Frontal Lobe Syndromes

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Background

The frontal lobe is the largest lobe in the brain, yet it is often not specifically evaluated in routine neurologic examinations. This may in part be due to the attention to detail and rigorous testing strategies required to probe frontal lobe functions. As successful completion of any cognitive task considered a frontal lobe function requires multiple brain regions both within and outside the frontal lobe, some authors prefer the term frontal systems disease. In any case, dysfunctions of the frontal lobe can give rise to relatively specific clinical syndromes. When a patient's history suggests frontal lobe dysfunction, detailed neurobehavioral evaluation is necessary.

Traditional classification systems divide the frontal lobes into the precentral cortex (the strip immediately anterior to the central or Sylvian fissure) and prefrontal cortex (extending from the frontal poles to the precentral cortex and includes the frontal operculum), which is broken into: orbitofrontal cortex (including the orbitobasal or ventromedial and the inferior mesial regions), ventrolateral prefrontal cortex, dorsolateral prefrontal cortex, medial prefrontal cortex (containing the anterior cingulate gyrus, and prelimbic and infralimbic cortices), and the caudal prefrontal cortex (which includes the frontal eye fields). Each of these areas has widespread connectivity.

Given the unique connectivity between the frontal regions and deeper brain structures, lesions of these areas or their connections generate relatively distinctive clinical behaviors.

Broca aphasia from a lesion in areas 44 and 45 on the left hemisphere leads to nonfluent speech, agrammatism, paraphasias, anomia, and poor repetition. Lesions anterior, superior, and deep to (but sparing) the Broca area produce abnormal syntax and grammar but repetition and automatic language are preserved. This disorder is known as transcortical motor aphasia (also called commissural dysphasia) and uninhibited echolalia is common. Memory disturbances only develop with lesion extension into the septal nucleus of the basal forebrain. Appreciation of verbal humor is most impaired in right frontal polar pathology.

The image below shows an MRI that is suggestive of frontotemporal dementia.



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Axial brain MRI of a patient with progressive tremorless parkinsonism and frontal-predominant dementia (Mini Mental State Examination = 23/30; Frontal....

Pathophysiology

A detailed discussion of the pathophysiology of frontal lobe dysfunction is beyond the scope of this review and the reader is referred to 2 excellent reviews by Mesulam (2002) and Bonelli and Cummings (2007).[1, 2] As Mesulam has discussed, one way to think about the role of the frontal lobe is that it is the brain's way of modifying and interposing constraints on basic reflexive behaviors. For example, taking food when one is hungry is reflexive. Nonetheless, most adults can inhibit this behavior until the context is appropriate. Most hungry diners waiting in line at a restaurant do not usually help themselves to food from the plates of diners who have already been served, but some patients with frontal lobe dysfunction cannot inhibit this response.

Unlike most animals, a human's mental state is preoccupied a great deal with what has happened in the past or what may happen in the future. Parts of the frontal lobe are essential for this type of "time travel." Indeed, good judgment requires evaluating the possible consequences of a variety of future activities and selecting the one with the most good consequences and the fewest bad consequences.

This frontal lobe-mediated responsibility of decision-making depends on the valuation of a choice, such as its costs, benefits, and probability of success, as well as the assessment of the outcome of a given choice, in order to adapt future behaviors appropriately. The anterior cingulate cortex is primarily responsible for selecting choices and evaluating the outcome of that selection to ensure adaptation to the environment.[1] The orbitofrontal cortex is responsible for changes in behavior in response to unexpected outcomes.[2] Poor judgment and inappropriately weighting of the value of past experiences may, as a result, occur with frontal lobe dysfunction.

Working memory involves a complex circuit that involves many brain regions, including the dorsolateral frontal cortex, thalamus, and parts of the temporal and parietal cortices. Working memory is defined as memory for a limited amount of information (such as a telephone number) that needs to be kept in consciousness for a few seconds (until the number is dialed) and then may be lost forever. Most patients are able to hold 6 or 7 digits in working memory. Patients with frontal lobe impairment may have decreased capacity in working memory (eg, shortened digit span) or difficulty manipulating information in working memory (eg, impaired reverse digit span test).

Epidemiology

Frequency

United States

Data are not available for the epidemiology of frontal lobe dysfunction as a clinical syndrome, but data are available concerning the incidence and prevalence of the major causes of syndromes of frontal lobe dysfunction. For specifics on these data, please refer to the following linked Medscape Reference articles. Common causes (see also Causes) include the following:

Sex

Traumatic brain injury is much more common in men than women both in the United States and worldwide. Gender predominance depends on the specific underlying neurologic disorder.

