with bipolar disorder than among the general population.^12,13

Comorbidity with at least one other disorder is common in bipolar disorder.⁵ The most common comorbid personality disorder associated with bipolar disorder is borderline personality disorder, which is characterized by ongoing instability in moods and behavior. Persons with this disorder can experience intense episodes of anger, depression, and anxiety that may last from hours to days. The high prevalence of persistent symptoms despite treatment in bipolar disorder and the unstable and partly remitting course of borderline personality make it difficult to distinguish between the two disorders.¹⁴ The frequent mood changes that occur with borderline personality disorder may appear to overlap with the mood swings characterizing bipolar disorder, but the mood episodes in borderline personality disorder are of shorter duration than those in bipolar disorder. Other common comorbid disorders seen in patients with bipolar disorder include substance abuse disorders, anxiety disorders (especially panic disorder, generalized anxiety disorder, and obsessive-compulsive disorder), and attention-deficit/hyperactivity disorder.⁵

Primary care providers should be aware of other common comorbidities that may be present in patients with bipolar disorder. These patients commonly experience medical problems such as diabetes, obesity, and metabolic syndrome, which all lead to increased cardiovascular risk.^15-17

CLINICAL EVALUATION

The initial clinical evaluation of the patient should include a thorough medical, social, family, and psychiatric history. Medical conditions that may mimic bipolar disorder include neurologic conditions (eg, partial seizures, neoplasm, strokes, dementia, delirium) and endocrine disorders (eg, Cushing disease, hyperthyroidism/hypothyroidism), as well as vitamin deficiencies (B₁₂, folate, niacin, thiamine) and drug and substance use/misuse (alcohol, drugs including antidepressants and stimulants).⁴ All patients should have a baseline complete physical examination, including neurologic and mental status examinations. Diagnostic tests to assess for potential differential diagnoses and evaluate baseline levels include the following:

• Basic metabolic panel, including fasting glucose, to evaluate electrolytes and risk for diabetes or Cushing disease, and to assess baseline renal function
• Thyroid function tests
• Complete blood count to assess status prior to anticonvulsant treatment (eg, carbamazepine)
• Pregnancy test if applicable (prior to use of medications)
• Liver function tests to assess baseline measurements prior to use of medications
• Electrocardiography in patients older than 40 to establish baseline and assess QTc interval, especially with use of antipsychotics and carbamazepine
• Urine toxicology screen (to rule out substance abuse).

PSYCHIATRIC EVALUATION

Psychiatric evaluation should focus on age at onset of symptoms, the presence of hypomanic or manic symptoms, prior response to antidepressants, course of the disease including history and duration of depression or manic/hypomanic episodes, and sleep disturbances (increased during depressive episodes and significantly decreased during manic episodes). It is important to assess for a history of self-harm, suicidal ideation, suicide attempts, hospitalizations, legal issues, multiple career shifts, marriage and relationship issues, and smoking and alcohol/substance misuse. Patients with severe manic or depressive episodes may experience psychotic features such as grandiose or paranoid delusions and hallucinations. A history of symptoms from close family members or friends can assist in the diagnosis of bipolar patients.

The use of DSM-5 criteria, as summarized earlier, improves the accuracy of bipolar diagnosis.³ In addition, validated tools are available to help clinicians screen for bipolar disorder, although it is important to remember that a positive screening result is not sufficient to establish a bipolar disorder diagnosis. A widely used instrument that has been validated for screening for bipolar disorder is the MDQ (available at www.dbsalliance.org/pdfs/MDQ.pdf). This self-report questionnaire consists of 15 questions that assess hypomanic or manic symptoms and functional impairment. The first 13 questions of the MDQ screen for a lifetime history of DSM-based hypomanic or manic symptoms. The last two questions ask whether these symptoms occurred at the same time and whether they caused dysfunction in various domains, such as work and family life. The MDQ is considered positive if a patient endorses at least seven of the symptom items, indicates that symptoms have occurred at the same time, and rates their dysfunction in life domains as “moderate” or “serious.” As a screening tool, the MDQ has a reported sensitivity of 73% and a specificity of 90% for bipolar disorder.¹¹ This questionnaire can and should be used by primary care providers to help determine if their patient is at risk and requires a comprehensive evaluation for bipolar disorder.

Notably, even after a clinician has properly diagnosed bipolar disorder, patients and family members are often reluctant to commence treatment due to the stigma associated with mental health disorders.¹⁸ To help offset the effects of stigma, patients should be referred for psychologic counseling, including family counseling.

MANAGEMENT

Management of bipolar disorder in the primary care setting includes psychiatric and psychologic counseling referrals. Primary care providers must know the medications used to treat bipolar disorder and their related adverse effects, toxicities, warnings, and drug interactions, as they may treat bipolar patients for other medical conditions. Early diagnosis and treatment/referral can improve prognosis and reduce the risk for relapse and subsequent disability.¹⁹ Inpatient management is generally recommended for severe manic episodes, psychotic episodes, patients who present a danger to themselves or others, and patients with suicidal or homicidal ideations/actions.

Medications are the primary treatment for all stages of bipolar disorder, and choice of medications is based on stage, previous response, and adverse effect profiles (see Table 1).^2,4,20 Generally, antidepressants (serotonin and norepinephrine reuptake inhibitors [SNRIs] and selective serotonin reuptake inhibitors [SSRIs]) should be avoided or should be used with an effective antimanic/mood stabilizer. Many patients with severe bipolar symptoms require more than two medications, and it is imperative that all primary care providers understand that often one drug alone is not sufficient treatment for patients with bipolar disorder. For less severe manic or hypomanic states, monotherapy with antipsychotics may be effective.

Medications for severe acute manic episodes generally include the mood stabilizers lithium, valproate, or carbamazepine in conjunction with an antipsychotic, such as haloperidol, or an atypical antipsychotic, such as asenapine, aripiprazole, olanza­pine, quetiapine, or risperidone.² The goal of initial therapy in patients with acute mania is rapid resolution of symptoms and restoration of adequate sleep. Lithium has a slower onset of action than valproate and carbamazepine and requires titration and monitoring. Valproate and carbamazepine have a faster onset of action but are less effective than lithium.² Atypical antipsychotics have a more rapid onset of action than mood stabilizers and are effective in controlling acute manic symptoms, psychosis, and sleep disturbances. Patients with severe acute mania may require hospital admission for stabilization, for their safety and the safety of others.

Acute bipolar depressive episodes can be treated with several different medication options, including combination olanzapine and fluoxetine; the atypical antipsychotic quetiapine; and recently lurasidone, alone or in combination with lithium or valproate. Lamotrigine is more effective for maintenance and prevention of depressive episodes than for treatment of acute episodes, and it is also indicated for treatment of bipolar II. Valproate is more effective than lithium for mixed states and can be titrated more rapidly for faster antimanic effects.⁴

Generally, due to the high rate of recurrence, maintenance medications should be continued indefinitely. Maintenance medications include the mood stabilizers, lamotrigine, and many of the antipsychotics, including olanzapine.⁴ Adherence to medications is essential in management of bipolar disorder and can decrease the risk for relapses and destabilization. Poor adherence to medications is common, however, with rates reported at approximately 50%.²¹ Patient and family education, as well as psychotherapy, can improve adherence rates.² Primary care providers should educate patients and family members about medication options and adverse effects and must stress the need for adherence to prevent relapse. Providers should also understand the safety profile of mood stabilizers and antipsychotics and the required monitoring of laboratory tests for patients on these medications.

Psychosocial treatments are an elemental component of management. Patients should be referred early for psychologic treatments including, but not limited to, family therapy, group therapy, cognitive-behavioral therapy, and psychotherapy, which have been shown to improve daily functioning, recognition of recurrences, and medication adherence.² The rate of relapse is significantly lower in patients receiving combination psychotherapy and pharmacotherapy.²²

Clinical pearls that every primary care provider should know about bipolar disorder are summarized in Table 2.

CONCLUSION

Given the substantial impact of bipolar disorder on patients and the community, primary care clinicians must maintain a high index of suspicion for this disorder. An early and accurate diagnosis may reduce the burden of bipolar disorder and improve outcomes. However, diagnosing and treating patients with bipolar disorder is challenging for primary care and specialty clinicians alike. In particular, establishing a diagnosis can be difficult, even for the most seasoned clinician, due to the diversity of symptoms. Nonetheless, diagnosing bipolar disorder, initiating treatment, and monitoring and referring patients when necessary are certainly within the purview of the primary care provider.

ILLUSTRATIVE CASE

A 21-year-old G1P0 at 35 weeks, 2 days of gestation presents to labor and delivery reporting a “gush of clear fluid.” On exam, you confirm she has preterm rupture of membranes. She is contracting every 3 minutes and has a cervix dilated to 3 cm. Is there any neonatal benefit to providing corticosteroids in this late preterm period?

