Symptomatology and Neuropathology of patients presenting with focal cortical signs.

Here, we describe two patients who presented with focal cortical signs and underwent neuropathological examination. Case 1 was a 73-year-old woman with progressive speech disorder and abnormal behavior. She showed agraphia of the frontal lobe type, featured by the omission of kana letters when writing, other than pyramidal tract signs, pseudobulbar palsy, and frontal lobe dementia. Neuropathological examination, including TAR DNA-binding protein 43 (TDP-43) immunohistochemistry, revealed bilateral frontal and anterior temporal lobe lesions accentuated in the precentral gyrus and posterior part of the middle frontal gyrus. Both upper and lower motor neurons showed pathological changes compatible with amyotrophic lateral sclerosis. Case 2 was a 62-year-old man with progressive speech disorder and hand clumsiness. He had a motor speech disorder, compatible with apraxia of speech, and limb apraxia of the limb-kinetic and ideomotor type. Neuropathological examination revealed degeneration in the left frontal lobe, including the precentral gyrus, anterior temporal, and parietal lobe cortices. Moreover, numerous argyrophilic neuronal intracytoplasmic inclusions (Pick body) and ballooned neurons were observed in these lesions and the limbic system. The pathological diagnosis was Pick disease involving the peri-Rolandic area and parietal lobe. In these two cases, the distribution of neuropathological changes in the cerebral cortices correlated with the clinical symptoms observed.

Pseudobulbar dysarthria in the initial stage of motor neuron disease with dementia: a clinicopathological report of two autopsied cases.

We retrospectively analyzed the clinical features of two cases of neurodegenerative disease, whose initial symptoms were motor speech disorder and dementia, brought to autopsy. We compared the distributions of pathological findings with the clinical features. The main symptom of speech disorder was dysarthria, involving low pitch, slow rate, hypernasality and hoarseness. Other than these findings, effortful speech, sound prolongation and initial difficulty were observed. Moreover, repetition of multisyllables was severely impaired compared to monosyllables. Repetition and comprehension of words and sentences were not impaired. Neither atrophy nor fasciculation of the tongue was observed. Both cases showed rapid progression to mutism within a few years. Neuropathologically, frontal lobe degeneration including the precentral gyrus was observed. The bilateral pyramidal tracts also showed severe degeneration. However, the nucleus of the hypoglossal nerve showed only mild degeneration. These findings suggest upper motor neuron dominant motor neuron disease with dementia. We believe the results indicate a subgroup of motor neuron disease with dementia whose initial symptoms involve pseudobulbar palsy and dementia, and which shows rapid progression to mutism.

[An autopsied case of corticobasal degeneration with onset of nonfluent aphasia revealing symmetrical cerebral involvement].

Herein we describe a patient with established corticobasal degeneration with onset of nonfluent aphasia and showing symmetrical cerebral involvement. A 64-year-old man with a speech disorder for 2 years visited our hospital. He had nonfluent aphasia (reduced spontaneous speech, loss of intonation, anomia, repetition disorder, and difficulty in speaking short sentences). He also showed right-sided motor neglect, hypertonus of the left lower limb, a mask-like facial expression, and difficulty in closing his eyes. He was restless and walked around even during examination, suggesting frontotemporal dementia (FTD). Single-photon emission computed tomography (SPECT) revealed symmetrical reduction of cerebral blood flow in the bilateral fronto-temporo-parietal lobes. His neurological condition deteriorated gradually and a year later he could not speak comprehensive sentences. Magnetic resonance imaging (MRI) of the head at age 70 showed symmetrical atrophy of the bilateral fronto-temporal lobes. He died of respiratory failure after clinical problems lasting ten years. On pathological examination, the fixed brain weighed 1,010 g and showed bilateral symmetrical atrophy of the frontal lobes. Histopathological examination revealed neuronal loss and gliosis in the frontal lobes, especially in the frontal convexity, superior frontal gyrus and precentral gyrus. Gallyas-Braak silver staining showed astrocytic plaques, argyrophilic threads and coiled bodies mainly in the frontal lobes. The substantia nigra showed severe neuronal loss on both sides and presence of free melanin. Pathological diagnosis was corticobasal degeneration (CBD). We believe that the patient had nonfluent aphasia and FTD reflected in bilateral degeneration of the frontal lobes. Some cases of CBD may present with symmetrical degeneration of the brain, even though left-hemisphere symptoms such as aphasia reveal themselves at an early stage.

