Vertical Gaze Palsy Research Articles

Truncal Contrapulsion in Pretectal Syndrome

Truncal contrapulsion in association with pretectal syndrome has not been described previously. We report a patient with vertical-gaze palsy and severe truncal contrapulsion due to an infarction in the mesodiencephalic junction. Truncal contrapulsion in this patient may have resulted from the disruption of the ascending fibers in the crossed cerebellothalamic tract.

Infective Endocarditis Presenting With Parinaud’s Dorsal Midbrain Syndrome

We present a case of vertical gaze palsy in a 13-year-old girl caused by underlying infective endocarditis, secondary to an infected navel piercing. This case illustrates that infective endocarditis does not always present with classic signs.

Dementia with Lewy bodies with supranuclear gaze palsy: a matter of diagnosis

Description of a case of probable dementia with Lewy bodies featuring parkinsonism, dementia and supranuclear gaze palsy. This is the first patient to our knowledge affected with vertical gaze palsy receiving clinical diagnosis of DLB when alive and to be treated with cholinesterase inhibitors.

Neurodegenerative disorders mimicking progressive supranuclear palsy: a report of three cases

Progressive supranuclear palsy (PSP) is rarely confused with other parkinsonian disorders once the vertical gaze palsy appears. Corticobasal degeneration is the most common differential diagnostic entity. We describe three cases diagnosed during life as PSP but found to have another neurologic disorder at autopsy. No explanation for the gaze palsies was found in any case.

Uncommon neurodegenerative causes of dementia

A group of neurodegenerative diseases is outlined that affect cortical and subcortical areas of the brain. These diseases give rise to atypical forms of dementia and, unlike Alzheimer's disease (AD), are often associated with neurological symptoms. Clinical symptoms reflect the localization of the degenerative process rather than the nature of the underlying histopathology. Degeneration of the frontal and anterior temporal lobe presents initially with behavioral alterations, but later in the course, impairment of cognition and activities of daily living develops. Posterior cortical atrophy affects the parietal and occipital association cortices and causes complex visual disturbances. In corticobasal degeneration (CBD) the focus of pathology includes the frontoparietal cortex and several subcortical nuclei, causing symmetrical rigidity, bradykinesia, myoclonus and dystonia. Progressive supranuclear palsy (PSP) involves the frontal, temporal and parietal cortex as well as parts of the brain stem. Clinical features include a hypokinetic rigid syndrome with nuchal dystonia and vertical gaze palsy. Huntington's disease is a prototypical autosomal dominant disorder that affects the extrapyramidal system and causes choreatic movements in combination with personality changes and cognitive deterioration. Amyotrophic lateral sclerosis (ALS) with dementia is a neurodegeneration of the frontotemporal cortex and of the anterior horn of the spinal cord. Behavioral change similar to frontotemporal dementia (FTD) is paralleled or followed by the classic features of motor neuron disease.

Atypical progressive supranuclear palsy underlying progressive apraxia of speech and nonfluent aphasia

Progressive supranuclear palsy (PSP) is a clinicopathological entity typically presenting as an akinetic rigid syndrome with early falls, axial rigidity, vertical supranuclear gaze palsy and levodopa resistance. Pathological features consist of tau deposition in neuronal and glial cells located mainly in subcortical and brainstem structures. Rare cases with the pathological diagnosis of atypical PSP have been described in which neocortical tau deposition is more widespread than what is usually seen in typical PSP. Progressive nonfluent aphasia (PNFA) is a syndrome characterized by spontaneous nonfluent speech and early preserved comprehension of language. Apraxia of speech (AOS) is a motor speech disorder that may be a feature of PNFA. We report the clinical and pathological findings of four cases that presented with features most consistent with PNFA predominated by AOS. Pathological features in these four cases included the typical features of PSP subcortically and in brainstem structures, but combined with tau-positive neuronal and glial pathology in the neocortex. Comprehensive semiquantitative analyses of tau burden including neurofibrillary tangles and pretangles, coiled bodies, tufted astrocytes and threads were undertaken in the four cases of atypical PSP and compared to 10 cases of typical PSP. Semiquantitative analysis demonstrated that in atypical PSP, the pathology shifts from subcortical grey and brainstem regions, commonly affected in typical PSP, towards neocortical regions. This shift in pathology accounts for the presentation of PNFA and AOS observed in our patients, as well as the lack of classic features of PSP. These cases demonstrate that atypical PSP can present as AOS and PNFA without the classic features of PSP. Supported by grants AG 16574 and AG 07216 from the National Institute on Aging, and the Society for Progressive Supranuclear Palsy brain bank. We extend our appreciation to the patients and families for participating in research on aging and dementia. We appreciate the generous donation of antibodies for our studies from Dr. Peter Davies, Albert Einstein College of Medicine, Bronx, NY. Case 4 has already been published. This study was presented at the 9th International Conference on Alzheimer’s Disease and Related Disorders, July 17–22, 2004 in Philadelphia, Pennsylvania, USA.

