The patient was diagnosed with an acquired ocular motor apraxia and supranuclear vertical ophthalmoplegia, presumably from some type of degenerative process. There were no other signs of Parkinson disease or progressive supranuclear palsy (PSP). The differential diagnosis included fronto-temporal lobar degeneration (FTLD) and cortico-basal degeneration. A vascular process was considered unlikely in view of the MRI findings.
Subsequently, the patient developed bucco-facial apraxia, severe dysarthria, swallowing apraxia, and total vertical ophthalmoplegia, retaining dissociation between reactive and voluntary horizontal saccades. There was no postural imbalance, dementia, or signs of lower motor neuron disease (MND). Following her death 3 years after the initial presentation, a postmortem examination was performed according to the BrainNet Europe Consortium protocol (6). Autopsy consent was obtained in accordance with French and European regulations.
The unfixed brain weighed 1,035 g and showed severe cortical atrophy affecting the fronto-temporal and parietal lobes. The basal nuclei and hippocampus showed less severe reduction in bulk. Pigmentation of the substantia nigra was normal. The cerebellum, cerebral peduncles, pontine base, medullary pyramids, and cervical spinal cord were unremarkable.
An impressive histological feature visible in the sections of the cortex stained with hematoxylin and eosin is the presence of spongiform change, most conspicuous in the superficial cortical regions. Spongiform change is a feature of a number of different diseases, including neurodegenerative disorders, ischemia, and prion disease. Involvement of superficial cortical layers is characteristic of several neurodegenerative disorders, including Alzheimer disease and FTLD. Immunohistochemical staining for various abnormal protein aggregates has become an essential part of the evaluation of FTLD and other neurodegenerative disorders. In the present case (Fig. 3), immunohistochemical evaluation demonstrates ubiquitin, TDP43, and the ubiquitin-binding protein p62 in the cytoplasm of both neurons and glial cells and within neuropil threads in the posterior frontal cortex, motor neurons in the brainstem (hypoglossal nucleus), and spinal cord, and in brainstem nuclei, including the rostral mesencephalic premotor oculomotor region. Ubiquitin reactivity is also present in neurons and neuropil threads in the pars compacta of the substantia nigra and in striatal fibers. No convincing TPD43 or ubiquitin reactivity is identified within the dentate gyrus of the hippocampus. The distribution of abnormal TDP43 and ubiquitin reactivity places this case in the category of TDP43/ubiquitin-related FTLD with MND, a variant of FTLD that is often, but not invariably, associated with signs and symptoms of MND.
Our patient presented with a reading disorder that was related to a rare form of acquired, progressive ocular motor apraxia suggestive of frontal lobe dysfunction. Acquired ocular motor apraxia is clinically defined by loss of voluntary control of saccades and pursuit, with preservation of reflexive eye movements, including slow and quick phases (reflexive saccades) of vestibular nystagmus (i.e., VOR) (8). Conservation of VOR slow phases and preservation of quick phases pointed to impaired cortical control of eye movements. The loss of initiation of saccades in this case was thought to reflect bilateral disruption of the descending neuronal ocular motor pathways from the frontal (FEF) and parietal (PEF) eye fields (9). The prominent alteration of leftward saccades suggested predominant right hemisphere involvement, and the dissociated preservation of reactive saccades supported a prominent involvement of the (right) FEF pathway (10).
This ocular motor disturbance corresponds to the mirror-model of the psychic paralysis of gaze or gaze apraxia observed in Balint syndrome, secondary to bilateral posterior parietal lobe lesions, in which voluntary saccades may be more easily initiated than reactive saccades (11). Clinical examination also revealed an upward vertical saccadic palsy, with preservation of downward saccades, vertical smooth pursuit, and VOR, consistent with a supranuclear vertical ophthalmoplegia. The absence of upward quick phases suggested tegmental brainstem involvement of premotor ocular motor neurons (8). This progressive upward vertical ophthalmoplegia associated with apraxia of lid closure met the criteria for possible PSP (12); however, the prominent ocular motor apraxia in our patient differed from the more subtle impaired control of voluntary saccades (antisaccade errors) usually seen in patients with PSP (13).
The clinical discrepancies between our patient’s signs of FTLD and those of PSP were consistent with the lack of neuropathologic features of PSP. FTLD includes various neurodegenerative diseases characterized by selective degeneration of the frontal and temporal lobes. Neuropathologically, FTLD is associated with distinct pathological patterns, mainly abnormal accumulation of tau protein (FTLD-tau) or ubiquitin inclusions (FTLD-U subtype) (14). In FTLD-U, the majority of cases, as in our patient, show TDP-43 (TAR DNA-binding protein-43)–positive inclusions (FTLD-TDP) (15). Subtle and asymptomatic frontal ocular motor impairment (decreased horizontal saccade gain and increased antisaccade errors) and PSP-like eye movement abnormalities have been demonstrated in FTLD, usually later in the clinical course (13,16,17). Primary symptomatic ocular motor impairment in FTLD is unusual.
We found abnormal inclusions in the rostral portions of the medial longitudinal fasciculus, the premotor ocular motor relay for vertical saccades (18). These findings could explain the PSP-like supranuclear ophthalmoplegia. FTLD-TDP lesions were present in the FEFs as well as in modulators of the descending supranuclear pathways (striatum and substantia nigra). These findings would explain the patient's ocular motor apraxia.
Pathological analysis confirmed FTLD-MND, characterized by FTLD with TDP-43 inclusions, in a patient who did not develop signs of lower MND nor fronto-temporal dementia. According to Sampathu FTLD classification (7), this case was subtype 2, which often also exhibits TDP-43–positive inclusions in both upper and lower motor neurons (19). Motor neuron involvement is consistent with the high incidence of MND in these patients (20); however, clinical features of MND or dementia may be lacking in patients belonging to the neuropathological spectrum of FTLD-MND (21,22). The presence of specific inclusions in the hypoglossal nuclei but not in the ocular motor nuclei is also classically described in FTLD-MND patients (23). This pathological selectivity is partially explained by the fact that the TDP-43 proteinopathy may only affect nuclei that receive direct projections from cortical areas (24). The pathophysiological vulnerability of some neuronal populations may determine the clinical phenotype.
In conclusion, ocular motor apraxia previously has not been described as a predominant clinical syndrome associated with FTLD. The findings in our patient broaden the clinical picture of FLTD with TDP-43 immunoreactive inclusions to include primary progressive ocular motor apraxia.
The authors are grateful to C. Urquizar for his technical assistance.
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