Age

The relative likelihood of different causes of frontal lobe dysfunction is a function of patient age. In teenagers and young adults, the most common causes are intellectual disability, traumatic brain injury, and drug intoxication. In middle-aged patients, brain tumors, cerebrovascular disease, infections such as HIV, multiple sclerosis, and early onset degenerative dementias are common. In late life, cerebrovascular disease and degenerative dementias are predominant causes of frontal lobe dysfunction. The main degenerative dementias with frontal lobe predominance, frontotemporal lobar degenerations, together with Alzheimer disease, are the most common degenerative dementias in the pre-senile age (younger than 65 years).

History

The examiner must obtain a history from an informant who knows the patient well. One of the seeming paradoxes of frontal lobe dysfunction is that informants may complain about the patient's "inability to do anything," yet on at least cursory mental status testing, the patient appears normal or only mildly impaired. This dissociation should be a clue that frontal lobe dysfunction may be present. Symptoms of possible frontal lobe dysfunction that should be probed include change in performance at work and changes organizing and executing difficult tasks such as holiday dinners or travel itineraries.[3] The examiner should inquire about the following changes:

In addition to these data, the examiner should obtain careful developmental, head trauma, and social histories, including educational and personal attainments. The examiner should also probe about possible substance abuse, whether the patient was a victim of past abuse (physical, sexual, or psychiatric) and about major psychiatric stressor (eg, deaths of friends or family, divorce or separation, job loss or financial reversals). Indeed, a detailed past psychiatric history is required.

Physical

Dysfunction of parts of the frontal lobe is sometimes associated with aphasia or severe impairment of attention and can make formal neuropsychologic testing or neurobehavioral evaluation problematic.

Many commonly used brief mental state tests, including the Mini-Mental State Examination, are not designed to test frontal lobe function—they are insensitive and not specific to frontal lobe dysfunction. A person with a Mini-Mental State score of 26 from early Alzheimer disease may have relatively preserved frontal lobe function, yet a patient with Pick disease with a similar score may have profound frontal lobe dysfunction. Two validated bedside tools that extend the cognitive screen to the frontal lobes are the Frontal Assessment Battery (FAB)[4] and the Montreal Cognitive Assessment (MoCA).[5] These instruments may be helpful for bedside evaluation of frontal lobe function.

FAB was shown to be sensitive to frontal lobe damage of the right hemisphere in stroke patients. The findings indicated that several FAB scores (including composite and item scores) provided valid measures of right hemispheric lateral frontal lobe dysfunction, specifically of focal lesions near the anterior insula, in the right middle frontal gyrus, and in the right inferior frontal gyrus.[6]

Most neurologists and psychiatrists are familiar with the general principles of evaluating frontal lobe function but a careful detailed evaluation usually requires consultation with a neuropsychologist or cognitive (behavioral) neurologist. Tests relatively sensitive to frontal lobe dysfunction include the following:

Causes

The manifestations of a frontal lobe syndrome in any patient depend on many factors, including baseline intelligence and education, site of the lesions, whether the lesions developed slowly or rapidly, age, possibly sex, and function of nonfrontal brain regions. Causes of frontal lobe dysfunction include mental retardation, cerebrovascular disease, head trauma, brain tumors, brain infections, neurodegenerative diseases including multiple sclerosis, and normal pressure hydrocephalus.

Cerebrovascular disease

The anterior cerebral artery supplies the medial surface of the brain, including the ventromedial frontal lobe, the cingulum, the premotor cortex, and the motor strip. Bilateral anterior cerebral artery infarct is associated with a syndrome of quadriparesis (legs worse than arms) and akinetic mutism.

Occlusion of the artery of Huebner may cause infarction of the head of the caudate nucleus and may result in an agitated confusional state that with time evolves to akinesia, abulia, and mutism, along with personality changes. Language may also be affected.

The anterior branches of the upper division of the middle cerebral artery supply parts of the lateral prefrontal and frontal cortex. Infarction of these arteries may be characterized by planning deficits, impairment of working memories, and apathy as well as weakness of the contralateral face and arm.

Borderzone infarctions between the distribution of the anterior and middle cerebral arteries are characterized by wedge-shaped lesions between the superior and middle frontal gyri and may result in the man-in-the-barrel syndrome with proximal weakness at the shoulder and hip.

