□ CASE REPORT □

Two Cases of Accompanied by Involvement of the Skeletal System and Bulbar Palsy

Yasuyuki Ohta, Takeshi Hayashi, Makiko Nagai, Miyuki Okamoto, Shoko Nagotani, Isao Nagano, Nobuhiko Ohmori, Yasushi Takehisa, Tetsuro Murakami, Mikio Shoji, Tatsushi Kamiya and Koji Abe

Abstract

We report two patients with spinocerebellar ataxia (SCA) with cranial and spinal motor neuron involve- ment. They initially presented with cerebellar ataxia, followed by bulbar palsy and limb motor neuron sign. One of the patients had a brother with allied disorder. SCA type 1 (SCA1), SCA3 and SCA6 have been re- ported to involve the motor neuron system, but they were excluded by DNA analyses in the present two pa- tients. These two patients may form a distinct disease entity among SCAs.

Key words: spinocerebellar ataxia, motor neuron disease, bulbar palsy, tongue , MRI

(DOI: 10.2169/internalmedicine.46.6261)

speaking from 58 years of age. These symptoms progressed Introduction slowly, and swallowing became difficult from 61 years of age. At age 62, his tongue became atrophic. In February Spinocerebellar ataxia (SCA) is a disease affecting the 2004, at age 63, he was referred to our hospital. He had a spinocerebellar, autonomic and extrapyramidal systems. Al- brother 15 years older (Fig. 1A; Brother 1), who had suf- though some cases of hereditary SCA, such as SCA type 1 fered unsteady gait and from 40 years of age and (SCA1), SCA2, SCA3 and SCA6, affect motor neurons had unaccounted for motor neuron disorder, and died of (1-7), other types rarely affect them. Atrophy and fascicula- myocardial infarction at age 61. His parents, his other two tion of the tongue are characteristic in motor neuron dis- brothers and his son were asymptomatic. eases such as amyotrophic lateral sclerosis (ALS), but have He weighed 51 kg and was 170 cm tall. Physical exami- also been reported in some cases of SCA1 and SCA3 (6); nation revealed no remarkable findings. Neurologically, he other types of SCA rarely show these features. Here, we re- did not present , apraxia or agnosia. The Mini- port two cases of SCA accompanied by motor neuron in- Mental State Examination (MMSE) gave a score of 27/30, volvement, with severe atrophy and of the indicating an immediate memory disturbance. There were tongue, in which SCA1 and SCA3 were excluded by DNA saccadic eye movements, vertical and lateral gaze limitation, analysis. scanning speech, and severe atrophy, weakness and fascicu- lation of the tongue (Fig. 1B). Ocular fundus was normal, Case Report and there was not blepharoptosis. He showed marked mus- cle atrophy and fasciculation in all extremities as well as the Patient 1. A 52-year-old man, who had a medical history trunk, and his muscle tone was decreased. However, he did of type 2 diabetes mellitus for more than 10 years, gradually not have in the extremities or the trunk. developed an unsteady gait. At age 54, action ap- His deep tendon reflexes were brisk in all extremities, and peared in both upper limbs, and he found difficulty in Hoffmann’s, Trömner and Wartenberg reflexes were all posi-

Department of , Graduate School of Medicine, Dentistry and Pharmacy, Okayama University, Okayama Received for publication September 23, 2006; Accepted for publication December 27, 2006 Correspondence to Dr. Yasuyuki Ohta, [email protected]

751 DOI: 10.2169/internalmedicine.46.6261

Figure 1. The family tree (A), photograph of tongue (B), muscle sample (C) and MRI im- ages (D-F) of patient 1. (B) The tongue is atrophic. (C) Biopsy sample of left biceps brachii muscle shows small angular fiber and small group atrophy (hematoxylin-eosin stain, scale bar = 100 μm). (D) Axial T1-weighted MRI shows cerebellar atrophy (arrows). (E) Sagittal T1-weighted MRI shows atrophy of the upper region of the cerebellar vermis (large arrow), and the cervical appeared to be slightly atrophic (arrowheads). (F) The thoracic and lumbar spinal cord ap- peared to be slightly atrophic by sagittal T1-weighted MRI (arrows).

