eMedicine Specialties > Neurology > Behavioral Neurology and Dementia

Dementia in Motor Neuron Disease

Joe Verghese, MD, MRCPI, Associate Professor, Department of Neurology, Albert Einstein College of Medicine

Updated: Nov 1, 2006

Introduction

Background

Most patients with motor neuron disease (MND) are free of cognitive impairment, but there is growing evidence of an association between MND and frontal lobe or frontotemporal dementia (FTD). Some propose that frontotemporal lobe dementia with motor neuron disease (FTD/MND) is nosologically distinct; others suggest that it is part of a spectrum of diseases encompassing classic MND at one end and FTD at the other.

Pathophysiology

Pyramidal cell loss in frontal and temporal lobes and degeneration of motor neurons in the hypoglossal nucleus and spinal motor neurons characterize FTD/MND. Pyramidal neurons in the premotor cortex usually are preserved. Signs and symptoms reflect frontal and temporal lobe dysfunction with lower motor neuron-type weakness, muscle atrophy, and fasciculations.

Frequency

United States

Frontal lobe dementia is the second or third most common type of degenerative dementia in autopsy series. The precise frequency of the subgroup of FTD patients with FTD/MND in autopsy or population studies is unknown (but rare).

International

In a Scandinavian autopsy series, dementia was reported in 2-6% of patients with MND. The relative frequency of FTD/MND in all patients with dementia appears similar in the United States and Japan. Certain populations (eg, Chamorro Indians of Guam, indigenous residents of the Kii peninsula) have a disproportionately higher incidence and prevalence of overlap degenerative syndromes (MND, dementia, parkinsonism).

Mortality/Morbidity

Progressive dementia with symptoms of executive dysfunction, personality change, and motor weakness leads to severe morbidity.
Death usually occurs within 3 years of onset from inanition, pulmonary failure, and aspiration.
Patients with FTD/MND generally follow a more rapid course than patients with either FTD or MND alone. They are more likely to have a bulbar form of MND, which may help explain its more aggressive course.

Race

FTD/MND has been described in patients of Asian, European, and African descent. No data are available about incidence and prevalence among racial groups.

Sex

Men appear to be affected slightly more frequently than women, but this difference may not be significant.

Age

The mean age of onset in sporadic cases varies among series but overall is 55-65 years. Familial cases tend to be younger.

Clinical

History

FTD/MND usually presents as a change in personality with deterioration in social conduct.
- Initial behavioral changes vary but include abulia, apathy, and reduced spontaneity and/or initiation.
- Some patients become strikingly disinhibited, overactive, and frankly inappropriate with emotional lability.
With disease progression, even those patients manifesting disinhibition and restlessness become increasingly apathetic.
Stereotypic behavior and repetitive rituals of hoarding, dressing, wandering, and toileting can be observed.
Patients may overeat, exhibit hyperoral tendencies, and develop food fads (although this is more exceptional); some patients may hold food in their mouth for prolonged periods without swallowing.
Dynamic spontaneous speech output progressively declines, resulting in anarthria and mutism. Visuospatial skills are relatively spared throughout illness, but there is significant memory impairment.
- A subset of patients presents with rapidly progressive aphasia.
- Despite progression to anarthria, autopsy studies show that anarthria can occur in the absence of significant hypoglossal nucleus involvement.
- Memory also is impaired, but this is not as distinguishing as the frontal lobe or language features.
- Posterior cortical functions (eg, visuospatial skills) are preserved and/or spared until the preterminal stages.
- The clinical pattern reflects the topographic pattern of atrophy, often visible radiographically, with asymmetric frontotemporal atrophy.
- If asymmetrically worse in the left (language-dominant) hemisphere, aphasia is a likely and prominent clinical feature.
Throughout the course of the disease, signs and symptoms of MND also progress.
- Cognitive changes often precede signs of MND.
- Limb weakness and dysphagia eventually become disabling, although some patients have a primarily bulbar pattern of weakness with relative sparing of limb strength.
Recently, consensus clinical criteria detailing core and supportive features for FTD syndromes were published.

