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Progressive external ophthalmoplegia

Progressive external ophthalmoplegia is a disorder of the mitochondria. It is characterized by multiple mitochondrial DNA deletions in skeletal muscle. The most common clinical features include adult onset of weakness of the external eye muscles (ophthalmoplegia) and exercise intolerance. more...

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Additional symptoms are variable, and may include cataracts, hearing loss, sensory axonal neuropathy, ataxia, depression, hypogonadism, and parkinsonism. Both autosomal dominant and autosomal recessive inheritance can occur; autosomal recessive inheritance is usually more severe.

It is usually diagnosed by neurologists. There is no proven treatment; experimental agents such as coenyzme Q10 may provide benefit.


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Amyotrophic lateral sclerosis with supranuclear ophthalmoplegia and rigidity
From Neurological Research, 10/1/99 by Kobayashi, Masako

Ophthalmoplegia is rarely reported in patients with amyotrophic lateral sclerosis (ALS). We describe a patient with sporadic ALS, who had developed progressive external ophthalmoplegia of supranuclear origin and rigidity in the neck. Autopsy findings showed histopathological abnormalities consistent with ALS. In addition to these findings, there was neuronal loss and gliosis in the putamina and globi pallidi, and gliosis in the periaqueductal gray matter. Our case appears to raise the possibility that ALS comprises a heterogenous group of disorders. [Neurol Res 1999; 21: 661-664]

Keywords: Amyotrophic lateral sclerosis; ophthalmoplegia; rigidity; autopsy


Amyotrophic lateral sclerosis (ALS) is characterized by pure motor neuron syndrome. Sensory system, higher cortical function, and the extrapyramidal system are not affected. Furthermore, certain motor neurons, such as those innervating external ocular muscles and the bladder and anal sphincter nucleus, are typically spared. However, in a few patients with ALS, these signs and symptoms do occur1. There are several reports of patients with concurrent, ophthalmoplegia and ALS2-12. Parkinsonism is another key feature of the parkinsonism-- dementia complex in the Western Pacific13. However, Parkinsonian signs are not usually seen in patients with classic ALS outside the Mariana Islands14. We describe a patient with ALS proved post-mortem and supranuclear ophthalmoplegia and rigidity.


A 50-year-old man was admitted to the department on January 16, 1985, complaining of increasing difficulty in swallowing accompanied with dysarthria, dysphagia, weight loss, generalized loss of strength (mostly affecting the neck muscles), and limitation of upper gaze. The present illness began approximately five years prior to admission, when he first noted a 'nasal twang' to his speech and some difficulty in chewing and swallowing. Later he noted twitchings in his arm muscles. He had no visual symptoms or sensory disturbances. The family history was normal and there was no personal history of poliomyelitis or personality change. The patient worked as a TV producer and had no known exposure to toxic substances. General physical examination findings revealed a markedly debilitated (45 kg) man, but who was alert and oriented. Blood pressure was 120/ 80 mmHg. There was marked limitation of upward gaze, but downward gaze was full. Convergence was absent. Lateral gaze was slightly limited in both directions. There was no nystagmus at any direction. Oculocephalic maneuvers elicited fuller lateral and upward gazes. Pupillary light reactions were normal, and ptosis was absent. Symmetrical facial weakness and palatal dysarthria were present. The pharyngeal reflex was absent. Lingual fasciculations were evident and the tongue was markedly wasted. There was diffuse weakness and wasting of arms, hands and legs. Fasciculations were widespread over the trunk and four extremities. Deep tendon reflexes were hyperactive, and the plantar reflexes were extensor. Sensation and cerebellar functions were normal. Moderate neck rigidity was also noted. There was no rigidity or tremor in the extremities. Laboratory tests, including blood count and smear, blood chemistries, VDRL, protein electrophoresis, and studies of creatine kinase, serum neutrophils, ceruloplasmin, vitamin B12, thyroid functions, magnesium, lipids, and urinary excretion of mercury, lead, arsenic, and porphobilinogen, yielded normal findings. Studies of protein, glucose, cells, gamma globulin, oligoclonal bands in CSF revealed no abnormalities. Results of brain CT, and visual evoked response studies were normal. Nerve conduction velocities were normal, and an electromyograph (EMG) showed fasciculations with positive waves and fibrillations. Biopsy taken from left quadriceps femoris showed neurogenic atrophy of muscle by light microscopy. The patient died of pneumonia five years after onset. Autopsy revealed there was bilateral bronchopneumonia.

The brain weighed 1400 g. The leptomeninges were normal. The precentral gyri showed marked narrowing. In the coronal sections, the precentral gyri had a mottled, brownish discoloration. Other structures of the cerebral and cerebellar hemispheres appeared normal. The transverse section of brain stem and spinal cord did not show significant abnormalities except for marked atrophy of hypoglossal nerves and anterior roots of the spinal cord.