[A clinicopathological study of young-onset dementia: report of 2 autopsied cases].

We retrospectively examined the clinical features and the neuroradiological findings on autopsy of 2 cases of young-onset dementia. The patient in case 1 was a 43-year-old woman who was unable to determine the time on the clock and who made frivolous remarks. Neuropsychological test batteries demonstrated memory impairment and frontal lobe dysfunction. T2-weighted magnetic resonance imaging (MRI) of the head revealed abnormal high-intensity signals around the lateral ventricles and thinning of the corpus callosum. Single photon emission computed tomography (SPECT) revealed patchy reduction in the accumulation of tracers in both the frontal lobes. Her neurological condition gradually deteriorated, and she died 13 years after the onset of the disease. She was clinically diagnosed with atypical Alzheimer's disease on the basis of visual cognitive impairment and memory impairment observed in the initial phase. However, the neuropathological diagnosis was adult-onset leukodystrophy with axonal spheroids. The patient in case 2 was a 43-year-old man who had gradually started behaving selfishly and had become ill-tempered and apathetic. He was admitted to a hospital. He was anosognosic and showed frontal lobe dysfunction. T2-weighted MRI scan of the brain showed abnormal high-intensity signals around the lateral ventricles; atrophy of the frontal and temporal lobes, hippocampus, and brainstem; and thinning of the corpus callosum. SPECT revealed patchy reduction in the accumulation of tracers in both the frontal lobes and the cerebellum. His neurological condition gradually deteriorated, and he died after being clinically ill for 7 years. The patient was clinically diagnosed with frontotemporal dementia on the basis of the clinical features and MRI findings. However, the neuropathological diagnosis was chronic meningoencephalitis. The frequency of neurological metabolic and inflammatory diseases is significantly high although it is not as high as that of degenerative diseases in young-onset dementia. Since such diseases may respond to therapy, they should be considered in the differential diagnosis of young-onset dementia, especially in patients presenting with atypical clinical features. Neuroradiological examination may contribute to the differential diagnosis of atypical dementia at young age.

Is lesion of Exner's area linked to progressive agraphia in amyotrophic lateral sclerosis with dementia? An autopsy case report.

Agraphia, as a neuropsychological symptom of ALS, especially ALS with dementia (ALS-D), has recently attracted more attention. However, the brain lesion responsible has not been identified. Here we present an autopsy case of ALS-D of a patient with obvious agraphia, without aphasia, that also presented cerebrospinal degeneration with TDP-43-pathology compatible with ALS-D. Of the pre-motor frontal lobe cortices, degeneration and immuno-histochemical pathology were most obvious in the caudal area of the left middle frontal gyrus, or Exner's area. Assuring this area plays a pivotal role in the kanji and kana formation used in writing the Japanese language, this case of ALS-D showed both agraphia and Exner's area stressed pathological lesions. It may thus be the first case to indicate an intimate relationship between the neuropsychological symptoms and an associated lesion for ALS-D.

[A case of hypothyroidism displaying "dropped head" syndrome].

We describe a patient with hypothyroidism displaying "dropped head" syndrome. A 50-year-old man visited our clinic because he was unable to hold his head in the natural position. He had weakness and hypertrophy of the neck extensor muscles. Tendon reflexes were diminished or absent in all limbs. Mounding phenomena were observed in the bilateral upper extremities. Blood biochemical analysis revealed hypothyroidism, hyperlipidemia, and elevated levels of muscle-derived enzymes. Magnetic resonance imaging (MRI) of the neck demonstrated swelling and hyperintensity of the neck extensor muscles on T2-weighted images. The result of biopsy of the right biceps brachii muscle suggested mild atrophy of type 2 fibers. The diameters of the muscle fibers exhibited mild variation. No inflammatory changes were observed. We diagnosed hin as having "dropped head" syndrome due to hypothyroidism. Administration of thyroid hormone agent gradually improved his condition, and he became able to hold his head in the natural position. Levels of muscle-derived enzymes normalized and his hyperlipidemia remitted. Neck MRI also revealed improvement. Our findings suggest that hypothyroidism should be considered in the differential diagnosis of "dropped head" syndrome, although only a few cases like ours have been reported.

