A case of motor neuron disease with progressive aphasia and dementia]

We report a 71-year-old woman showing rapidly progressive non-fluent aphasia and dementia accompanied by motor neuron disease (MND). There was no family history of dementia or motor neuron disease. There was 10 months history of dysarthria and dysphagia. On examination, she showed profound difficulty in articulation. Her comprehension was impaired in that she was unable to obey three-stage command. Her written language was also impaired with phonological spelling errors, syntactic errors, and perseveration. Neuroradiological investigations showed atrophic changes and hypoperfusion of left temporal and bilateral parietal region revealed by MRI and SPECT, respectively. Her subsequent decline was rapid. It might be likely that aphasia is much more common in dementia with bulbar MND than is currently recognized because bulbar palsy might mask the language disorder.     

Rapidly progressive aphasic dementia with motor neuron disease: a distinctive clinical entity

The association of motor neuron disease (MND) with rapidly progressive aphasic dementia has been recognized as a distinct clinical syndrome within the group of frontotemporal dementias (FTDs). Although the clinical and neuropsychological features of this syndrome have been defined, a small number of post-mortem studies have been published with heterogeneous neuropathological findings. We performed cognitive, neuro-imaging and neuropathological studies on a 71-year-old male with rapidly progressive aphasic dementia and MND. We initially found a selective non-fluent aphasia associated with hypoperfusion of the left frontotemporal cortex. Proton magnetic resonance spectroscopy revealed an asymmetric change of brain metabolites, with greater changes in the left temporal lobe. The bulbar manifestations of MND occurred over the following 6 months, and the patient died of bronchopneumonia. The neuropathological examination revealed loss of neurons in the hypoglossal nucleus and anterior horns of the cervical spinal cord with microvacuolation and dot-like ubiquitin-positive deposits in the frontoparietotemporal cortex, but no changes suggestive of Alzheimer's, Pick's or Lewy body disease. These findings support the conclusion that MND with rapidly progressive aphasic dementia is a distinctive clinical entity within the group of FTD-MND.     

Activities of daily living in motor neuron disease: role of behavioural and motor changes

Impairment in the activities of daily living (ADL) in motor neuron disease (MND) has been little investigated. The contributions of both behavioural and motor changes on functional performance have not been explored. A postal survey in New South Wales, Australia, included assessments of ADL, behavioural change (carer-based) and MND severity. Eighty-two patients were subdivided into groups according to onset presentation: bulbar (n=23) and limb (n=59). There were significant differences in ADL performance between limb and bulbar onset groups depending on ADL task. Disability was also dependent on disease severity as measured by the Amyotrophic Lateral Sclerosis Functional Rating Scale - Revised (ALSFRS - R) score. Importantly, variance in ADL scores was dependent on both motor and behavioural factors. This study confirms the progressive disabling nature of MND, which is dependent on disease severity and shows qualitative differences depending on onset presentation. A model combining motor and behavioural changes explained 57% of variance on ADL performance, with important implications for clinical intervention.     

A case of motor neuron disease with dementia, presenting motor aphasia as an initial symptom]

We report a case of motor neuron disease (MND) with dementia, presenting motor aphasia as an initial symptom. A 67-year-old man was admitted to our hospital because of speech disturbance slowly progressing for 2 years. On physical examination, he showed no neurological abnormalities except for non-fluent aphasia and increased deep tendon reflexes without laterality. MRI demonstrated bilateral fronto-temporal atrophy, dominating the left hemisphere. This finding was confirmed by surface anatomy scanning (SAS), showing an obvious atrophy in the left inferior frontal gyrus, compared with the right one. SPECT with 123I-IMP revealed some irregular defects in the bilateral frontotemporal region. Because he showed dementia, bulbar palsy with tongue atrophy, weakness of upper extremities and facial muscles, snout reflex, and the atrophy and fasciculation in limbs in addition to motor aphasia soon after the discharge from our hospital, he was diagnosed as having MND with dementia. At age 68, he died of a respiratory failure 3 years after the onset of the disease. MND with dementia seldom shows motor aphasia as an initial symptom. We must include, however, the MND with dementia as an differential diagnosis when we see the patients with progressive aphasia.     