Microscopic findings

Cerebral cortex: Striking neuronal loss and diffuse gliosis were seen in the precentral gyri. In the motor area, the Betz cells were completely depleted. Sections from the frontal, temporal, and parietal cortex showed no abnormalities. Marked pallor and gliosis were noted in the white matter adjacent to the most severely involved areas of the precentral gyri. Sections taken from the internal capsule showed slight spongy change.

Basal ganglia: Extensive neuronal loss and astrogliosis were present in the putamina and globi pallidi symmetrically (Figure 1).

Brain stem: Pallor and moderate astrogliosis were present in cerebral peduncles, basis pontis, and medullary pyramide bilaterally. Both corticospinal tracts appeared to be affected equally. Oculomotor, the trochlear, and the abducens nuclei appeared normal. The periaqueductal gray matter exhibited moderate gliosis (Figure 2). Superior colliculus, inferior colliculus, nucleus of Darkschewitsch, substantia nigra, medial longitudinal fascicles, and reticular formation were normal. Loss of neurons was observed in the facial and hypoglossal nuclei.

Spinal cord: Myelin pallor, axon loss, and gliosis were conspicuous in the lateral corticospinal tracts at all levels. The dorsal columns appeared normal. Striking neuronal loss and gliosis were seen in the anterior horn (Figure 3). Onufrowicz nuclei were not observed within the sections available for examination. Budina bodies were not found in the motor neurons of the brain stem and spinal cord. Neurofibrillary tangles and neurite plaques were not present through the brain.


Autopsy of our case revealed degeneration of both the upper and lower motor neuron systems, consistent with ALS. There have been few reports of ophthalmoplegia in patients with ALS confirmed by post-mortem (Table 1). The majority of these had incomplete ophthalmoplegia. This may be due to either nuclear or supranuclear lesions. Van Bogaert2 reported a case of ALS in a 16year-old boy with convergent strabismus progressing to complete ophthalmoplegia. Chromatolytic neurons and gliosis were seen in the oculomotor and abducens nuclei. Takahata et aL3 described a 32-year-old man who, in addition to the usual clinical manifestations of ALS, had limitation of eye movements. Gliosis was seen in the oculomotor nuclei. Harvey et al.4 reported a patient with ALS in whom there was extensive neuronal loss and gliosis in the oculomotor, the trochlear, and the abducens nuclei. Kushner et al.5 reported two patients with nystagmus, with ALS proved at post-mortem. One of them had a supranuclear paresis of horizontal and upward gaze. Chromatolytic neurons and gliosis were seen in the oculomotor, the trochlear, and abducens nuclei, as well as fibrous gliosis in the pretectal region, nucleus of Darkschewitsch and periaqueductal gray matter. They suggested that ALS with ocular signs was characterized by early age at onset and brief duration. Chromatolytic neurons are unusual in ALS but have been seen, especially in cases with rapid progression15. Walsh and Hoyt16, while attesting to the rarity of ocular

involvement in ALS, reported a case of a 44-year-old woman with ALS in whom bilateral ptosis and nearly complete ophthalmoplegia, sparing only the inferior recti, developed near the end of her course. The disturbance of extra-ocular movements in their case began with paralysis of upward gaze, which occured three months after the patient's initial presentation with dysphagia. In the course of the next 2 3/4 years, this finding had progressed to total ophthalmoplegia. Lawyer and Netsky17, however, described post-mortem changes in the oculomotor nuclei in four of 54 cases of ALS proved post-mortem with no clinical ophthalmoparesis. It has recently been reported that some patients with ALS treated with long-term respiratory support trend developed external ophthalmoplegia, and their autopsies revealed degeneration in the ocular motor system6-8. In our case ophthalmoplegia seems to be supranuclear orgin and a respirator was not used. Autopsy showed no degeneration in the oculomotor, trochlear, and abducens nuclei but gliosis was present in the periaqueductal gray matter. Other cases of supranuclear ophthalmoplegia in ALS have been reported by Hayashi et al.6. In addition to ophthalmoplegia, our patient exhibited rigidity in the neck. However, he had no tremor, no rigidity in the extremities, and no dementia. Hudson reviewed ALS and parkinsonism, and eight patients had ALS with parkinsonism1. He reported that degeneration of the substantia nigra or globys pallidus was found in all cases but one, in addition to neuronal loss or gliosis in corpus striatum, thalamus and corpus Luysii. Other cases showed neuronal loss and gliosis in the substantia nigra and globus pallidus with neurofibrillary tangle in the substantia nigra. Brait et al.14 reported four patients with ALS and parkinsonism, and autopsy was available in one of them, showing that there was degeneration in the substantia nigra and spinocerebellar tracts. In our case, cell loss was seen in the putamina and globi pallidi but the substantia nigra was normal. Ophthalmoplegia, amyotrophy and rigidity with or without dementia has also been reported in Joseph disease or other motor system degeneration such as dentatorubropallidoluysian degeneration and progressive supranuclear palsy18,19.