Approximately 12% of all births in the United States are the result of preterm labor,² and 8% are born in the late preterm period, defined as 34 to 36 weeks’ gestation.³ To reduce the risk of neonatal death and respiratory complications, both the American College of Obstetricians and Gynecologists and the National Institutes of Health recommend a course of corticosteroids between 24 and 34 weeks’ gestation for women at increased risk of preterm delivery.^2,4 Due to a lack of evidence from randomized controlled trials (RCTs) on the benefit of corticosteroids in late preterm labor, there have not been recommendations to extend this period.⁵ However, multiple studies have shown that babies born during the late preterm period have more neonatal complications than term newborns.^6-8

A retrospective chart review of more than 130,000 live births found newborns delivered between 34 and 36 weeks had higher rates of respiratory distress than those delivered at 39 weeks (ventilator use dropped from 3.3% at 34 weeks to 0.3% at 39 weeks and transient tachypnea decreased from 2.4% at 34 weeks to 0.4% at 39 weeks).⁶ Another retrospective review of more than 230,000 newborns, of which 19,000 were born in the late preterm period, revealed that more neonates born between 34 and 36 weeks’ gestation had respiratory distress syndrome than neonates delivered at 39 weeks (10.5% at 34 weeks, 6% at 35 weeks, 2.8% at 36 weeks vs 0.3% at 39 weeks; P<.001 for the trend).⁸

STUDY SUMMARY

Late preterm newborns breathe better with antenatal betamethasone

This randomized placebo-controlled trial examined the effectiveness of betamethasone in preventing neonatal respiratory complications for 2831 women at high probability of preterm delivery between 34 weeks and 36 weeks, 6 days of gestation. “High probability of preterm delivery” was defined as preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement; spontaneous rupture of membranes; or anticipated preterm delivery for any other indication either through induction or cesarean section between 24 hours and 7 days after the planned randomization.

Patients were randomly assigned to receive either 2 intramuscular injections (12 mg each) of betamethasone or placebo, 24 hours apart. The 2 doses were successfully given in 60% of the betamethasone group and 59% of the placebo group. In 95% of the cases where the second dose was not given, it was because delivery occurred within 24 hours of the first dose.

The primary outcome was the need for respiratory support within 72 hours of birth, which was defined as one or more of the following: the use of continuous positive airway pressure (CPAP) or high-flow nasal cannula for at least 2 consecutive hours, supplemental oxygen for at least 4 continuous hours, extracorporeal membrane oxygenation (ECMO), or mechanical ventilation.

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period.

The median time to delivery from enrollment was 31 to 33 hours, and 31.4% underwent cesarean delivery. In the intention-to-treat analysis, the primary outcome was significantly lower in the betamethasone group than in the placebo group (11.6% vs 14.4%; relative risk [RR]=0.80; 95% CI, 0.66-0.97; P=.02; number needed to treat [NNT]=35). Secondary outcomes (severe complications, representing a composite of the use of CPAP or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen for at least 24 continuous hours, ECMO, mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery) were also lower in the betamethasone group (8.1% vs 12.1%; RR=0.67; 95% CI, 0.53-0.84; P<.001; NNT=25). The betamethasone group also had a lower risk of transient tachypnea of the newborn (6.7% vs 9.9%; RR=0.68; 95% CI, 0.53-0.87; P=.002).

There were no significant differences in the occurrence of maternal chorioamnionitis (about 2%) or endometritis (about 1%) between the groups. Hypoglycemia in the newborn occurred more in the betamethasone group (24% vs 15%; RR=1.6; 95% CI, 1.37-1.87; P<.001; number needed to harm [NNH]=11). The betamethasone group had 2 neonatal deaths: one from septic shock and the other from a structural cardiac anomaly and arrhythmia.

WHAT’S NEW

Betamethasone makes a difference even in the late, late preterm period

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period. The findings were similar to those from the Antenatal Steroids for Term Elective Caesarean Section Research Team.⁹ Their trial showed a reduction in respiratory complications in term neonates delivered via elective cesarean section to mothers who received antenatal betamethasone (NNT=37 to prevent admission to a special care nursery with respiratory distress). The findings were also consistent with those of a recent meta-analysis (including this trial) evaluating the occurrence of respiratory complications with the use of antenatal betamethasone in women expected to deliver in the late preterm period or with a planned cesarean delivery at ≥37 weeks’ gestation.¹⁰

CAVEATS

Neonates may develop hypoglycemia

The authors of the study reported an increased risk of hypoglycemia in the neonates receiving antenatal betamethasone. The long-term implications of this are unclear, however, given that there was a reduction in intermediate care nursery and neonatal intensive care unit stays that were 3 days or longer in the betamethasone group. Also, there was no difference in hospital length of stay between the 2 groups. In addition, it’s not clear if there are any long-term neonatal complications of betamethasone use in the late preterm period.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible since betamethasone is readily available

There are minimal challenges to implementing this strategy, as betamethasone is routinely used for preterm labor and is readily available on labor and delivery units.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 21-year-old G1P0 at 35 weeks, 2 days of gestation presents to labor and delivery reporting a “gush of clear fluid.” On exam, you confirm she has preterm rupture of membranes. She is contracting every 3 minutes and has a cervix dilated to 3 cm. Is there any neonatal benefit to providing corticosteroids in this late preterm period?

Approximately 12% of all births in the United States are the result of preterm labor,² and 8% are born in the late preterm period, defined as 34 to 36 weeks’ gestation.³ To reduce the risk of neonatal death and respiratory complications, both the American College of Obstetricians and Gynecologists and the National Institutes of Health recommend a course of corticosteroids between 24 and 34 weeks’ gestation for women at increased risk of preterm delivery.^2,4 Due to a lack of evidence from randomized controlled trials (RCTs) on the benefit of corticosteroids in late preterm labor, there have not been recommendations to extend this period.⁵ However, multiple studies have shown that babies born during the late preterm period have more neonatal complications than term newborns.^6-8

A retrospective chart review of more than 130,000 live births found newborns delivered between 34 and 36 weeks had higher rates of respiratory distress than those delivered at 39 weeks (ventilator use dropped from 3.3% at 34 weeks to 0.3% at 39 weeks and transient tachypnea decreased from 2.4% at 34 weeks to 0.4% at 39 weeks).⁶ Another retrospective review of more than 230,000 newborns, of which 19,000 were born in the late preterm period, revealed that more neonates born between 34 and 36 weeks’ gestation had respiratory distress syndrome than neonates delivered at 39 weeks (10.5% at 34 weeks, 6% at 35 weeks, 2.8% at 36 weeks vs 0.3% at 39 weeks; P<.001 for the trend).⁸

STUDY SUMMARY

Late preterm newborns breathe better with antenatal betamethasone

This randomized placebo-controlled trial examined the effectiveness of betamethasone in preventing neonatal respiratory complications for 2831 women at high probability of preterm delivery between 34 weeks and 36 weeks, 6 days of gestation. “High probability of preterm delivery” was defined as preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement; spontaneous rupture of membranes; or anticipated preterm delivery for any other indication either through induction or cesarean section between 24 hours and 7 days after the planned randomization.

Patients were randomly assigned to receive either 2 intramuscular injections (12 mg each) of betamethasone or placebo, 24 hours apart. The 2 doses were successfully given in 60% of the betamethasone group and 59% of the placebo group. In 95% of the cases where the second dose was not given, it was because delivery occurred within 24 hours of the first dose.

The primary outcome was the need for respiratory support within 72 hours of birth, which was defined as one or more of the following: the use of continuous positive airway pressure (CPAP) or high-flow nasal cannula for at least 2 consecutive hours, supplemental oxygen for at least 4 continuous hours, extracorporeal membrane oxygenation (ECMO), or mechanical ventilation.

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period.

The median time to delivery from enrollment was 31 to 33 hours, and 31.4% underwent cesarean delivery. In the intention-to-treat analysis, the primary outcome was significantly lower in the betamethasone group than in the placebo group (11.6% vs 14.4%; relative risk [RR]=0.80; 95% CI, 0.66-0.97; P=.02; number needed to treat [NNT]=35). Secondary outcomes (severe complications, representing a composite of the use of CPAP or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen for at least 24 continuous hours, ECMO, mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery) were also lower in the betamethasone group (8.1% vs 12.1%; RR=0.67; 95% CI, 0.53-0.84; P<.001; NNT=25). The betamethasone group also had a lower risk of transient tachypnea of the newborn (6.7% vs 9.9%; RR=0.68; 95% CI, 0.53-0.87; P=.002).

There were no significant differences in the occurrence of maternal chorioamnionitis (about 2%) or endometritis (about 1%) between the groups. Hypoglycemia in the newborn occurred more in the betamethasone group (24% vs 15%; RR=1.6; 95% CI, 1.37-1.87; P<.001; number needed to harm [NNH]=11). The betamethasone group had 2 neonatal deaths: one from septic shock and the other from a structural cardiac anomaly and arrhythmia.