Severe cortical involvement in MV2 Creutzfeldt-Jakob disease: an autopsy case report.

MV2 type sporadic Creutzfeldt-Jakob disease (sCJD) is reported to have a long duration and marked involvement of the cerebral deep gray matter. We describe an autopsied long-surviving sCJD case of MV2. In the early stages, the patient exhibited memory impairment, attention deficit and semantic memory disorder. Diffusion-weighted MRI showed abnormal hyperintensity signals along the cerebral cortex, sparing the thalami and basal ganglia. Pathological observations included: severe spongiosis throughout the cerebral cortex, several kuru plaques and plaque-like PrP deposits in the cerebellum, with only minimal degeneration in the thalami and basal ganglia. Our case suggests that MV2 has a wide clinicopathological spectrum, which ranges from "VV2" to "MM2" type.

An autopsy case of frontotemporal dementia with severe dysarthria and motor neuron disease showing numerous basophilic inclusions.

We report a clinicopathological study of a patient suffering from frontotemporal dementia (FLD) with severe dysarthria and concomitant motor neuron disease (MND). The patient was a 52-year-old woman with almost simultaneous emergence of severe dysarthria and FTD. The severe dysarthria subsequently evolved into anterior opercular syndrome. Motor neuron signs then emerged, and the patient developed akinetic mutism approximately 2 years after the onset of the disease. The patient died of pneumonia after a 7-year clinical illness. Pathologically, severe and widespread degeneration in the frontal and temporal lobes, including the anterior opercular area, limbic system, basal ganglia, spinal cord and cerebellum, and frequent ubiquitin- and tau-negative basophilic inclusions were observed. The pyramidal tracts and anterior horns of the cervical cord also showed marked degeneration. Cases showing basophilic inclusions reported so far have been divided into two groups: early onset FTD and MND with basophilic inclusions. Our case presented clinicopathological features of both FTD and MND, which suggests that cases showing basophilic inclusions may constitute a clinicopathological entity of FTD/MND.

[An autopsied case of paraneoplastic neurologic syndrome (limbic encephalitis, cerebellar degeneration, and pseudohypertrophy in the inferior olivary nuclei) associated with T cell lymphoma].

We describe a patient with paraneoplastic neurologic syndrome confirmed on postmortem examination. This 42-year-old man was admitted due to general fatigue, emaciation and acute-onset disorientation. Neurological examination revealed disorientation, moderate cognitive impairment, cerebellar ataxia, bilateral limitations and nystagmus in all directions during external ocular movement, swallowing disorder, bilateral Babinski sign, sensory disturbance in the distal parts of all extremities, and Romberg's sign. T-cell lymphoma was diagnosed following biopsy of the cervical lymph node. Neurological condition improved slightly after chemotherapy, but subsequently deteriorated. At about 6 years after the disease onset, brain magnetic resonance imaging (MRI) revealed atrophy of bilateral hippocampi and the upper vermis of the cerebellum. The patient died of pneumonia after a clinical course of about 6 years and 6 months. Pathologically, neuronal loss, reactive gliosis and perivascular lymphocytic infiltration were observed in the hippocampi, cerebellum, and inferior olivary nuclei. Lymphocytes around the vessels were positive for LCA and UCHL-1, but negative for CD8 and L26, and thus were considered to be T cells. No lymphoma cell was observed in the central nervous system or lymphatic organs. Based on the pathological findings, paraneoplastic neurologic syndrome (limbic encephalitis, cerebellar degeneration and olivary pseudohypertrophy) associated with T-cell type malignant lymphoma was diagnosed. Only three other cases of paraneoplastic neurologic syndrome associated with T-cell lymphoma have been reported. In those cases, death occurred due to the deterioration of malignant lymphoma, whereas the present patient died about 6 years after the remission of malignant lymphoma. Prognosis may thus depend on the course of the malignant lymphoma. In the present patient, neurological symptoms deteriorated after remission of malignant lymphoma, and no pathological lesion were found in the lymphatic organs. Lesions in the central nervous system in paraneoplastic neurological syndromes may follow a course independent of the original malignant disease.

[An autopsied case of medullary glioma with an abrupt onset of headache and hemiparesis].