Cognitive change in motor neurone disease/amyotrophic lateral sclerosis (MND/ALS)

A motor neuronopathy complicating frontotemporal dementia (FTD) has been recognised and designated FTD/motor neurone disease (MND). FTD is characterised by profound character change and altered social conduct, and executive deficits, reflecting focal degeneration of the frontal and temporal neocortex. The motor neuronopathy comprises bulbar palsy and limb amyotrophy. The major histological change is typically of microvacuolation of the cerebral cortex, with atrophy of the bulbar neurones and anterior horn cells of the spinal cord. Ubiquitinated inclusion bodies occur in large pyramidal cortical neurones and in surviving cranial nerve nuclei and anterior horn cells. Evidence is emerging that some patients with classical MND/amyotrophic lateral sclerosis (ALS), who are thought not to be demented, develop cognitive deficits in the realm of frontal executive functions. Moreover, frontal lobe abnormalities have been demonstrated by neuroimaging. The findings point to a link between FTD/MND and cMND/ALS and suggest that a proportion of patients with cMND/ALS go on to develop FTD. Patients with cMND/ALS may not be equally vulnerable. The hypothesis is that patients who present with bulbar palsy and amyotrophy, rather than corticospinal and corticobulbar features, may be most susceptible to the development of FTD.     

Dementia of frontal lobe type in Kennedy's disease.

The pathomorphological correlate of Kennedy's disease (KD) is a degeneration of spinal and bulbar alpha-motor neurons. The disease is caused by a CAG repeat expansion in the first exon of the X-chromosomal androgene receptor gene. Contrary to the common belief that cognitive disorders in motor neuron diseases (MND) are either rare or only mild, there is now an increasing number of case reports on dementia in amyotrophic lateral sclerosis (ALS). In ALS, dementia of the frontal lobe type (frontotemporal dementia, FTD) seems to be the characteristic pattern. However, in KD cognitive dysfunction has not been studied systematically. Here we present a case with clinical characteristics of FTD in a patient with genetically confirmed KD. It remains speculative whether there is an association between KD and FTD comparable to a genetic linkage between ALS and FTD, which has been proposed in recent years. However, we suggest that cognitive dysfunction may be more common in KD than reported until today.     

The relationship between extramotor ubiquitin-immunoreactive neuronal inclusions and dementia in motor neuron disease

Dementia is thought to be an uncommon complication of motor neuron disease (MND). In addition to the characteristic motor system degeneration, pathological studies of MND patients with dementia have demonstrated changes in extramotor cortex; ubiquitin-immunoreactive inclusions are present in neocortical layer II neurons and hippocampal dentate granule cells. To examine how specifically this pathology is associated with dementia in MND, we performed ubiquitin immunohistochemistry on sections of hippocampus, prefrontal and temporal neocortex from 29 cases of MND, 10 with dementia and 19 with no clinical history of cognitive impairment. All cases with dementia had numerous ubiquitin-positive inclusions in dentate granule cells, whereas involvement of the neocortex was more variable. Six (32%) of the nondemented cases had ubiquitin pathology, which was similar to the demented cases in its morphology and distribution but of slightly less severe degree. These findings demonstrate that, although ubiquitinated inclusions in extramotor cortex are a consistent finding in MND with dementia, they are also common in MND in the absence of documented cognitive abnormalities. Such cases may either represent a subclinical stage of pathology or indicate that cognitive dysfunction is an underrecognized complication of MND.     

Creutzfeldt-Jakob disease presenting as bulbar palsy

Creutzfeldt-Jakob disease (CJD) is a degenerative neurological disorder caused by a prion protein. The diagnosis may be challenging in unusual early presentations. A bulbar symptom as the initial complaint is a rare presentation for CJD, with only a few reports so far. These patients can be misdiagnosed with motor neuron disease or the Miller Fisher variant of Guillain-Barré syndrome. We describe a 69-year-old woman with CJD who presented with bulbar symptoms at the onset.     