WHAT’S NEW

Betamethasone makes a difference even in the late, late preterm period

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period. The findings were similar to those from the Antenatal Steroids for Term Elective Caesarean Section Research Team.⁹ Their trial showed a reduction in respiratory complications in term neonates delivered via elective cesarean section to mothers who received antenatal betamethasone (NNT=37 to prevent admission to a special care nursery with respiratory distress). The findings were also consistent with those of a recent meta-analysis (including this trial) evaluating the occurrence of respiratory complications with the use of antenatal betamethasone in women expected to deliver in the late preterm period or with a planned cesarean delivery at ≥37 weeks’ gestation.¹⁰

CAVEATS

Neonates may develop hypoglycemia

The authors of the study reported an increased risk of hypoglycemia in the neonates receiving antenatal betamethasone. The long-term implications of this are unclear, however, given that there was a reduction in intermediate care nursery and neonatal intensive care unit stays that were 3 days or longer in the betamethasone group. Also, there was no difference in hospital length of stay between the 2 groups. In addition, it’s not clear if there are any long-term neonatal complications of betamethasone use in the late preterm period.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible since betamethasone is readily available

There are minimal challenges to implementing this strategy, as betamethasone is routinely used for preterm labor and is readily available on labor and delivery units.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATIVE CASE

A 21-year-old G1P0 at 35 weeks, 2 days of gestation presents to labor and delivery reporting a “gush of clear fluid.” On exam, you confirm she has preterm rupture of membranes. She is contracting every 3 minutes and has a cervix dilated to 3 cm. Is there any neonatal benefit to providing corticosteroids in this late preterm period?

Approximately 12% of all births in the United States are the result of preterm labor,² and 8% are born in the late preterm period, defined as 34 to 36 weeks’ gestation.³ To reduce the risk of neonatal death and respiratory complications, both the American College of Obstetricians and Gynecologists and the National Institutes of Health recommend a course of corticosteroids between 24 and 34 weeks’ gestation for women at increased risk of preterm delivery.^2,4 Due to a lack of evidence from randomized controlled trials (RCTs) on the benefit of corticosteroids in late preterm labor, there have not been recommendations to extend this period.⁵ However, multiple studies have shown that babies born during the late preterm period have more neonatal complications than term newborns.^6-8

A retrospective chart review of more than 130,000 live births found newborns delivered between 34 and 36 weeks had higher rates of respiratory distress than those delivered at 39 weeks (ventilator use dropped from 3.3% at 34 weeks to 0.3% at 39 weeks and transient tachypnea decreased from 2.4% at 34 weeks to 0.4% at 39 weeks).⁶ Another retrospective review of more than 230,000 newborns, of which 19,000 were born in the late preterm period, revealed that more neonates born between 34 and 36 weeks’ gestation had respiratory distress syndrome than neonates delivered at 39 weeks (10.5% at 34 weeks, 6% at 35 weeks, 2.8% at 36 weeks vs 0.3% at 39 weeks; P<.001 for the trend).⁸

STUDY SUMMARY

Late preterm newborns breathe better with antenatal betamethasone

This randomized placebo-controlled trial examined the effectiveness of betamethasone in preventing neonatal respiratory complications for 2831 women at high probability of preterm delivery between 34 weeks and 36 weeks, 6 days of gestation. “High probability of preterm delivery” was defined as preterm labor with intact membranes and at least 3 cm dilation or 75% cervical effacement; spontaneous rupture of membranes; or anticipated preterm delivery for any other indication either through induction or cesarean section between 24 hours and 7 days after the planned randomization.

Patients were randomly assigned to receive either 2 intramuscular injections (12 mg each) of betamethasone or placebo, 24 hours apart. The 2 doses were successfully given in 60% of the betamethasone group and 59% of the placebo group. In 95% of the cases where the second dose was not given, it was because delivery occurred within 24 hours of the first dose.

The primary outcome was the need for respiratory support within 72 hours of birth, which was defined as one or more of the following: the use of continuous positive airway pressure (CPAP) or high-flow nasal cannula for at least 2 consecutive hours, supplemental oxygen for at least 4 continuous hours, extracorporeal membrane oxygenation (ECMO), or mechanical ventilation.

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period.

The median time to delivery from enrollment was 31 to 33 hours, and 31.4% underwent cesarean delivery. In the intention-to-treat analysis, the primary outcome was significantly lower in the betamethasone group than in the placebo group (11.6% vs 14.4%; relative risk [RR]=0.80; 95% CI, 0.66-0.97; P=.02; number needed to treat [NNT]=35). Secondary outcomes (severe complications, representing a composite of the use of CPAP or high-flow nasal cannula for at least 12 continuous hours, supplemental oxygen for at least 24 continuous hours, ECMO, mechanical ventilation, stillbirth, or neonatal death within 72 hours after delivery) were also lower in the betamethasone group (8.1% vs 12.1%; RR=0.67; 95% CI, 0.53-0.84; P<.001; NNT=25). The betamethasone group also had a lower risk of transient tachypnea of the newborn (6.7% vs 9.9%; RR=0.68; 95% CI, 0.53-0.87; P=.002).

There were no significant differences in the occurrence of maternal chorioamnionitis (about 2%) or endometritis (about 1%) between the groups. Hypoglycemia in the newborn occurred more in the betamethasone group (24% vs 15%; RR=1.6; 95% CI, 1.37-1.87; P<.001; number needed to harm [NNH]=11). The betamethasone group had 2 neonatal deaths: one from septic shock and the other from a structural cardiac anomaly and arrhythmia.

WHAT’S NEW

Betamethasone makes a difference even in the late, late preterm period

This study demonstrated clear benefit in neonatal respiratory outcomes when betamethasone vs placebo was used in the late preterm period. The findings were similar to those from the Antenatal Steroids for Term Elective Caesarean Section Research Team.⁹ Their trial showed a reduction in respiratory complications in term neonates delivered via elective cesarean section to mothers who received antenatal betamethasone (NNT=37 to prevent admission to a special care nursery with respiratory distress). The findings were also consistent with those of a recent meta-analysis (including this trial) evaluating the occurrence of respiratory complications with the use of antenatal betamethasone in women expected to deliver in the late preterm period or with a planned cesarean delivery at ≥37 weeks’ gestation.¹⁰

CAVEATS

Neonates may develop hypoglycemia

The authors of the study reported an increased risk of hypoglycemia in the neonates receiving antenatal betamethasone. The long-term implications of this are unclear, however, given that there was a reduction in intermediate care nursery and neonatal intensive care unit stays that were 3 days or longer in the betamethasone group. Also, there was no difference in hospital length of stay between the 2 groups. In addition, it’s not clear if there are any long-term neonatal complications of betamethasone use in the late preterm period.

CHALLENGES TO IMPLEMENTATION

Challenges are negligible since betamethasone is readily available

There are minimal challenges to implementing this strategy, as betamethasone is routinely used for preterm labor and is readily available on labor and delivery units.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 22-year-old woman presented to the emergency department (ED) with a 24-hour history of nausea, vomiting, diarrhea, generalized abdominal pain, and mild headache. She denied shortness of breath, chest pain, or anxiety, and didn’t have a history of cardiac problems. The physical examination revealed tachycardia (heart rate, 135 beats/min) and a respiratory rate of 24 breaths per minute. The patient was diagnosed with dehydration and was given 3 liters of intravenous (IV) fluids. After fluid administration, her heart rate decreased to 94 beats/min and she was discharged home.

The patient returned to the ED later that same day with recurrent nausea, vomiting, and a mild fever. This time she reported a several week history of palpitations, heat intolerance, agitation, mild cognitive impairment, and difficulty sleeping. Her mother accompanied her to this visit and added that the patient had unintentionally lost 13 pounds over the past 2 weeks. The patient denied pain or enlargement in her neck, obstructive symptoms, hives, pruritus, or changes in vision. Reexamination revealed tachycardia (132 beats/min) with no murmurs, rubs, or gallops; increased respiratory rate (26 breaths/min); and diffuse thyromegaly without distinct nodules. The thyroid was nontender to palpation. The patient was also found to have a fine resting tremor, hyperactive deep tendon reflexes, and clonus in her lower extremities. Bibasilar crackles were noted on lung exam.

THE DIAGNOSIS

An electrocardiogram (EKG) revealed sinus tachycardia with some sinus arrhythmia. A chest radiograph revealed prominent pulmonary vasculature and the presence of Kerley B lines consistent with marked pulmonary edema. Laboratory testing revealed an elevated N-terminal pro b-type natriuretic peptide level of 2420 pg/mL (normal range: <100 pg/mL). Evaluation of thyroid function revealed overt hyperthyroidism with an elevated free thyroxine of 4.6 ng/dL (normal range: 0.8-1.8 ng/dL), a total triiodothyronine of 199 ng/dL (normal range: 60-181 ng/dL), and a suppressed thyroid-stimulating hormone level of <0.02 mcU/mL (normal range: 0.35-5 mcU/mL). A subsequent thyroid ultrasound showed a diffusely enlarged thyroid gland with a thickened isthmus, but no nodules.

The patient’s results were discussed with the on-call endocrinology provider at the time of her revisit to the ED. The patient was started on antithyroid medications (methimazole 20 mg/d) and a beta-blocker (atenolol 25 mg/d). Arrangements were made for an outpatient endocrine consultation within 3 days of her visit to the ED.