Physical

Patients usually perform poorly on tests of frontal lobe function (ie, Wisconsin card sorting, picture sequencing, verbal fluency tests). Memory is impaired, but less consistently in the mild stages.
Clinical signs of MND usually follow or accompany dementia onset. MND signs include bulbar weakness with dysarthria and dysphagia, limb weakness, muscle wasting and fasciculations, and, of greatest concern, dyspnea.
Akinesia and rigidity are uncommon in this disorder but more common in patients with a longer interval between onset of dementia and neurologic signs (more than 24 mo in a Japanese series). This may reflect, in part, the variable involvement of the substantia nigra and other pigmented brainstem nuclei that are observed in roughly 50% of patients at autopsy. This, in turn, may vary between populations (more common in Chamorro Indians).

Causes

Worldwide, FTD/MND is sporadic with unknown etiology.
A minority of patients has a family history, but this overlap syndrome may be related to other neurodegenerative overlap syndromes that include variable degrees of dementia, MND, and parkinsonism.
Familial cases of this type are linked to a mutated region of chromosome 17, which contains the tau gene. It is possible that a similar genetic association will be found for FTD/MND.

Differential Diagnoses

Alzheimer Disease
Amyotrophic Lateral Sclerosis
Dementia With Lewy Bodies
Frontal and Temporal Lobe Dementia
Frontal Lobe Syndromes
Pick Disease

Workup

Laboratory Studies

Obtain typical blood studies, thyroid function tests, vitamin B12 and folate levels, and Venereal Disease Research Laboratory test. Refer to Amyotrophic Lateral Sclerosis for a full listing of the MND workup.

Imaging Studies

Computed tomography (CT) scan may show mild, generalized cerebral atrophy or asymmetric frontotemporal atrophy.
Because of greater resolution than CT, MRI studies may reveal selective frontal and anterior temporal atrophy that cannot be appreciated on CT.
Single photon emission computed tomography imaging often demonstrates reduced blood flow in an asymmetric, frontotemporal pattern.
A recent study reported that glucose hypometabolism on PET imaging in patients with dementia associated with motor neuron disease affected only the frontal lobes, sparing the temporal lobes. This is in contrast to frontotemporal dementia where glucose hypometabolism is seen in both frontal lobes and temporal lobes. In Alzheimer disease, PET scans may reveal glucose hypometabolism in the parietal and temporal regions bilaterally.

Other Tests

Electroencephalogram can remain normal even in later stages of dementia, but often mild dysrhythmic slowing occurs that is sometimes asymmetric.
Electromyography may demonstrate widespread denervation in limb muscles. Early in the disease, especially in predominantly bulbar onset patients, findings may not fulfill the Lambert or El Escorial criteria for MND.

Histologic Findings

Early in the disease, FTD/MND preferentially affects frontal and temporal lobes, the hypoglossal nucleus, and spinal motor neurons. Later and terminal stages reveal histologic evidence of widespread cortical involvement. In the frontal and temporal lobes, microscopic changes include loss of pyramidal cells, spongiform neuropil change, and astrocytic gliosis. Ubiquinated, tau-negative inclusions are present within the frontal cortex and the dentate gyrus of the hippocampus. Pick cells (inflated neurons) and Pick bodies (ubiquitin and tau-positive intracellular inclusions) are absent. Betz cells in the precentral gyrus usually are affected.

In approximately 50% of patients, neuronal loss and pigmentary incontinence in the substantia nigra and other pigmented brainstem neurons occurs, even in patients without clinically overt parkinsonism. There can be marked hypoglossal and spinal motor neuron degeneration (although this is not essential for patients to progress to an anarthric state) and ubiquinated tau-negative inclusions in the spinal neurons.

Treatment

Medical Care

Direct prehospital care to aspects of MND that accompany the dementia.
Evaluate and treat sialorrhea, impaired breathing, swallowing, and mobility.
Consider neuroprotective agents (eg, riluzole, gabapentin) or nutritional supplements (eg, creatine) to preserve muscle bulk, but note that their efficacy in FTD/MND is even more uncertain than in MND.

Surgical Care

There is no surgical treatment for FTD/MND.
Consider gastrostomy tube feeding for patients with severe bulbar symptoms, severe dysphagia, and relatively mild dementia and limb weakness.

Diet

Patients may develop bulbar palsy, necessitating parenteral nutrition or percutaneous gastrostomy. Prior to gastrostomy, mechanically soft diets can be tried.

Activity

Level of activity is dictated by progression of MND.

Medication

No specific treatment is available for FTD/MND. Treatments for MND, such as riluzole and gabapentin, do not appear to affect the course of the dementia-inducing illness. Riluzole is currently the only licensed medication for MND. Available data from therapeutic trials in MND do not show beneficial cognitive effects, although there are no specific contraindications in this context. Gabapentin has been studied in trials as a disease-modifying agent in patients with MND but does not demonstrate specific cognitive-enhancing properties.