tive. The was flexor. He showed marked trun- high-amplitude motor unit potentials (3.0-6.5 mV) with a cal and limb ataxia. The sensory and autonomic systems discrete interference pattern on voluntary contraction of the were unremarkable. muscle. The latency and amplitude of the motor-evoked po- Laboratory blood tests revealed elevation of fasting blood tentials (MEPs) were normal in all extremities. Magenetic sugar (191 mg/dl, normal range = 65 to 105 mg/dl), total resonance imaging (MRI) of the brain revealed severe atro- cholesterol (249 mg/dl, normal range = 130 to 220 mg/dl) phy in the cerebellar vermis and mild atrophy in the frontal, and triglyceride (377 mg/dl, normal range = 50 to 150 mg/ temporal and parietal lobes, and the cerebellar hemispheres dl). His was normal. SCA1, SCA3, SCA (Fig. 1D, E). The cervical, thoracic and lumbar spinal cord 6 and X-linked spinal and bulbar muscular atrophy (SBMA) appeared to be slightly atrophic by MRI (Fig. 1E, F). Tc-99 were ruled out by DNA analysis. Motor nerve conduction m ethyl cysteinate dimer (ECD) single photon emission velocity was slightly decreased in the right tibial nerve (38 computed tomography (SPECT) revealed hypoperfusion in m/sec). The amplitudes of the compound muscle action po- the cerebellum and bilateral parietal lobe, and especially se- tential (CMAP) and sensory nerve action potential (SNAP) vere hypoperfusion in the upper side of the cerebellar ver- of the right median nerve were decreased (CMAP ampli- mis. Muscle biopsy of left biceps brachii showed small an- tude, 4.4 mV; SNAP amplitude, 7.7 μV). gular fiber and small group atrophy, which suggested neuro- (EMG) of the tongue, sternocleidomastoid muscles, upper genic muscular atrophy (Fig. 1C). and lower extremities, and paraspinal muscles demonstrated Patient 2. A 55-year-old woman, who had a medical his-

752 DOI: 10.2169/internalmedicine.46.6261

Figure 2. Photograph of tongue (A), external ophthalmoplegia (B) and MRI images (C-E) of pa- tient 2. (A) The tongue is atrophic. (B) Bilateral abductive eye position (central picture), vertical gaze limitation (vertical pictures) and lateral gaze limitation with severe adductive limitation (lat- eral pictures). (C) Axial T2-weighted MRI shows cerebellar atrophy (arrows) and a subtle hyperin- tense lesion, an ‘inverted T-sign’, in the pons (arrowheads). (D) Sagittal T1-weighted MRI shows atrophy of the upper region of the cerebellar vermis (large arrow), and the cervical spinal cord ap- peared to be slightly atrophic (arrowheads). (E) The thoracic and lumbar spinal cord appeared to be slightly atrophic by sagittal T1-weighted MRI (arrows).

tory of hip joint replacements for osteoarthrosis at age 52, Ocular fundus was normal, and there was no blepharoptosis. developed an unsteady gait. At age 57, she felt ataxia in She showed marked muscle atrophy and slight muscle both upper limbs. She found difficulty in speaking, and her weakness in all extremities as well as in the trunk, fascicula- gait disturbance progressed slowly from 64 years of age. At tion in bilateral lower extremities, and hypotonia in all ex- age 70, she developed double vision and difficulty in swal- tremities. The deep tendon reflexes were brisk in all ex- lowing. At age 73, her tongue became atrophic. In February tremities, and Hoffmann’s, Trömner and Wartenberg reflexes 2003, at age 74, she was referred to our hospital. Her par- were all positive. Her plantar reflex was extensor. She ents, brothers and sons were asymptomatic. showed marked truncal and limb ataxia. The sensory and She weighed 41 kg and was 145 cm tall. Physical exami- autonomic systems were unremarkable. nation revealed no remarkable findings. Neurologically, she Laboratory blood tests and cerebrospinal fluid were nor- did not show aphasia, apraxia or agnosia. Her MMSE score mal. SCA1, SCA2, SCA3, and SCA6 were ruled out by was 19/30, indicating disorientation, acalculia and an imme- DNA analysis. Motor nerve conduction velocity and ampli- diate memory disturbance. She showed bilateral exotropia, tudes of the CMAP was normal in the bilateral median and and vertical and lateral gaze limitation with severe adductive tibial nerves. The amplitudes of the SNAP of bilateral me- limitation (Fig. 2B), slurred speech, and severe atrophy, dian nerve were decreased (right 5.9 μV; left 5.1 μV) and weakness and fasciculation of the tongue. The tongue atro- SNAP of bilateral sural nerves was not evoked. EMG of the phy was especially severe in the tongue base (Fig. 2A). upper and lower extremities demonstrated high-amplitude

753 DOI: 10.2169/internalmedicine.46.6261

Table 1. Clinical Comaprison of Previous and the Present Cases of Spinocerebellar Ataxia Ac companied by Involvement of the Motor Neuron Systems