Upon evaluation in the outpatient endocrinology clinic, a thyrotropin receptor antibody test was positive, confirming Graves’ disease. The patient was given a diagnosis of thyrotoxicosis secondary to hyperthyroidism due to Graves’ disease. Her marked pulmonary edema was secondary to thyrotoxicosis and aggressive hydration with IV fluids.

DISCUSSION

Hyperthyroidism is a common metabolic disorder with prominent cardiovascular manifestations.¹ Classically, patients with hyperthyroidism develop irritability, heat intolerance, emotional lability, muscle weakness, menstrual abnormalities, and weight loss (despite an increased appetite). Cardiovascular manifestations include palpitations in up to 85% of patients, and dyspnea on exertion and fatigue in approximately 50% of patients.² Hyperthyroidism has also been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.^3,4 Hyperthyroidism may complicate preexisting cardiac disease or may cause cardiac complications in individuals without structural abnormalities. (Our patient had no known structural abnormalities.)

Hyperthyroidism has been shown to produce changes in cardiac contractility, myocardial oxygen consumption, cardiac output, blood pressure, and systemic vascular resistance.In a small subset of patients with severe hyperthyroidism and exaggerated sinus tachycardia or atrial fibrillation, rate-related left ventricular dysfunction may cause heart failure.⁵ The assessment of thyrotoxic manifestations, especially potential cardiovascular complications, is essential to formulating an appropriate treatment plan.⁶ Cardiac evaluation may require an echocardiogram, EKG, Holter monitor, or myocardial perfusion studies.

Beta-blockers, diuretics among treatment options

Treatment with beta-blockers to reduce heart rate should be first-line therapy.⁷ In patients with overt heart failure involving pulmonary congestion, the use of diuretics may be appropriate.⁸

Our patient continued to take the medications prescribed during her ED visit: methimazole 20 mg/d and atenolol 25 mg/d for her Graves’ disease. A chest radiograph one month later revealed resolution of her pulmonary edema.

THE TAKEAWAY

The cardiovascular manifestations of hyperthyroidism remain some of the most common signs and symptoms of thyroid disease. Pulmonary edema and congestive heart failure, however, are uncommon. Physicians need to be aware of this rare—but important—clinical presentation of a common condition.

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

THE CASE

A 39-year-old man who worked in construction presented to our clinic with complaints of muscle cramps and muscle pain that had been bothering him for several months. The cramps and pain started in both of his arms and subsequently became diffuse and generalized. He also reported an unintentional 15-pound weight loss.

His exam at that time was unremarkable. He was diagnosed with dehydration and cramping due to overexertion at work. A basic metabolic panel, hemogram, lipid panel, and thyroid stimulating hormone level were ordered. The patient’s triglyceride level, which was 227 mg/dL, was the only significant result (normal level: <150 mg/dL).

The patient’s symptoms continued to worsen until he returned to the clinic 6 months later, again complaining of muscle cramps and pain throughout his body. At that second visit, he also reported profound overall weakness and the development of diffuse muscle twitching, which his wife had observed while he was sleeping. As a result of these worrisome symptoms, he had become anxious and depressed.

A review of his medical record revealed a weight loss of about 20 pounds over the previous year. On exam, he had diffuse fasciculations in all the major muscle groups, including his tongue. The patient’s strength was 4/5 in all muscle groups. His deep tendon reflexes were 3+. He had a negative Babinski reflex (ie, he had downward facing toes with plantar stimulation), and cranial nerves II to XII were all intact. His rapid alternating movements and gait were slow.

THE DIAGNOSIS

Based on the exam, the primary diagnostic consideration for the patient was amyotrophic lateral sclerosis (ALS). Lab tests were ordered and revealed normal calcium and electrolyte levels, a normal erythrocyte sedimentation rate, a normal C-reactive protein level, and a negative test for acetylcholine receptor antibodies. However, the patient had an elevated creatine kinase level of 664 U/L (normal: 30-200 U/L). The patient was sent to a neuromuscular specialist, who identified signs of upper and lower motor neuron disease in all 4 of the patient’s extremities (he had foot drop that had not been present previously) and a very brisk jaw jerk. Along with the tongue fasciculations, the results of the specialist’s physical exam suggested ALS. Four-limb electromyography (EMG) showed widespread fasciculations and some large motor unit potentials and recruitment abnormalities, which were also consistent with ALS. It appeared that the patient’s weight loss was due to both muscle atrophy and the amount of calories burned from his constant twitching.

Extensive testing was done to rule out other potential causes of the patient’s symptoms, including magnetic resonance imaging (MRI) of the spine and brain (which was normal). In addition, the patient’s aldolase level and antineutrophil cytoplasmic antibodies were normal. The patient tested negative for human immunodeficiency virus and antibodies to double-stranded DNA. After serial neurologic exams, the final diagnosis of ALS was made.

DISCUSSION

ALS, also known as Lou Gehrig’s disease, is a degenerative motor neuron disease.^1-3 The incidence in North America is 1.5 to 2.7 per 100,000 per year, and the prevalence is 2.7 to 7.4 per 100,000.⁴ The incidence of ALS increases with each decade of life, especially after age 40, and peaks at 74 years of age.⁴ The male to female ratio is 1:1.5-2.⁴ ALS affects upper and lower motor neurons and is progressive; however, the rate of progression and phenotype vary greatly between individuals.² Most patients with ALS die within 2 to 5 years of onset.⁵

There is no specific test for ALS; the diagnosis is made clinically based on the revised El Escorial World Federation of Neurology criteria, also known as the Airlie House criteria.^2,6,7 These criteria include evidence of lower motor neuron degeneration by clinical, electrophysiologic, or neuropathologic exam; evidence of upper motor neuron disease by clinical exam; progressive spread of symptoms or signs within a region or to other regions (by history or exam); and the absence of electrophysiologic, neuroimaging, or pathologic evidence of other disease processes that could explain the symptoms. If patients have evidence of upper and lower motor neuron disease, they should be reevaluated in 4 weeks to see if symptoms are improving or progressing.

Like our patient, many patients will have an elevated creatine kinase level (some with levels as high as 1000 U/L), and calcium may also be elevated because, rarely, ALS is associated with primary hyperparathyroidism.⁸ Electrophysiologic studies can be helpful in identifying active denervation of lower motor neurons.^4,6,7

The differential diagnosis for ALS includes myasthenia gravis, inclusion-body myositis, multifocal motor neuropathy, benign fasciculations, hereditary spastic paraplegia, primary lateral sclerosis, post-polio progressive muscle atrophy, cervical spondylosis, and multiple sclerosis. A negative acetylcholine receptor antibody test will rule out myasthenia gravis, imaging of the spine can rule out cervical spondylosis, and electrophysiologic testing helps eliminate the other conditions (TABLE 1⁴).

Treatment in specialty clinics can prolong survival

The mainstays of treatment are symptom management, multidisciplinary care (by physicians, physical/occupational/speech therapists, nutritionists, psychologists, psychotherapists, and genetic counselors), palliative care, and counseling about end-of-life issues for patients and family.^1,5 Utilization of an ALS specialty clinic can provide access to all of these services and should be considered, as there is evidence that treatment in such clinics can prolong survival.⁵ The location of ALS specialty clinics can be found on the ALS Association’s Web site at http://www.alsa.org/community/.

Despite treatment, however, ALS is a progressive disease. The prognosis is poor, with a median survival of 2 to 5 years after diagnosis.⁹

The El Escorial World Federation of Neurology criteria for the diagnosis of ALS address how to treat the most common symptoms of ALS that occur as the disease progresses. These symptoms include dyspnea, muscle spasms, spasticity, sialorrhea, and pseudobulbar affect (TABLE 2^1,5).

Our patient was started on baclofen 10 mg 3 times per day (titrated up as needed) for muscle spasms and cramps, which resulted in some improvement of his cramps, but no improvement in the spasms. He was also started on sertraline 50 mg for anxiety and depression. His overall weakness continued to progress, and we recommended that the patient get ankle-foot orthosis braces to help with the mobility impairment caused by foot drop.

We then referred him to an ALS specialty clinic recommended by the neuromuscular specialist. The patient is now enrolled in a clinical trial designed to test a cerebrospinal fluid marker for diagnosis and for a new drug aimed at symptom management.

THE TAKEAWAY

Muscle cramps and pain are early signs of ALS. Although ALS is uncommon, patients who present with muscle cramps and muscle pain should have a creatine kinase test ordered (which, if elevated, should prompt further investigation into ALS as the possible cause). Patients should also undergo a neurologic examination to seek evidence of upper and lower motor neuron disease. They should then be reevaluated in 4 weeks to see if symptoms are improving or progressing. If no improvement is seen and symptoms are progressive, a work-up for ALS should be considered.

The mainstay of treatment for patients with ALS is multidisciplinary symptom management and palliative care. Utilization of an ALS specialty clinic should also be recommended, as it can improve survival.⁵

A 62-year-old man with end-stage renal disease presented to our dermatology clinic with 2-month-old ulcerations on his distal left ring finger. He was on hemodialysis and had a radiocephalic arteriovenous fistula (AVF) on his left arm. He had been empirically treated elsewhere with oral trimethoprim-sulfamethoxazole for a presumed bacterial infection, without improvement. He was then treated for contact dermatitis with topical clobetasol, which led to ulcer expansion and worsening pain.