The clinical spectrum of isolated peripheral motor dysfunction

Introduction: Isolated peripheral motor dysfunction due to lower motor neuron or peripheral nerve disorders presents an interesting challenge to clinicians because of the diverse differential diagnosis with a broad range of prognoses. Methods: We retrospectively reviewed clinical data of adults who presented over 12 years with muscle weakness, atrophy, or fasciculations, but without hyperreflexia or sensory involvement. Results: In 119 patients, 52% had a motor neuron disease (MND), 13% had immune neuropathies, 11% had genetic neuronopathies, 10% had residual or post‐polio syndrome, 5% had benign fasciculation, 1% had an infectious etiology, and 8% were not given a final diagnosis. Only MND patients had cognitive dysfunction or frontal release signs. Bulbar and respiratory symptoms virtually excluded consideration of immune neuropathy. Conclusions: Only half of the patients were diagnosed with MND. A significant minority have treatable conditions. Cognitive involvement, frontal release signs, and bulbar or respiratory symptoms are strongly suggestive of MND. Muscle Nerve 51: 358–362, 2015     

Neuronal intranuclear inclusions distinguish familial FTD-MND type from sporadic cases

Ubiquitin-immunoreactive (ub-ir) neuronal cytoplasmic inclusions are characteristically found in the extramotor cortex in patients with motor neuron disease and dementia (MND-dementia) and a subset of patients with frontotemporal dementia without motor symptoms (FTD-MND type). Recently, ub-ir neuronal intranuclear inclusions have been described in a small number of patients with familial FTD-MND type. To better define the sensitivity and specificity of this pathological change, we examined postmortem tissue from 14 patients with FTD-MND type (8 familial, 6 sporadic), 10 cases of MND-dementia (5 familial, 5 sporadic), and 19 cases of MND with no history of cognitive dysfunction (2 familial, 17 sporadic). Numerous intranuclear inclusions were found in multiple anatomic sites in 6/8 cases of familial FTD-MND. Rare intranuclear inclusions were present in the hippocampal dentate granule cells in 1 case of familial MND-dementia. No sporadic cases had intranuclear inclusions. These findings suggest that intranuclear inclusions are specific for familial FTD and may identify a subset of families with a common molecular pathogenesis. Although intranuclear inclusions are most characteristic of families in which the clinical presentation is pure FTD, they may also be found in some pedigrees with both FTD and MND; further supporting the hypothesis that FTD-MND type and MND-dementia represent a clinicopathological spectrum of disease.     

Where fronto-temporal dementia should be placed in the history of Pick's disease and related disorders]

Pick syndrome, non-Alzheimer type dementia with primary degeneration in the anterior portion of the brain, has been shown to include several disease-entities besides classic Pick's disease. Fronto-temporal dementia (FTD) proposed by Lund & Manchester group is a concept that includes Pick's disease, and its "clinical diagnostic features" are useful because they distinguish dementia with frontal and anterior temporal involvement from Alzheimer type dementia. FTD is classified into three types, the frontal lobe degeneration (FLD) type, Pick type and motor neuron disease (MND) type, and neuropathological diagnostic features of each type are presented. In Japan, however, cases neuropathologically corresponding to the FLD type, which has mild frontal dominant degeneration with heavy heredity, have not been previously reported. Classic Japanese Pick's disease is consistent with Pick type, however, cases of Pick's disease with and without Pick body exist in nearly the same number in Japan. The latter may include heterogeneous types, which should be elucidated. MND type corresponds to Japanese cases, called Yuasa-Mitsuyama disease or dementia with motor neuron disease, and could be actually diagnosed because such patients do not exhibit severe personality change and accompany symptoms of amyotrophic lateral sclerosis or spinal progressive muscular atrophy in their clinical course. In addition, Pick syndrome includes progressive subcortical gliosis, corticobasal degeneration, basophilic inclusion body disease and fronto-temporal dementia with parkinsonism linked chromosome 17. Progressive aphasia and semantic dementia are neuropsychologically important concepts, however, they are symptom-complex and are dominated only by where the degeneration begins and how it progresses. They should not be confused with pathologically confirmed disease-entities.     