motor unit potentials (3.0-9.5 mV) with a discrete interfer- few cases of SCA2 have been reported to involve fascicula- ence pattern on voluntary contraction of the muscle. The la- tion of the tongue (9), but there are no reports of tongue at- tency and amplitude of the MEPs were normal in all ex- rophy. As previously reported, tongue atrophy was present tremities. The thermoregulatory sweat test revealed slight in one case of SCA6 (10, 11). However, SCA1, SCA3 and hypohidrosis in bilateral lower extremities. MRI of the brain SCA6 were excluded by DNA analysis in the present two revealed severe atrophy in the cerebellar vermis and mild at- patients. rophy in the frontal, temporal and parietal lobes, and the SCA with involvement of motor neurons is very rare; cerebellar hemispheres (Fig. 2C, D). An axial T2-weighted seven cases have been reported (10-17) (Table 1). Among image showed a subtle hyperintense lesion, an ‘inverted T- them, six were reported from Japan (10, 11, 13-17). The sign’, in the pons (Fig. 2C), which suggested that the trans- clinical features of our two patients and the six previously verse pontine fibers were affected (8). The cervical, tho- reported cases were ataxia as the first symptom, followed racic and lumbar spinal cord appeared to be slightly atrophic within 10 years by involvement of the motor neuron system, by MRI (Fig. 2D, E). Tc-99 m ECD SPECT revealed hy- except for patient 2, and all cases having bulbar signs (10, poperfusion in the cerebellar vermis and bilateral hemi- 11, 13-17). Although three previously reported cases pre- spheres. sented with atrophy and fasciculation of the tongue (10, 11, 14, 16) and severe neuronal loss from the hypoglossal nu- Discussion cleus in autopsy findings (10, 11, 14), which is characteris- tic of our patients, our patient 1 is the only familial case. Patients 1 and 2 initially presented with truncal ataxia This suggests that patient 1 may be the first reported case of (unsteady gait) at ages 52 and 55, respectively. Ataxia of the hereditary SCA, although involvement of motor neurons was trunk and limbs progressed insidiously in both cases. Patient unclear in his brother. Autopsy was performed in five previ- 1 developed bulbar signs ( and tongue atrophy) at ous reported cases (10-15), and Bunina bodies was present age 61, 9 years after the onset. Patient 2 also developed bul- in the case of Ohara et al (10, 11), and skein-like inclu- bar signs, at age 70, 15 years after the onset. When we saw sions were present in the case of Suenaga et al (15) and in patient 1 at 10 years after the onset, and patient 2 at 19 that of Ohara et al. Bunina bodies and skein like inclusions years after the onset, they presented with severe cerebellar have been generally considered as the histological hallmark ataxia, upper and signs, and bulbar of ALS (18), but Ohara’s case was SCA6 and Suenaga’s signs with severe atrophy and fasciculation of the tongue. case had clinically been considered as SCA3. Because these Thus, we considered these two patients to be cases of SCA two cases had progressed more slowly than in ALS, it is dif- accompanied by cranial and spinal motor neuron involve- ficult to consider that SCA and ALS coexisted by chance. ment, in which severe atrophy and fasciculation of the Neurological examination of patient 2 revealed bilateral tongue were characteristic. Because patient 1 had a brother exotropia, and vertical and lateral gaze limitation with se- 15 years older who had developed unsteady gait and dysar- vere adductive limitation (Fig. 2B), which is a unique exter- thria at age 40, we considered that he had familial SCA. nal ophthalmoplegia. There has been no previous report of Some types of hereditary SCA, such as SCA1, SCA2, this type of external ophthalmoplegia. Because some neuro- SCA3 and SCA6, affect the motor neuron system (1-7). pathological examinations have reported gliosis in the me- About 15% of cases of SCA1 and SCA3 have been reported dial longitudinal fasciculus (MLF) and neuronal loss and to involve atrophy and fasciculation of the tongue (6). A gliosis in the oculomotor nuclei in SCA3 and olivoponto-

754 DOI: 10.2169/internalmedicine.46.6261 cerebellar atrophy (19, 20), we consider that disturbance of generative disease might be a distinctive disorder of Japa- bilateral oculomotor nuclei and MLF might be the cause of nese. If these cases are a simple coincidence of SCA and the external ophthalmoplegia in patient 2. ALS, similar cases would have been reported from other Both SCA and ALS are rare neurodegenerative diseases. countries. Although the etiology of this multiple system de- We speculate that the disease in the present patients is not a generative disease remains unclear, it might suggest a com- simple coincidence of SCA and ALS, because our two pa- mon mechanism for SCA and motor neuron disease. tients showed marked muscle atrophy in all extremities and the trunk but not muscle weakness; SCA1, SCA2 and SCA3 This work was partly supported by Grant-in-Aid for Scientific which affect the motor neuron system often show muscle at- Research (B) 18390257, (C) 18590957 and (Hoga) 17659445 rophy but rarely show muscle weakness (1-6). Eight of nine and National Project on Protein Structural and Functional Analy- cases of SCA accompanied by involvement of the motor ses (Nakagawa A) from the Ministry of Education, Science, Cul- neuron system have been reported from Japan (10, 11, 13- ture and Sports of Japan, and by grants (Itoyama Y, Imai T and 17) (Table 1). It is suggested that this multiple system de- Kuzuhara S) from the Ministry of Health and Welfare of Japan.

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