At our clinic, the patient reported intermittent pain in his finger and paresthesias during activity and dialysis, but no tenderness of the ulcers. He had atrophy of the intrinsic left hand muscles (his non-dominant hand) with associated weakness. Three weeks earlier, he’d received a blood transfusion for anemia. Afterward, the pain in his hand improved and the ulcers decreased in size.

On exam, the AVF had a palpable thrill over the left forearm. The radial pulses were palpable bilaterally (2+) and the left ulnar artery was palpable, but diminished (1+). The patient’s left hand was cooler than the right (with a slight cyanotic hue and visible intrinsic muscle atrophy) and had decreased sensation to pain and temperature. Four ulcers with dry yellow eschar were located over the dorsal interphalangeal joints (FIGURES 1A AND 1B). They were essentially non-tender, but there was tenderness in the adjacent intact skin. There was violaceous blue edematous congestion noted on the fourth finger, and the distal phalange was constricted, giving it a “pseudoainhum” appearance.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Dialysis access steal syndrome

We suspected dialysis access steal syndrome (also known as AVF steal syndrome), so a duplex ultrasound was performed. The ultrasound was inconclusive. (We couldn’t confirm a limitation in blood flow, nor delineate anatomy.) So, we referred the patient for a thoracic and upper extremity angiogram.

The angiogram demonstrated multifocal, moderate to severe, areas of stenosis at the distal left brachial artery. The radial artery was patent at the level of the wrist, but showed diffuse narrowing beyond the level of the arteriovenous (AV) anastomosis. There was only a faint palmar arch identified on the radial aspect of the hand with digital branches feeding the radial portion of the hand. In contrast, the ulnar artery was not seen within the mid- and distal forearm (FIGURE 2). Palmar branches to the ulnar half of the hand were not identified. The fistula itself didn’t show any stenosis.

Based on these findings, our suspicions of dialysis access steal syndrome were confirmed.

Dialysis access steal syndrome is caused by a significant decrease or reversal of blood flow in the arterial segment distal to the AVF or graft, which is induced by the low resistance of the fistula outflow. Patients with adequate collateral vasculature are able to compensate for the steal effect; however, patients with end-stage renal disease typically have preexisting vascular disease that increases the risk for vascular steal and, ultimately, demand ischemia after placement of an AVF.¹ Interestingly, a steal effect occurs in 73% of patients after AVF construction, yet it is estimated that only 10% of patients demonstrating a steal phenomenon become symptomatic.²

In our patient’s case, the vaso-occlusive properties of topical steroids explain why the superpotent steroid (clobetasol) he was prescribed increased his pain and worsened the underlying problem.

A broad differential; a useful exam maneuver

The differential diagnosis of ulcers includes infection (mainly from bacterial or mycobacterial sources), trauma facilitated by neuropathy (neuropathic ulceration), vasculitis, and ischemia. When the history and physical exam suggest ischemic ulceration, then thromboembolism, thoracic outlet syndrome, vasculitis, atherosclerosis, and steal syndrome become more likely causes.

Signs and symptoms of ischemic steal syndrome are initially subtle and include extremity coolness, neurosensory changes, intrinsic muscle weakness, ulceration, and ultimately, gangrene of the affected extremity.^3,4 A cold, numb, and/or painful hand during dialysis is another clue.³ Factors that increase the likelihood of the syndrome include age >60 years, female sex, and the presence of diabetes or peripheral artery disease.^2,3,5,6

The confirmatory diagnosis of steal syndrome is made via a fistulogram (angiography) with and without manual compression.

One physical exam maneuver that can help make the diagnosis of steal syndrome is manual occlusion of the AVF. If palpable distal pulses disappear when the AVF is patent and reappear when the fistula is occluded with downward pressure, then AVF steal syndrome is likely.⁴ Pain at rest, sensory loss, loss of pulse, and digital gangrene are emergency symptoms that warrant immediate surgical evaluation.³

Tests will confirm suspicions. Doppler ultrasound can be used to assess changes in the blood flow rate of the affected vessels when the AVF is patent vs when it is occluded. Similarly, pulse oximetry can be used with and without AVF occlusion to compare changes in oxygen saturation. The confirmatory diagnosis, however, is made via a fistulogram (angiography) with and without manual compression.⁶ Images taken after dye injection into the AVF show dramatic improvement of distal blood flow with AVF compression.

Treatment requires surgery

Severe steal-related ischemic manifestations that threaten the function and viability of digits require surgical treatment that is primarily directed toward improving distal blood flow and secondarily toward preserving hemodialysis access. Several surgical treatments are commonly used, including access ligation, banding, elongation, distal arterial ligation, and distal revascularization and interval ligation.^2-5,7

Our patient. Distal revascularization was attempted, but unfortunately, the patient’s gangrene was progressive (FIGURE 3) and surgical amputation of the left fourth finger was performed at the metacarpal’s proximal metaphyseal flare. The patient was transitioned to peritoneal dialysis to avoid further ischemia.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, Department of Dermatology, Indiana University, 545 Barnhill Drive, Indianapolis, IN 46202; srahnama@iupui.edu.

A 62-year-old man with end-stage renal disease presented to our dermatology clinic with 2-month-old ulcerations on his distal left ring finger. He was on hemodialysis and had a radiocephalic arteriovenous fistula (AVF) on his left arm. He had been empirically treated elsewhere with oral trimethoprim-sulfamethoxazole for a presumed bacterial infection, without improvement. He was then treated for contact dermatitis with topical clobetasol, which led to ulcer expansion and worsening pain.

At our clinic, the patient reported intermittent pain in his finger and paresthesias during activity and dialysis, but no tenderness of the ulcers. He had atrophy of the intrinsic left hand muscles (his non-dominant hand) with associated weakness. Three weeks earlier, he’d received a blood transfusion for anemia. Afterward, the pain in his hand improved and the ulcers decreased in size.

On exam, the AVF had a palpable thrill over the left forearm. The radial pulses were palpable bilaterally (2+) and the left ulnar artery was palpable, but diminished (1+). The patient’s left hand was cooler than the right (with a slight cyanotic hue and visible intrinsic muscle atrophy) and had decreased sensation to pain and temperature. Four ulcers with dry yellow eschar were located over the dorsal interphalangeal joints (FIGURES 1A AND 1B). They were essentially non-tender, but there was tenderness in the adjacent intact skin. There was violaceous blue edematous congestion noted on the fourth finger, and the distal phalange was constricted, giving it a “pseudoainhum” appearance.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Dialysis access steal syndrome

We suspected dialysis access steal syndrome (also known as AVF steal syndrome), so a duplex ultrasound was performed. The ultrasound was inconclusive. (We couldn’t confirm a limitation in blood flow, nor delineate anatomy.) So, we referred the patient for a thoracic and upper extremity angiogram.

The angiogram demonstrated multifocal, moderate to severe, areas of stenosis at the distal left brachial artery. The radial artery was patent at the level of the wrist, but showed diffuse narrowing beyond the level of the arteriovenous (AV) anastomosis. There was only a faint palmar arch identified on the radial aspect of the hand with digital branches feeding the radial portion of the hand. In contrast, the ulnar artery was not seen within the mid- and distal forearm (FIGURE 2). Palmar branches to the ulnar half of the hand were not identified. The fistula itself didn’t show any stenosis.

Based on these findings, our suspicions of dialysis access steal syndrome were confirmed.

Dialysis access steal syndrome is caused by a significant decrease or reversal of blood flow in the arterial segment distal to the AVF or graft, which is induced by the low resistance of the fistula outflow. Patients with adequate collateral vasculature are able to compensate for the steal effect; however, patients with end-stage renal disease typically have preexisting vascular disease that increases the risk for vascular steal and, ultimately, demand ischemia after placement of an AVF.¹ Interestingly, a steal effect occurs in 73% of patients after AVF construction, yet it is estimated that only 10% of patients demonstrating a steal phenomenon become symptomatic.²

In our patient’s case, the vaso-occlusive properties of topical steroids explain why the superpotent steroid (clobetasol) he was prescribed increased his pain and worsened the underlying problem.

A broad differential; a useful exam maneuver

The differential diagnosis of ulcers includes infection (mainly from bacterial or mycobacterial sources), trauma facilitated by neuropathy (neuropathic ulceration), vasculitis, and ischemia. When the history and physical exam suggest ischemic ulceration, then thromboembolism, thoracic outlet syndrome, vasculitis, atherosclerosis, and steal syndrome become more likely causes.

Signs and symptoms of ischemic steal syndrome are initially subtle and include extremity coolness, neurosensory changes, intrinsic muscle weakness, ulceration, and ultimately, gangrene of the affected extremity.^3,4 A cold, numb, and/or painful hand during dialysis is another clue.³ Factors that increase the likelihood of the syndrome include age >60 years, female sex, and the presence of diabetes or peripheral artery disease.^2,3,5,6

The confirmatory diagnosis of steal syndrome is made via a fistulogram (angiography) with and without manual compression.