Lacunar infarcts that occur in the deep white matter of the frontal lobe, caudate, or putamen may cause dysfunction of frontostriatal circuits.

Some patients with aneurysms and/or hemorrhage of the anterior communicating artery develop infarctions in the basal forebrain. In addition to the akinesia and personality changes already described, patients may develop a striking confabulatory amnesia that is severe and permanent and that resembles Wernicke-Korsakoff syndrome. Mild anomia may also be present. Finally, a syndrome of affective (as opposed to apathetic) depression may occur after strokes affecting predominantly the left frontal lobe.[12]

Tumors

A classic presentation of frontal lobe dysfunction is an olfactory groove meningioma characterized by anosmia, loss of inhibition, memory impairment, headaches, and visual symptoms. The frontal lobes are also common sites for primary and metastatic brain tumors.

Traumatic lesions

Closed head injuries are often associated with unilateral or bilateral contusions of the orbitofrontal cortex. Some patients recover completely and others sustain lifelong impairments. The orbitofrontal cortex is susceptible to contrecoup injury when the accelerating brain strikes against bony prominences on the nonaccelerating surface of the anterior cranial fossa.

Prefrontal lobotomies were performed on some patients in the late 1940s and early 1950s with schizophrenia or other severe psychiatric illnesses. In these procedures, fibers connecting the frontal lobe with the basal ganglia were cut. Although some claimed that such patients performed normally on neuropsychological tests, studies were incomplete and lacked appropriate tests sensitive to frontal lobe dysfunction. Many patients performed normally on selected neuropsychological tests but were still unable to function independently.

Other structural causes of frontal lobe dysfunction

Hydrocephalus of any cause may be associated with frontal lobe dysfunction due to increased intracranial pressure and/or stretching of frontostriatal pathways. Normal pressure hydrocephalus (NPH) has received substantial attention as a reversible cause of dementia. Unfortunately, not all patients who seem to meet criteria for NPH are helped with surgery. Core features of NPH are gait apraxia, urinary incontinence, and frontal-predominant cognitive impairment.

Tourette syndrome, a tic disorder associated with prominent behavioral disorders such as obsessive-compulsive disorder, is associated with alterations in frontal lobe regions connected to the striatum. In particular, prefrontal areas and anterior cingulate gyrus are reduced in volume compared with age- and sex-matched healthy individuals.[5, 13] In this condition, tics are worse when the volume of the orbitofrontal and right cingulate gyrus is less.

Frontotemporal lobar degenerations (FTLD)

These disorders include at least 4 clinically distinguishable neurocognitive syndromes based on the location of the pathologic burden: (1) behavioral variant of frontotemporal dementia (bvFTD), (2) primary progressive aphasia (PPA), also known as progressive nonfluent aphasia (PNFA), (3) logopenic progressive aphasia (LPA) and (4) semantic dementia (SD), also known as fluent PPA. These disorders are all slowly progressive neurodegenerative disorders.[14] The bvFTD and PNFA are the only FTLDs truly affecting the frontal lobes. Although LPA and SD are considered within the spectrum of FTLD, they result from primary involvement of the parietal and temporal regions, respectively.

Infectious causes of frontal lobe dysfunction

HIV frequently affects basal ganglia, hippocampus, and the deep white matter of the frontal lobe. The spectrum of cognitive impairment in HIV ranges from no impairment to HIV-dementia. Abscesses in the frontal lobe can also impair frontal lobe function.

Laboratory Studies

Choice of blood tests depends on clinical setting.

In many cases, tests of thyroid function, B-12 level, and serology for syphilis are appropriate.

In other instances, testing for HIV or connective tissue disorders is indicated.

Imaging Studies

CT scanning is adequate to diagnose acute bleeds and ventriculomegaly (hydrocephalus).

MRI is more sensitive and specific than CT for showing tumors, focal or diffuse atrophy, subdural hematomas, or vascular and microvascular pathology.