Incidence and prevalence of motor neuron disease in two Danish counties

A total of 186 cases of motor neuron disease (MND) was identified in two Danish counties during the period 1974-1986. The average annual incidence rate was 1.4/100,000 population, and the male:female ratio of incidence rates was 1.5. Mean age at diagnosis was 64.3 +/- 10.0 years. The incidence rates increased significantly with advancing age and reached a maximum at age 60-79 years, followed by a nonsignificant decrease. The average point prevalence was 3.1/100,000 population. Bulbar symptoms were part of the initial symptoms in 65% of cases, and patients with bulbar onset were older than patients with spinal onset. Age- and sex-specific incidence rates indicated a marked male preponderance amongst the youngest patients, in contrast to a female preponderance in patients above 60 years with bulbar onset of MND. Familial MND accounted for 2.7% of cases.     

Post‐traumatic stress disorder mistaken for behavioural and psychological symptoms of dementia: case series and recommendations of care

In late life, traumas may act cumulatively to exacerbate vulnerability to post‐traumatic stress disorder (PTSD). PTSD is also a risk factor for cognitive decline. Major neurocognitive disorder (MND) can be associated with worsening of already controlled PTSD symptoms, late‐life resurgence or de novo emergence. Misidentifying PTSD symptoms in MND can have negative consequences for the patient and families. We review the literature pertaining to PTSD and dementia and describe five cases referred for consultation in geriatric psychiatry initially for behavioural and psychological symptoms of dementia (BPSD), which were eventually diagnosed and treated as PTSD in MND subjects. We propose that certain PTSD symptoms in patients with MND are misinterpreted as BPSD and therefore, not properly addressed. For example, flashbacks could be interpreted as hallucinations, hypervigilance as paranoia, nightmares as sleep disturbances, and hyperreactivity as agitation/aggression. We suggest that better identification of PTSD symptoms in MND is needed. We propose specific recommendations for care, namely: clarifying diagnosis by distinguishing PTSD symptoms coexisting with different types of dementia from a specific dementia symptom (BPSD), gathering a detailed history of the trauma in order to personalise non‐pharmacological interventions, adapting psychotherapeutic strategies to patients with dementia, using selective serotonin reuptake inhibitors as first‐line treatment and avoiding antipsychotics and benzodiazepines. Proper identification of PTSD symptoms in patients with MND is essential and allows a more tailored and efficient treatment, with decrease in inappropriate use of physical and chemical restraints.     

A neuropsychological investigation of dementia in motor neurone disease (MND)

Different clinical criteria for diagnosing dementia were compared in a sample of 69 patients with motor neurone disease (MND). Participants’ performances on a computerised battery of neuropsychological tests were evaluated to assess the usefulness of these tests in predicting dementia in MND. The results indicated that when diagnostic criteria for frontotemporal (FTD) were used as part of a questionnaire method of diagnosing dementia the incidence of dementia in MND was considerably greater than traditional estimates suggest. Through a series of logistic and multiple regressions the results demonstrated that neuropsychological test performance related well to diagnostic classifications of dementia. MND patients with a clinical diagnosis of dementia were likely to demonstrate impaired new learning; poor working memory and planning; slowness in information processing and rigidity in thinking. These features, which are typical of cases of FTD, suggest that the dementia of MND is usefully characterised as a form of FTD. The finding that neuropsychological impairment correlated with behavioural features of dysexecutive impairment in daily living, indicates that the management focus in MND must be broadened to include cognitive/behavioural issues.     

Inferring thought and action in motor neurone disease

The traditional assumption that classical motor neurone disease (MND) invariably spares cognitive function is now recognised to be incorrect. Deficits have most commonly been demonstrated on executive tasks suggesting impaired function of frontal systems. Yet, crucial aspects of frontal lobe function have not hitherto been explored. The study used tests of theory of mind (ToM) (interpretation of cartoons and stories) to examine the ability of 16 patients with MND to interpret social situations and ascribe mental states to others. Only minor differences were elicited in the MND group as a whole compared to controls, and performance was not differentially affected for cartoons and stories requiring inference of another's mental state (mental) compared to control (physical) cartoons and stories. However, abnormalities were elicited on both mental and physical tasks in a subgroup of patients with bulbar signs. Moreover, examination of individual patient scores revealed a spectrum of performance ranging from normal to severely impaired. Errors were qualitatively similar to those seen in frontotemporal dementia (FTD). Performance on the ToM tasks was significantly correlated with conventional, untimed measures of executive function, suggesting that ToM deficits in MND are likely to be linked to a more general executive failure. The findings contribute to the understanding of ToM performance in neurodegenerative disease and provide further evidence of the association between MND and FTD.     