One physical exam maneuver that can help make the diagnosis of steal syndrome is manual occlusion of the AVF. If palpable distal pulses disappear when the AVF is patent and reappear when the fistula is occluded with downward pressure, then AVF steal syndrome is likely.⁴ Pain at rest, sensory loss, loss of pulse, and digital gangrene are emergency symptoms that warrant immediate surgical evaluation.³

Tests will confirm suspicions. Doppler ultrasound can be used to assess changes in the blood flow rate of the affected vessels when the AVF is patent vs when it is occluded. Similarly, pulse oximetry can be used with and without AVF occlusion to compare changes in oxygen saturation. The confirmatory diagnosis, however, is made via a fistulogram (angiography) with and without manual compression.⁶ Images taken after dye injection into the AVF show dramatic improvement of distal blood flow with AVF compression.

Treatment requires surgery

Severe steal-related ischemic manifestations that threaten the function and viability of digits require surgical treatment that is primarily directed toward improving distal blood flow and secondarily toward preserving hemodialysis access. Several surgical treatments are commonly used, including access ligation, banding, elongation, distal arterial ligation, and distal revascularization and interval ligation.^2-5,7

Our patient. Distal revascularization was attempted, but unfortunately, the patient’s gangrene was progressive (FIGURE 3) and surgical amputation of the left fourth finger was performed at the metacarpal’s proximal metaphyseal flare. The patient was transitioned to peritoneal dialysis to avoid further ischemia.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, Department of Dermatology, Indiana University, 545 Barnhill Drive, Indianapolis, IN 46202; srahnama@iupui.edu.

A 62-year-old man with end-stage renal disease presented to our dermatology clinic with 2-month-old ulcerations on his distal left ring finger. He was on hemodialysis and had a radiocephalic arteriovenous fistula (AVF) on his left arm. He had been empirically treated elsewhere with oral trimethoprim-sulfamethoxazole for a presumed bacterial infection, without improvement. He was then treated for contact dermatitis with topical clobetasol, which led to ulcer expansion and worsening pain.

At our clinic, the patient reported intermittent pain in his finger and paresthesias during activity and dialysis, but no tenderness of the ulcers. He had atrophy of the intrinsic left hand muscles (his non-dominant hand) with associated weakness. Three weeks earlier, he’d received a blood transfusion for anemia. Afterward, the pain in his hand improved and the ulcers decreased in size.

On exam, the AVF had a palpable thrill over the left forearm. The radial pulses were palpable bilaterally (2+) and the left ulnar artery was palpable, but diminished (1+). The patient’s left hand was cooler than the right (with a slight cyanotic hue and visible intrinsic muscle atrophy) and had decreased sensation to pain and temperature. Four ulcers with dry yellow eschar were located over the dorsal interphalangeal joints (FIGURES 1A AND 1B). They were essentially non-tender, but there was tenderness in the adjacent intact skin. There was violaceous blue edematous congestion noted on the fourth finger, and the distal phalange was constricted, giving it a “pseudoainhum” appearance.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Dialysis access steal syndrome

We suspected dialysis access steal syndrome (also known as AVF steal syndrome), so a duplex ultrasound was performed. The ultrasound was inconclusive. (We couldn’t confirm a limitation in blood flow, nor delineate anatomy.) So, we referred the patient for a thoracic and upper extremity angiogram.

The angiogram demonstrated multifocal, moderate to severe, areas of stenosis at the distal left brachial artery. The radial artery was patent at the level of the wrist, but showed diffuse narrowing beyond the level of the arteriovenous (AV) anastomosis. There was only a faint palmar arch identified on the radial aspect of the hand with digital branches feeding the radial portion of the hand. In contrast, the ulnar artery was not seen within the mid- and distal forearm (FIGURE 2). Palmar branches to the ulnar half of the hand were not identified. The fistula itself didn’t show any stenosis.

Based on these findings, our suspicions of dialysis access steal syndrome were confirmed.

Dialysis access steal syndrome is caused by a significant decrease or reversal of blood flow in the arterial segment distal to the AVF or graft, which is induced by the low resistance of the fistula outflow. Patients with adequate collateral vasculature are able to compensate for the steal effect; however, patients with end-stage renal disease typically have preexisting vascular disease that increases the risk for vascular steal and, ultimately, demand ischemia after placement of an AVF.¹ Interestingly, a steal effect occurs in 73% of patients after AVF construction, yet it is estimated that only 10% of patients demonstrating a steal phenomenon become symptomatic.²

In our patient’s case, the vaso-occlusive properties of topical steroids explain why the superpotent steroid (clobetasol) he was prescribed increased his pain and worsened the underlying problem.

A broad differential; a useful exam maneuver

The differential diagnosis of ulcers includes infection (mainly from bacterial or mycobacterial sources), trauma facilitated by neuropathy (neuropathic ulceration), vasculitis, and ischemia. When the history and physical exam suggest ischemic ulceration, then thromboembolism, thoracic outlet syndrome, vasculitis, atherosclerosis, and steal syndrome become more likely causes.

Signs and symptoms of ischemic steal syndrome are initially subtle and include extremity coolness, neurosensory changes, intrinsic muscle weakness, ulceration, and ultimately, gangrene of the affected extremity.^3,4 A cold, numb, and/or painful hand during dialysis is another clue.³ Factors that increase the likelihood of the syndrome include age >60 years, female sex, and the presence of diabetes or peripheral artery disease.^2,3,5,6

The confirmatory diagnosis of steal syndrome is made via a fistulogram (angiography) with and without manual compression.

One physical exam maneuver that can help make the diagnosis of steal syndrome is manual occlusion of the AVF. If palpable distal pulses disappear when the AVF is patent and reappear when the fistula is occluded with downward pressure, then AVF steal syndrome is likely.⁴ Pain at rest, sensory loss, loss of pulse, and digital gangrene are emergency symptoms that warrant immediate surgical evaluation.³

Tests will confirm suspicions. Doppler ultrasound can be used to assess changes in the blood flow rate of the affected vessels when the AVF is patent vs when it is occluded. Similarly, pulse oximetry can be used with and without AVF occlusion to compare changes in oxygen saturation. The confirmatory diagnosis, however, is made via a fistulogram (angiography) with and without manual compression.⁶ Images taken after dye injection into the AVF show dramatic improvement of distal blood flow with AVF compression.

Treatment requires surgery

Severe steal-related ischemic manifestations that threaten the function and viability of digits require surgical treatment that is primarily directed toward improving distal blood flow and secondarily toward preserving hemodialysis access. Several surgical treatments are commonly used, including access ligation, banding, elongation, distal arterial ligation, and distal revascularization and interval ligation.^2-5,7

Our patient. Distal revascularization was attempted, but unfortunately, the patient’s gangrene was progressive (FIGURE 3) and surgical amputation of the left fourth finger was performed at the metacarpal’s proximal metaphyseal flare. The patient was transitioned to peritoneal dialysis to avoid further ischemia.

CORRESPONDENCE
Sahand Rahnama-Moghadam, MD, Department of Dermatology, Indiana University, 545 Barnhill Drive, Indianapolis, IN 46202; srahnama@iupui.edu.

EVIDENCE SUMMARY

A systematic review and meta-analysis of 84 moderate- to high-quality RCTs with 24,010 patients evaluated the use of “eHealth” interventions in preventing and treating overweight and obesity in adults 35 to 65 years of age (75% female).¹ The studies included 183 active intervention arms with durations as long as 24 months (64% <6 months, 46% >6 months). The term eHealth included all forms of information technology used to deliver health care, but predominantly the Internet (Web site/Web-based), e-mail, and text messaging. Sixty percent (84) of eHealth interventional arms used one modality and 34% (47) used 2. Some intervention arms included non-eHealth modalities, such as paper-based measures and counseling.

The eHealth interventions were associated with significantly greater weight loss than minimal or no intervention (TABLE).¹ Comparing eHealth interventions with no intervention showed significant differences by eHealth type (P=.05). The greatest weight loss accompanied interventions that combined Web-based measures with a non-eHealth intervention, (mean difference [MD]= −3.7 kg; 95% confidence interval [CI], −4.46 to −2.94), followed by mobile interventions alone (MD= −2.4 kg; 95% CI, −4.09 to −0.71) and Web-based interventions alone (MD= −2.2 kg; 95% CI, −2.98 to −1.44).

Similarly, comparing combined interventions (eHealth + eHealth or eHealth + non-eHealth) with a minimal intervention control showed a trend for difference by eHealth type (P=.005). Only a combination of eHealth with non-eHealth interventions resulted in significantly greater weight loss (Web site + non-eHealth: MD= −2.7 kg; 95% CI, −3.76 to −1.54; text + non-eHealth: MD= −1.8 kg; 95% CI, −2.49 to −1.12; computer + non-eHealth: MD=1.1 kg; 95% CI, −1.36 to −0.89).