Many behavioral neurology specialists would obtain a deoxyglucose PET scan in patients with a clinical diagnosis of frontotemporal dementia. A pattern of decreased frontal lobe glucose utilization with preserved temporal-parietal glucose utilization would favor the diagnosis of a frontotemporal dementia. The opposite pattern is characteristic of Alzheimer disease.[16]

In one study, 18-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) was able to identify nearly half of the cases of behavioral variant of frontotemporal dementia (bvFTD) that were not detected by magnetic resonance imaging. According to the authors, high specificity of 18F-FDG-PET can enable exclusion of psychiatric and other neurodegenerative disorders. The 18F-FDG-PET study was performed in 52 patients with suspected bvFTD who lacked characteristic structural neuroimaging results.[17]

Other Tests

Neuropsychology: Many tests are described in Physical.

EEG may be exceptionally considered if evidence of subclinical seizure activity is suspected, particularly in rapidly progressive symptomatic cases.

Procedures

Lumbar puncture may be needed to look for signs of occult infection.

Medical Care

Medical care depends entirely on the pathology present. Physical and occupational therapy remain an important cornerstone of motor symptom management in FTD. Speech therapy may also help patients manage symptoms associated with aphasia, apraxia, and dysarthria. Recent advances in the understanding of FTLD pathophysiology and genetics have led to development of potentially disease-modifying therapies, as well as symptomatic therapies aimed at ameliorating social and behavioral deficits.[18]

Consultations

Consultation with a neuropsychologist and/or behavioral neurologist is indicated to determine the nature and extent of the cognitive deficits present and to help work with the patients and families.

Formal consultation with a neuropsychologist is often advantageous to clarify the extent of the brain damage and to make appropriate cognitive treatment plans. Neuropsychologists are also exceedingly helpful because of their psychological background in dealing with patients and their families.

The patient and family frequently deny or minimize the importance of the deficit. Consultation can help ensure that the home setting is truly appropriate for the patient and/or family.

If a home setting is agreed on, these consultants can determine the need for assistance. Assistants can include physical, occupational, and/or speech therapists; home health aides; visiting nurses; respite care staff; and adult day-care staff, who are trained to help the patient succeed in the desired setting. Consultation with a social worker may also be helpful.

Activity

Patients with frontal lesions and deficits frequently need supervision because of their lack of impulse control and their inability to form and follow plans and strategies.

Medication Summary

No medications are available to help frontal injuries.

Drugs that help memory in Alzheimer dementia are rarely of benefit for frontal lobe deficits or problems.

Further Outpatient Care

Outpatient care monitors what tasks a patient can accomplish in his home or residential facility and what tasks are sources of difficulty for the patient and his caregivers. Assessing how patients spend their time each day is useful.

Further Inpatient Care

Excluding rare cases in which surgical care may be indicated (eg, tumors, subdural hematomas), most care is directed at providing a safe, secure environment for the patient and at supporting caregivers.

Family education about the patient's deficit is essential.

Discharge planning and family meetings may be necessary if the family remains unrealistic about the possibility of home discharge. In such a meeting, team members, including therapists, nurses, and physicians, can elaborate on the patient's needs and impress on the family the sometimes-unrealistic nature of their expectations.

Services, as described in Consultations, can be arranged for patients.

Prognosis

The prognosis depends on the underlying pathology.

Patient Education

For patients in whom frontal lobe dysfunction is the result of strokes, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education article Stroke.