We describe an 89-year-old woman who presented with an abrupt onset of headache and right hemiparesis. With the initial diagnosis of cerebral infarction, we started therapy using sodium ozagrel. The right hemiparesis worsened, however, and a continuous intravenous heparin injection showed no effect. Furthermore, nystagmus in the bilateral eyes, dysphagia, left hemiparesis, and central ventilation disorder appeared one after another in three weeks. A magnetic resonance images (MRI) of the head, performed on the fifth hospital day with regular intervals of axial sections, disclosed no lesion responsible for right hemiparesis. MRI of the brainstem and upper cervical cord, performed after two weeks with smaller intervals of axial sections, revealed a T2 high signal lesion in the left side of the medulla oblongata and upper cervical cord. After about five weeks from the onset of the disease, she died of pneumonia. With the pathological examination, we diagnosed as glioma originated in the left ventral part of medulla oblongata. Five similar cases of brainstem glioma have been reported so far. Our patient, the oldest one, showed an exceptionally rapid clinical course, instructing us to consider the possibility of medullary glioma even in the elderly patients presenting with acute onset hemiparesis followed by rapid and progressive appearance of brainstem signs.

Argyrophilic grain disease presenting with frontotemporal dementia: a neuropsychological and pathological study of an autopsied case with presenile onset.

A right-handed Japanese man with no consanguinity exhibited personality changes, speech disorder and abnormal behaviors, such as stereotypical, running-away, environment-dependent, and going-my-way behaviors, since the age of 49 years. At age 52 years, neuropsychological examination revealed frontal lobe dysfunctions, mild memory impairment, and transcortical sensory aphasia. MRI showed symmetrical severe atrophy of the anterior part of the temporal and frontal lobes. The clinical diagnosis was FTD. He died at age 54 years after a clinical illness of approximately 5 years. Numerous argyrophilic grains were observed throughout the limbic system, temporal lobe, frontal lobe and brainstem. In addition, there were many tau-positive neurons and glial cells. These findings are all compatible with argyrophilic grain disease (AGD). Our case, however, is atypical AGD because of the young age of onset of the disease and sharply circumscribed cortical atrophy exhibiting severe neuronal loss and gliosis. Our case, together with some other similar cases of atypical AGD, gives rise to the possibility that this type of AGD would constitute a part of pathological background of FTD.

[A case presenting with trochlear nerve palsy and segmental sensory disturbance due to circumscribed midbrain and upper pontine hemorrhage].

We describe a patient presenting with trochlear nerve palsy and segmental sensory disturbance due to circumscribed mesencephalic hemorrhage. A 36-year-old man with no past illness visited our hospital complaining of sudden onset of diplopia, dysesthesia of the left face and upper extremity, and acuphenes of the left ear. Neurological examination revealed left trochlear nerve palsy and segmental sensory disturbance of the left side almost above T11 level. Pain and temperature sensation were disturbed, but vibration, joint position, graphesthesia, kinesthesia, and discrimination sensation were spared. Magnetic resonance imaging of the head, performed 7 days after onset, revealed acute to subacute phase hemorrhage at the right inferior colliculus. No abnormalities were identified on cerebral angiography. Symptoms gradually improved with conservative therapy. After about ten weeks, diplopia disappeared and area of sensory disturbance was reduced (disturbance of pain sensation reduced to about T4 level, temperature sensation to about T9). Segmental sensory disturbance usually accompanies spinal cord lesion. However, several cases of similar symptoms following cerebrovascular disease of the brainstem have been reported. Conversely, some reports have indicated that trochlear nerve palsy due to midbrain hemorrhage accompanies sensory disturbance contralateral to the lesion. The nature of sensory disturbance is thus variable. The present case suggests that segmental sensory disturbance might accompany trochlear nerve palsy caused by hemorrhage of the inferior colliculus, as intramedullary fibers of the trochlear nerve and spinothalamic tract are located nearby and somatotopy of the spinothalamic tract is preserved even at the level of the midbrain.

Lewy body-free nigral degeneration--a case report.

A 70-year-old Japanese woman developed progressive, dopa-responsive parkinsonism consisting of akinesia, resting tremor, rigidity, and postural instability. Neuropathological examination revealed a marked loss of nigral neurons, but no Lewy bodies (LBs) were observed. Lewy bodies were also absent from their usual site, with the exception of a small number seen in the dorsal motor nucleus of the vagus nerve (DVN) and sympathetic ganglion. We propose that our case and several similar reported cases represent Lewy body-free nigral degeneration.