Personal coaching plus smartphone monitoring beats interactive app

A 3-arm RCT of 385 overweight and obese participants (mean body mass index [BMI], 35 kg/m²) 18 to 35 years of age compared the effectiveness of weight loss interventions delivered by interactive smartphone application (CP [cell phone]), personal coaching enhanced by smartphone self-monitoring (PC), and usual care (control).² The PC arm attended 6 weekly group sessions and received monthly phone calls. The usual care arm received 3 handouts on healthy eating and physical activity.

The CP arm showed the least amount of weight loss (−0.9 kg, −1.5 kg, and −1.0 kg at 6, 12, and 24 months, respectively) and no significant difference compared with controls at all measurement points. The PC arm had significantly greater weight loss than controls at 6 months (−1.9 kg; 95% CI, −3.17 to −0.67) and significantly greater weight loss than CP at 6 months (−2.2 kg; 95% CI, −3.42 to −0.97) and 12 months (−2.1 kg; 95% CI, −3.94 to −0.27). After 24 months, however, there was no significant difference in mean weight loss among treatment arms.

Automated behavioral program reduced weight and waist circumference

An RCT of 339 prediabetic, overweight, and obese patients 30 to 69 years old (mean BMI, 31 kg/m²) compared the effectiveness of Alive-PD, a fully automated, tailored, behavioral program, to usual care (control) for diabetes prevention.³ In addition to behavioral support, the program included weekly emails, Web-based tracking, a mobile phone app, and automated phone calls.

At 6 months, the intervention group had significantly greater mean weight loss (−3.4 kg vs −1.3 kg; P<.001), mean BMI (−1.1 kg/m² vs −0.4 kg/m²; P<.001), and mean waist circumference (−4.6 cm vs 2.2 cm; P<.001).

Web-based program improves weight loss at 3 months, but not 12 months

An RCT of 65 overweight and obese participants (mean BMI, 32 kg/m²) with at least one cardiovascular risk factor compared the effect of a Web-based program with usual care on weight change at 3, 6, and 12 months.⁴ Participants in the intervention group were provided with Bluetooth-enabled scales and accelerometer activity bands to allow daily uploads. The Web-based program also provided weekly feedback based on the participant’s performance and a food diary.

The Web-based group had significantly greater weight loss at 3 months (mean= −3.4 kg [95% CI, −4.70 to −2.13] vs −0.5 kg [95% CI, −1.55 to 0.52]; P<.001) and 6 months (mean= −3.4 kg [95% CI, −4.95 to −1.98] vs −0.8 kg [95% CI, −2.23 to 0.61]; P=.02). At 12 months, however, the groups showed no significant difference (mean= −2.4 kg [95% CI, −3.48 to −0.97] vs −1.8 kg [95% CI, −3.15 to −0.44]; P=.77).

RECOMMENDATIONS

Guidelines from the American College of Cardiology, American Heart Association, and Obesity Society state that electronically delivered weight-loss programs may be prescribed, but may result in smaller weight loss than face-to-face interventions (SOR: B, moderate evidence from RCTs with some limitations or non-randomized trials).⁵

EVIDENCE SUMMARY

A systematic review and meta-analysis of 84 moderate- to high-quality RCTs with 24,010 patients evaluated the use of “eHealth” interventions in preventing and treating overweight and obesity in adults 35 to 65 years of age (75% female).¹ The studies included 183 active intervention arms with durations as long as 24 months (64% <6 months, 46% >6 months). The term eHealth included all forms of information technology used to deliver health care, but predominantly the Internet (Web site/Web-based), e-mail, and text messaging. Sixty percent (84) of eHealth interventional arms used one modality and 34% (47) used 2. Some intervention arms included non-eHealth modalities, such as paper-based measures and counseling.

The eHealth interventions were associated with significantly greater weight loss than minimal or no intervention (TABLE).¹ Comparing eHealth interventions with no intervention showed significant differences by eHealth type (P=.05). The greatest weight loss accompanied interventions that combined Web-based measures with a non-eHealth intervention, (mean difference [MD]= −3.7 kg; 95% confidence interval [CI], −4.46 to −2.94), followed by mobile interventions alone (MD= −2.4 kg; 95% CI, −4.09 to −0.71) and Web-based interventions alone (MD= −2.2 kg; 95% CI, −2.98 to −1.44).

Similarly, comparing combined interventions (eHealth + eHealth or eHealth + non-eHealth) with a minimal intervention control showed a trend for difference by eHealth type (P=.005). Only a combination of eHealth with non-eHealth interventions resulted in significantly greater weight loss (Web site + non-eHealth: MD= −2.7 kg; 95% CI, −3.76 to −1.54; text + non-eHealth: MD= −1.8 kg; 95% CI, −2.49 to −1.12; computer + non-eHealth: MD=1.1 kg; 95% CI, −1.36 to −0.89).

Personal coaching plus smartphone monitoring beats interactive app

A 3-arm RCT of 385 overweight and obese participants (mean body mass index [BMI], 35 kg/m²) 18 to 35 years of age compared the effectiveness of weight loss interventions delivered by interactive smartphone application (CP [cell phone]), personal coaching enhanced by smartphone self-monitoring (PC), and usual care (control).² The PC arm attended 6 weekly group sessions and received monthly phone calls. The usual care arm received 3 handouts on healthy eating and physical activity.

The CP arm showed the least amount of weight loss (−0.9 kg, −1.5 kg, and −1.0 kg at 6, 12, and 24 months, respectively) and no significant difference compared with controls at all measurement points. The PC arm had significantly greater weight loss than controls at 6 months (−1.9 kg; 95% CI, −3.17 to −0.67) and significantly greater weight loss than CP at 6 months (−2.2 kg; 95% CI, −3.42 to −0.97) and 12 months (−2.1 kg; 95% CI, −3.94 to −0.27). After 24 months, however, there was no significant difference in mean weight loss among treatment arms.

Automated behavioral program reduced weight and waist circumference

An RCT of 339 prediabetic, overweight, and obese patients 30 to 69 years old (mean BMI, 31 kg/m²) compared the effectiveness of Alive-PD, a fully automated, tailored, behavioral program, to usual care (control) for diabetes prevention.³ In addition to behavioral support, the program included weekly emails, Web-based tracking, a mobile phone app, and automated phone calls.

At 6 months, the intervention group had significantly greater mean weight loss (−3.4 kg vs −1.3 kg; P<.001), mean BMI (−1.1 kg/m² vs −0.4 kg/m²; P<.001), and mean waist circumference (−4.6 cm vs 2.2 cm; P<.001).

Web-based program improves weight loss at 3 months, but not 12 months

An RCT of 65 overweight and obese participants (mean BMI, 32 kg/m²) with at least one cardiovascular risk factor compared the effect of a Web-based program with usual care on weight change at 3, 6, and 12 months.⁴ Participants in the intervention group were provided with Bluetooth-enabled scales and accelerometer activity bands to allow daily uploads. The Web-based program also provided weekly feedback based on the participant’s performance and a food diary.

The Web-based group had significantly greater weight loss at 3 months (mean= −3.4 kg [95% CI, −4.70 to −2.13] vs −0.5 kg [95% CI, −1.55 to 0.52]; P<.001) and 6 months (mean= −3.4 kg [95% CI, −4.95 to −1.98] vs −0.8 kg [95% CI, −2.23 to 0.61]; P=.02). At 12 months, however, the groups showed no significant difference (mean= −2.4 kg [95% CI, −3.48 to −0.97] vs −1.8 kg [95% CI, −3.15 to −0.44]; P=.77).

RECOMMENDATIONS

Guidelines from the American College of Cardiology, American Heart Association, and Obesity Society state that electronically delivered weight-loss programs may be prescribed, but may result in smaller weight loss than face-to-face interventions (SOR: B, moderate evidence from RCTs with some limitations or non-randomized trials).⁵

EVIDENCE SUMMARY

A systematic review and meta-analysis of 84 moderate- to high-quality RCTs with 24,010 patients evaluated the use of “eHealth” interventions in preventing and treating overweight and obesity in adults 35 to 65 years of age (75% female).¹ The studies included 183 active intervention arms with durations as long as 24 months (64% <6 months, 46% >6 months). The term eHealth included all forms of information technology used to deliver health care, but predominantly the Internet (Web site/Web-based), e-mail, and text messaging. Sixty percent (84) of eHealth interventional arms used one modality and 34% (47) used 2. Some intervention arms included non-eHealth modalities, such as paper-based measures and counseling.

The eHealth interventions were associated with significantly greater weight loss than minimal or no intervention (TABLE).¹ Comparing eHealth interventions with no intervention showed significant differences by eHealth type (P=.05). The greatest weight loss accompanied interventions that combined Web-based measures with a non-eHealth intervention, (mean difference [MD]= −3.7 kg; 95% confidence interval [CI], −4.46 to −2.94), followed by mobile interventions alone (MD= −2.4 kg; 95% CI, −4.09 to −0.71) and Web-based interventions alone (MD= −2.2 kg; 95% CI, −2.98 to −1.44).