Why isn’t the frontal lobe evaluated in routine neurologic exams?What anatomy is relevant to frontal lobe syndromes?What are the clinical behaviors associated with frontal lobe lesions?What is the pathophysiology of frontal lobe syndromes?What is the effect of frontal lobe syndromes on the working memory of the brain?What is the incidence of frontal lobe syndromes in the US?How does the incidence of frontal lobe syndromes vary by sex?How does the etiology of frontal lobe syndromes vary by age?What should be the focus of history in the evaluation of frontal lobe syndromes?What is the role of neuropsychologic testing in the evaluation of frontal lobe syndromes?Which specialists should be consulted for the evaluation of frontal lobe syndromes?What is the go/no-gO test and how is it used to assess frontal lobe syndromes?What is the antisaccade test and how is it used to assess frontal lobe syndromes?What is the trail-making test (TMT) and how is it used to assess frontal lobe syndromes?What is the lexical fluency test (word generation, Thurstone test) and how is it used to assess frontal lobe syndromes?How is attention and concentration assessed in frontal lobe syndromes?What is the alternating sequences test and how is it used to assess frontal lobe syndromes?What is the applause test and how is it used to assess frontal lobe syndromes?What is the role of the Frontal Assessment Battery (FAB) and Montreal Cognitive Assessment (MoCA) in the evaluation of frontal lobe syndromes?How are nonspecific cognitive deficits assessed in the evaluation of frontal lobe syndromes?How is praxis assessed in the evaluation of frontal lobe syndromes?What is neglect and how is it assessed in frontal lobe syndromes?How is constructional apraxia assessed in frontal lobe syndromes?How is judgment assessed in frontal lobe syndromes?How are memory deficits assessed in frontal lobe syndromes?Which behavioral and personality changes are characteristic of frontal lobe syndromes?What are frontal release responses and how are they characterized in frontal lobe syndromes?What is utilization behavior and how is it characterized in frontal lobe syndromes?What is alien hand syndrome and how is it characterized in frontal lobe syndromes?How is gait impairment characterized in frontal lobe syndromes?How is incontinence characterized in frontal lobe syndromes?What are the causes of frontal lobe syndromes?What is the role of cerebrovascular diseases in the etiology of frontal lobe syndromes?What is the role of malignancy in the etiology of frontal lobe syndromes?What is the role of traumatic lesions in the etiology of frontal lobe syndromes?What causes hydrocephalus in frontal lobe syndromes?What are the signs and symptoms of Tourette syndrome in frontal lobe syndrome?What are frontotemporal lobar degenerations (FTLD) and how do they affect the frontal lobe?What are the signs and symptoms of behavioral variants of frontotemporal dementia (FTD)?What are infectious causes of frontal lobe syndromes?What are the differential diagnoses for Frontal Lobe Syndromes?What is the role of lab studies in the diagnosis of frontal lobe syndromes?What is the role of imaging studies in the diagnosis of frontal lobe syndromes?What is the role of EEG in the diagnosis of frontal lobe syndromes?What is the role of lumbar puncture in the diagnosis of frontal lobe syndromes?What is included in the treatment of frontal lobe syndromes?Which specialist consultations are needed for the diagnosis and management of frontal lobe syndromes?What activity restrictions are needed in the management of frontal lobe syndromes?Which medications are used in the treatment of frontal lobe syndromes?What is included in outpatient monitoring of patients with frontal lobe syndromes?When is inpatient care indicated for patients with frontal lobe syndromes?What is the prognosis of frontal lobe syndromes?Where can patient education resources about frontal lobe syndromes be found?

Author

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, Chief, Pediatric Neurology, Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Epileptologist, Medical Director, Tulane Center for Autism and Related Disorders, Co-Director, Developmental Neurogenetics Center, Tulane University School of Medicine

Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Biomarin; Supernus<br/>Received income in an amount equal to or greater than $250 from: Biomarin; Supernus; American Board of Pediatrics.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

Jasvinder Chawla, MD, MBA, Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Disclosure: Nothing to disclose.

Additional Contributors

Joseph Quinn, MD, MD, Assistant Professor, Department of Neurology, Portland VA Medical Center, Oregon Health Sciences University

Disclosure: Nothing to disclose.

Acknowledgements

Alberto J Espay, MD, MSc Associate Professor, Director of Clinical Research, Gardner Family Center for Parkinson's Disease and Movement Disorders, University of Cincinnati College of Medicine

Alberto J Espay, MD, MSc is a member of the following medical societies: American Academy of Neurology and Movement Disorders Society

Disclosure: Abbott Consulting fee Consulting; Chelsea therapeutics Consulting fee Consulting; Novartis Honoraria Speaking and teaching; TEVA Consulting fee Consulting; NIH Grant/research funds K23 Career Development Award; Eli Lilly Consulting fee Consulting; Great Lakes Neurotechnologies Other; Michael J Fox Foundation Grant/research funds Other; Lippincott Williams & Wilkins Royalty Book; American Academy of Neurology Honoraria Speaking and teaching

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Axial brain MRI of a patient with progressive tremorless parkinsonism and frontal-predominant dementia (Mini Mental State Examination = 23/30; Frontal Assessment Battery = 10/18; abnormal clock drawing task and additional constructional impairment) with moderate ideomotor apraxia. The MRI demonstrates predominantly frontal (A) and anterior temporal atrophy (B) suggestive of frontotemporal dementia.

Axial brain MRI of a patient with progressive tremorless parkinsonism and frontal-predominant dementia (Mini Mental State Examination = 23/30; Frontal Assessment Battery = 10/18; abnormal clock drawing task and additional constructional impairment) with moderate ideomotor apraxia. The MRI demonstrates predominantly frontal (A) and anterior temporal atrophy (B) suggestive of frontotemporal dementia.