1 Hudson AJ. Amyotrophic lateral sclerosis and its association with dementia, parkinson and other neurological disorders: A review. Brain 1981; 104: 217-247

2 Van Bogaert L. Contribution a la connaissance des troubles oculaires et vestibulaires dans la SLA. Rev Otoneuro Ophthalmol 1925; 3: 263-274

3 Takahata N, Yamanouchi N, Fukatsu R. Brainstem gliosis in a case with clinical manifestations of amyotrophic lateral sclerosis. Folia Psychiatr Neurol Jpn 1976; 30: 41-48

4 Harvey DG, Torack RM, Rosenbaum HE. Amyotrophic lateral sclerosis with ophthalmoplegia. Arch Neurol 1979; 36: 615-617 5 Kushner MJ, Parrish M, Burke A, Buhrens M, Hays AP, Frame B, Rowland LP. Nystagmus in motor neurol disease: Clinicopathological study of two cases. Ann Neurol 1984; 16: 71-77 6 Hayashi H, Kato S. Total manifestations of amyotrophic lateral sclerosis: ALS in the totally locked-in state. J Neurol Sci 1989; 93: 19-35

7 Mizutani T, Sakamaki S, Tsuchiya N, Kamei S, Kohzu H, Horiuchi R, Ida M, Shiozawa R, Takatsu T. Amyotrophic lateral sclerosis with ophthalmoplegia and multisystem degeneration in patients on long-term use of respirator. Acta Neuropathol 1992; 84: 372-377

8 Okamoto K, Hirai S, Amari M, lizuka T, Watanabe M, Murakami N, Takatama M. Oculomotor nuclear pathology in amyotrophic lateral sclerosis. Acta Neuropathol 1993; 85: 458-462

9 Jacobs L, Bozian D, Heffner RR, Barron SA. An eye movement disorder in amyotrophic lateral sclerosis. Neurology 1981; 31: 1282-1287

10 Leveille A, Kiernan J, Goodwin JA, Antel J. Eye movements in amyotrophic lateral sclerosis. Arch Neurol 1982; 39: 684-686

11 Gizzi M, DiRocco A, Sivak M, Cohen B. Ocular motor function in motor neuron disease. Neurology 1992; 42: 1037-1046

12 Okuda B, Yamamoto T, Yamasaki M, Maya K, Imai T. Motor neuron disease with slow eye movements and vertical gaze palsy. Acta Neurol Scand 1992; 85: 71-76

13 Hirano A, Malamud N, Elizan TS, Kurland LT. Amyotrophic lateral sclerosis and Parkinson ism-dementia complex on Guam: Further pathologic studies. Arch Neurol 1966; 15: 35-51

14 Brait K, Fahn S, Schwarz AA. Sporadic and familial parkinsonism and motor neuron disease. Neurology 1973; 23: 990-1002

15 Hirano A. Aspects of the ultrastructure of amyotrophic lateral sclerosis. Adv Neurol 1982; 36: 75-88

16 Walsh FB, Hoyt AB. Hereditofamilial and degenerative diseases. In: Walsh FB, Hoyt AB, eds. Clinical Neuro-ophthalmology, Vol 1, Baltimore: Williams & Wilkins, 1969: pp. 936-938

17 Lawyer T Jr, Netsky MG. Amyotrophic lateral sclerosis. A clinicoanatomic study of 53 cases. Arch Neurol Psychiatry 1953; 69: 171-192

18 Sakai T, Ohta M, Ishino H. Joseph disease in a non-Portuguese family. Neurology 1983; 33: 74-80

19 Goto I, Tobimatsu S, Ohta M, Hosokawa S, Shibasaki H, Kuroiwea Y. Dentatorubropallidoluysian degeneration: Clinical, neuroophthalmologic, biochemical, and pathologic studies on autosomal dominant form. Neurology 1982; 32: 1395-1399

Masako Kobayashi, Ken Ikeda, Masao Kinoshita and Yasuo Iwasaki

The Fourth Department of Internal Medicine, Toho University Ohashi Hospital, Ohashi, Tokyo, Japan

Correspondence and reprint requests to: Yasuo Iwasaki MD, The Fourth Department of Internal Medicine, Toho University Ohashi Hospital, 2-17-6, Ohashi, Meguro-ku, Tokyo, 153-1585, Japan.

Accepted for publication May 1999.

Copyright Forefront Publishing Group Oct 1999
Provided by ProQuest Information and Learning Company. All rights Reserved

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