Similarly, comparing combined interventions (eHealth + eHealth or eHealth + non-eHealth) with a minimal intervention control showed a trend for difference by eHealth type (P=.005). Only a combination of eHealth with non-eHealth interventions resulted in significantly greater weight loss (Web site + non-eHealth: MD= −2.7 kg; 95% CI, −3.76 to −1.54; text + non-eHealth: MD= −1.8 kg; 95% CI, −2.49 to −1.12; computer + non-eHealth: MD=1.1 kg; 95% CI, −1.36 to −0.89).

Personal coaching plus smartphone monitoring beats interactive app

A 3-arm RCT of 385 overweight and obese participants (mean body mass index [BMI], 35 kg/m²) 18 to 35 years of age compared the effectiveness of weight loss interventions delivered by interactive smartphone application (CP [cell phone]), personal coaching enhanced by smartphone self-monitoring (PC), and usual care (control).² The PC arm attended 6 weekly group sessions and received monthly phone calls. The usual care arm received 3 handouts on healthy eating and physical activity.

The CP arm showed the least amount of weight loss (−0.9 kg, −1.5 kg, and −1.0 kg at 6, 12, and 24 months, respectively) and no significant difference compared with controls at all measurement points. The PC arm had significantly greater weight loss than controls at 6 months (−1.9 kg; 95% CI, −3.17 to −0.67) and significantly greater weight loss than CP at 6 months (−2.2 kg; 95% CI, −3.42 to −0.97) and 12 months (−2.1 kg; 95% CI, −3.94 to −0.27). After 24 months, however, there was no significant difference in mean weight loss among treatment arms.

Automated behavioral program reduced weight and waist circumference

An RCT of 339 prediabetic, overweight, and obese patients 30 to 69 years old (mean BMI, 31 kg/m²) compared the effectiveness of Alive-PD, a fully automated, tailored, behavioral program, to usual care (control) for diabetes prevention.³ In addition to behavioral support, the program included weekly emails, Web-based tracking, a mobile phone app, and automated phone calls.

At 6 months, the intervention group had significantly greater mean weight loss (−3.4 kg vs −1.3 kg; P<.001), mean BMI (−1.1 kg/m² vs −0.4 kg/m²; P<.001), and mean waist circumference (−4.6 cm vs 2.2 cm; P<.001).

Web-based program improves weight loss at 3 months, but not 12 months

An RCT of 65 overweight and obese participants (mean BMI, 32 kg/m²) with at least one cardiovascular risk factor compared the effect of a Web-based program with usual care on weight change at 3, 6, and 12 months.⁴ Participants in the intervention group were provided with Bluetooth-enabled scales and accelerometer activity bands to allow daily uploads. The Web-based program also provided weekly feedback based on the participant’s performance and a food diary.

The Web-based group had significantly greater weight loss at 3 months (mean= −3.4 kg [95% CI, −4.70 to −2.13] vs −0.5 kg [95% CI, −1.55 to 0.52]; P<.001) and 6 months (mean= −3.4 kg [95% CI, −4.95 to −1.98] vs −0.8 kg [95% CI, −2.23 to 0.61]; P=.02). At 12 months, however, the groups showed no significant difference (mean= −2.4 kg [95% CI, −3.48 to −0.97] vs −1.8 kg [95% CI, −3.15 to −0.44]; P=.77).

RECOMMENDATIONS

Guidelines from the American College of Cardiology, American Heart Association, and Obesity Society state that electronically delivered weight-loss programs may be prescribed, but may result in smaller weight loss than face-to-face interventions (SOR: B, moderate evidence from RCTs with some limitations or non-randomized trials).⁵

When I became a family physician (FP), it never crossed my mind that I would one day be asking school-aged children about bullying. Not so much because bullying didn’t exist, but because I wasn’t aware of the pervasiveness and seriousness of the problem and because there were no professional recommendations to do so.

That said, my family had some first-hand experience with the issue: One of my children was bullied in grade school. When my wife found out, she promptly visited the 2 boys’ homes and told them and their parents that the behavior would stop or else! (She may have used more colorful language.) And it did stop. But times have changed, and so has the nature of bullying, which can now extend beyond the hallway to an entire school body in seconds with a few taps on a cell phone. And the adverse consequences can be significant, as described by McClowry and colleagues.

We need to ask our young patients a single question: "Are you being bullied?"The prevalence of bullying is discouragingly high, estimated to be about 20% in national surveys.¹ Because bullying occurs so frequently, public health, community-based, and school-based approaches, rather than one-on-one office-based interventions, are likely to have the greatest overall impact on decreasing bullying. Randomized trials bear this out, showing that prevention programs in schools can effectively reduce the behavior.^2,3

What is our responsibility as FPs? Screening is a reasonable first step, even in the absence of randomized trials demonstrating benefit. Because there have been no physician office-based trials of screening or interventions for bullying, we must rely on “expert opinion” at this time, with no assurance that what we do will actually help children. Absence of proof of benefit, however, does not mean absence of benefit, and doing nothing will definitely not help anyone. The authors recommend a single screening question: "Are you being bullied?"—especially for children who are at higher risk, such as those with disabilities/special health needs, LGBTQ+ status, and who are under- or overweight.

Clearly we need research to know which interventions truly help these children/adolescents and their parents. In the meantime, however, identifying the problem and offering emotional support are unlikely to harm—and may help. Opening the lines of communication, connecting children and their parents with available community resources, and supporting anti-bullying programs in your schools are additional ways we can make a difference today.

When I became a family physician (FP), it never crossed my mind that I would one day be asking school-aged children about bullying. Not so much because bullying didn’t exist, but because I wasn’t aware of the pervasiveness and seriousness of the problem and because there were no professional recommendations to do so.

That said, my family had some first-hand experience with the issue: One of my children was bullied in grade school. When my wife found out, she promptly visited the 2 boys’ homes and told them and their parents that the behavior would stop or else! (She may have used more colorful language.) And it did stop. But times have changed, and so has the nature of bullying, which can now extend beyond the hallway to an entire school body in seconds with a few taps on a cell phone. And the adverse consequences can be significant, as described by McClowry and colleagues.

We need to ask our young patients a single question: "Are you being bullied?"The prevalence of bullying is discouragingly high, estimated to be about 20% in national surveys.¹ Because bullying occurs so frequently, public health, community-based, and school-based approaches, rather than one-on-one office-based interventions, are likely to have the greatest overall impact on decreasing bullying. Randomized trials bear this out, showing that prevention programs in schools can effectively reduce the behavior.^2,3

What is our responsibility as FPs? Screening is a reasonable first step, even in the absence of randomized trials demonstrating benefit. Because there have been no physician office-based trials of screening or interventions for bullying, we must rely on “expert opinion” at this time, with no assurance that what we do will actually help children. Absence of proof of benefit, however, does not mean absence of benefit, and doing nothing will definitely not help anyone. The authors recommend a single screening question: "Are you being bullied?"—especially for children who are at higher risk, such as those with disabilities/special health needs, LGBTQ+ status, and who are under- or overweight.

Clearly we need research to know which interventions truly help these children/adolescents and their parents. In the meantime, however, identifying the problem and offering emotional support are unlikely to harm—and may help. Opening the lines of communication, connecting children and their parents with available community resources, and supporting anti-bullying programs in your schools are additional ways we can make a difference today.

When I became a family physician (FP), it never crossed my mind that I would one day be asking school-aged children about bullying. Not so much because bullying didn’t exist, but because I wasn’t aware of the pervasiveness and seriousness of the problem and because there were no professional recommendations to do so.

That said, my family had some first-hand experience with the issue: One of my children was bullied in grade school. When my wife found out, she promptly visited the 2 boys’ homes and told them and their parents that the behavior would stop or else! (She may have used more colorful language.) And it did stop. But times have changed, and so has the nature of bullying, which can now extend beyond the hallway to an entire school body in seconds with a few taps on a cell phone. And the adverse consequences can be significant, as described by McClowry and colleagues.

We need to ask our young patients a single question: "Are you being bullied?"The prevalence of bullying is discouragingly high, estimated to be about 20% in national surveys.¹ Because bullying occurs so frequently, public health, community-based, and school-based approaches, rather than one-on-one office-based interventions, are likely to have the greatest overall impact on decreasing bullying. Randomized trials bear this out, showing that prevention programs in schools can effectively reduce the behavior.^2,3

What is our responsibility as FPs? Screening is a reasonable first step, even in the absence of randomized trials demonstrating benefit. Because there have been no physician office-based trials of screening or interventions for bullying, we must rely on “expert opinion” at this time, with no assurance that what we do will actually help children. Absence of proof of benefit, however, does not mean absence of benefit, and doing nothing will definitely not help anyone. The authors recommend a single screening question: "Are you being bullied?"—especially for children who are at higher risk, such as those with disabilities/special health needs, LGBTQ+ status, and who are under- or overweight.

Clearly we need research to know which interventions truly help these children/adolescents and their parents. In the meantime, however, identifying the problem and offering emotional support are unlikely to harm—and may help. Opening the lines of communication, connecting children and their parents with available community resources, and supporting anti-bullying programs in your schools are additional ways we can make a difference today.