Heterogeneity of behavioural and language deficits in FTD–MND

Journal of Neurology - To comprehensively examine the clinical presentation of patients diagnosed with frontotemporal dementia–motor neuron disease (FTD–MND) compared to FTD subtypes....     

Coughing and choking in motor neuron disease

OBJECTIVES: To assess the frequency and severity of coughing and choking episodes, possible related factors, and their association with chest infections in patients with motor neuron disease (MND). METHODS: Thirty seven patients with MND and 23 healthy volunteers were studied. Cough was assessed using a questionnaire and a 3 day diary, and volitional cough quantified by peak cough flow and sound intensity. Other clinical symptoms, smoking habit, affective state, oral secretions, bulbar signs, and quantitative assessments of swallowing and respiratory function were documented. RESULTS: Patients with MND coughed and choked significantly more often and to a greater degree than the healthy volunteers (26 of 37 patients with MND and 2 of 23 volunteers, p<0.001). Female sex, older age, abnormal speech, reduced swallowing capacity, and low forced vital capacity (FVC)% predicted were each significantly associated with excessive coughing and choking episodes in patients with MND. Smokers had significantly more severe and prolonged episodes of coughing and choking than non-smokers (p<0.05). Patients with upper motor neuron bulbar signs had a greater tendency to severe and prolonged episodes of coughing and choking than those without (p<0. 05). Chest infections were reported only rarely among the patients who coughed and choked. CONCLUSIONS: Coughing and choking episodes are common in patients with MND but infrequently associated with overt chest infection. Upper motor neuron bulbar signs may both promote factors (for instance, dysphagia) which trigger cough and reduce volitional capacity to suppress it.     

Ubiquitin immunohistochemistry suggests classic motor neuron disease, motor neuron disease with dementia, and frontotemporal dementia of the motor neuron disease type represent a clinicopathologic spectrum

One of the characteristic pathologic changes in classic motor neuron disease (MND) is the presence of ubiquitin-immunoreactive (ub-ir) inclusions in the cytoplasm of lower motor neurons. In addition, cases of MND with dementia (MND-d) also have ub-ir neuronal cytoplasmic inclusions and dystrophic neurites in extramotor neocortex and hippocampus. Although this extramotor pathology is a highly sensitive marker for dementia in MND, similar changes are found in a subset of patients with frontotemporal dementia (FTD) with no motor symptoms (FTD-MND type). The purpose of this study is to more fully describe and compare the pattern of ub-ir pathology in these 3 conditions. We performed ubiquitin immunohistochemistry on postmortem tissue, representing a wide range of neuroanatomic structures, in cases of classic MND (n = 20), MND-d (n = 15), and FTD-MND type (n = 15). We found the variety of morphologies and the anatomic distribution of ub-ir pathology to be greater than previously documented. Moreover, the degree of overlap suggests that MND, MND-d, and FTD-MND type represent a spectrum of clinical disease with a common pathologic substrate. The only finding restricted to a specific subgroup of patients was the presence of ub-ir neuronal intranuclear inclusions in some cases of familial FTD.     

Motor neuron disease in inherited neurometabolic disorders

Inherited neurometabolic disorders represent a growing group of inborn errors of metabolism that present with major neurological symptoms or a complex spectrum of symptoms dominated by central or peripheral nervous system dysfunction. Many neurological presentations may arise from the same metabolic defect, especially in autosomal-recessive inherited disorders. Motor neuron disease (MND), mainly represented by amyotrophic lateral sclerosis, may also result from various inborn errors of metabolism, some of which may represent potentially treatable conditions, thereby emphasizing the importance of recognizing such diseases. The present review discusses the most important neurometabolic disorders presenting with motor neuron (lower and/or upper) dysfunction as the key clinical and neuropathological feature.