Acetylcholinesterase inhibitors (eg, donepezil, rivastigmine) are used to correct the cholinergic effect associated with Alzheimer disease. Although not studied specifically in FTD, anecdotal reports suggest they may increase irritability in patients with FTD.

FTD patients with profound presynaptic serotonergic deficits and behavioral disturbances may respond to selective serotonin reuptake inhibitors.

Selective dopamine-blockers, such as olanzapine, may be useful in agitated patients; monitor for side effects such as extrapyramidal syndromes. While plausible, it is not certain that treatment strategies for FTD apply to FTD/MND. Current treatments mainly are supportive and directed toward the features of MND.

Follow-up

Deterrence/Prevention

No effective methods exist.

Complications

Progressive bulbar palsy results in dysphagia, the risk of aspiration pneumonia, and mutism.
Muscular wasting and weakness may occur.
Parkinsonism may develop in some patients.
Dyspnea and hypoxic encephalopathy may be related positionally and can interfere with reclining for sleep.

Prognosis

Clinical signs of MND follow or accompany the onset of dementia.
MND is responsible for death, which usually occurs within 3 years of onset.

Patient Education

For excellent patient education resources, visit eMedicine's Dementia Center. Also, see eMedicine's patient education articles Dementia Overview, Dementia Medication Overview, and Dementia in Amyotrophic Lateral Sclerosis.

Miscellaneous

Medicolegal Pitfalls

Depending on the patient's occupation and level of cognitive and neurologic dysfunction, medical leave of absence or early retirement may be advisable.

References

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Hudson AJ. Amyotrophic lateral sclerosis and its association with dementia, parkinsonism and other neurological disorders: a review. Brain. Jun 1981;104(2):217-47. [Medline].
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Lomen-Hoerth C, Murphy J, Langmore S, et al. Are amyotrophic lateral sclerosis patients cognitively normal?. Neurology. Apr 8 2003;60(7):1094-7. [Medline].
Mitsuyama Y. Presenile dementia with motor neuron disease in Japan: clinico-pathological review of 26 cases. J Neurol Neurosurg Psychiatry. Sep 1984;47(9):953-9. [Medline].
Neary D, Snowden JS, Mann DMA, et al. Frontal lobe dementia and motor neuron disease. J Neurol Neurosurg Psychiatry. 1990;53:23-32. [Medline].
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Neary D, Snowden J. Fronto-temporal dementia: nosology, neuropsychology, and neuropathology. Brain Cogn. Jul 1996;31(2):176-87. [Medline].
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Strong MJ, Lomen-Hoerth C, Caselli RJ, et al. Cognitive impairment, frontotemporal dementia, and the motor neuron diseases. Ann Neurol. 2003;54 Suppl 5:S20-3. [Medline].
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Keywords

ALS dementia, frontotemporal dementia with motor neuron disease, FTD/MND, frontal lobe dementia with motor neuron disease, FLD/MND, MND, FTD

Contributor Information and Disclosures

Author

Joe Verghese, MD, MRCPI, Associate Professor, Department of Neurology, Albert Einstein College of Medicine
Joe Verghese, MD, MRCPI is a member of the following medical societies: American Academy of Neurology and American Geriatrics Society
Disclosure: Nothing to disclose.

Medical Editor

Rodrigo O Kuljis, MD, Esther Lichtenstein Professor of Psychiatry and Neurology, Director, Division of Cognitive and Behavioral Neurology, Department of Neurology, University of Miami School of Medicine
Rodrigo O Kuljis, MD is a member of the following medical societies: American Academy of Neurology and Society for Neuroscience
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Richard J Caselli, MD, Professor, Department of Neurology, Mayo Medical School, Rochester, MN; Chair, Department of Neurology, Mayo Clinic of Scottsdale
Richard J Caselli, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Medical Association, American Neurological Association, and Sigma Xi
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Howard A Crystal, MD, Professor, Departments of Neurology and Pathology, State University of New York Downstate; Consulting Staff, Department of Neurology, University Hospital and Kings County Hospital Center
Howard A Crystal, MD is a member of the following medical societies: American Academy of Neurology and American Neurological Association
Disclosure: Pfizer Honoraria Speaking and teaching; Myriad Honoraria Consulting

Further Reading