Late-onset frontotemporal dementia associated with progressive supranuclear palsy/argyrophilic grain disease/Alzheimer’s disease pathology

Progressive supranuclear palsy (PSP) is typically manifested by vertical supranuclear gaze palsy, frequent falls early in the disease course, axial rigidity and poor response to levodopa. Prominent anterograde memory dysfunction with subsequent impairment in other cognitive domains is characteristic of Alzheimer’s disease (AD). No clear clinical syndrome has been identified in argyrophilic grain disease (AGD). Frontotemporal dementia (FTD) is characterized by apathy, emotional blunting, disinhibition, and impairment in executive functioning despite relatively preserved memory and visuospatial abilities. Cognitive deficits are known to occur in PSP; however, overt clinical FTD without parkinsonism or supranuclear gaze palsy associated with PSP pathology has rarely been documented. We report an elderly patient with the typical clinical, neuropsychometric, and neuroimaging features of FTD who had autopsy findings most consistent with PSP plus AGD and AD in limbic structures. We suggest that PSP with or without coexisting AD and AGD be included in the differential diagnosis of patients presenting with FTD.

Nystagmus de convergence et paralysie de la verticalité du regard d’origine vasculaire

A case of convergence-retraction nystagmus with upward vertical gaze paralysis and skew deviation (right hypotropia), without any other neurological signs, is reported. The probably vascular lesion was located at the mesodiencephalic junction, lying between the right border of the posterior commissure, the right interstitial nucleus of Cajal and the periaqueductal grey matter, accounting for the three ocular motor signs. The particular interest of this case is due to the relative smallness of the lesion.

Lesion of the dorsorostral midbrain sparing the nigrostriatal tract mimics axial rigidity seen in progressive supranuclear palsy

We report on a patient with a residual dorsorostral midbrain lesion after resection of a pineal gland tumor. In addition to severe vertical gaze palsy, this patient exhibited other neurological features closely resembling progressive supranuclear palsy. Normal dopamine transporter single-photon emission computed tomography imaging excluded significant dopamine deficiency. We suggest that dorsorostral midbrain pathology rather than dopamine deficiency due to degeneration of nigrostriatal dopaminergic neurons or basal ganglia nuclei might be responsible for axial rigidity in extension.

Characteristics of two distinct clinical phenotypes in pathologically proven progressive supranuclear palsy: Richardson's syndrome and PSP-parkinsonism

The clinical diagnosis of progressive supranuclear palsy (PSP) relies on the identification of characteristic signs and symptoms. A proportion of pathologically diagnosed cases do not develop these classic features, prove difficult to diagnose during life and are considered as atypical PSP. The aim of this study was to examine the apparent clinical dichotomy between typical and atypical PSP, and to compare the biochemical and genetic characteristics of these groups. In 103 consecutive cases of pathologically confirmed PSP, we have identified two clinical phenotypes by factor analysis which we have named Richardson's syndrome (RS) and PSP-parkinsonism (PSP-P). Cases of RS syndrome made up 54% of all cases, and were characterized by the early onset of postural instability and falls, supranuclear vertical gaze palsy and cognitive dysfunction. A second group of 33 (32%) were characterized by asymmetric onset, tremor, a moderate initial therapeutic response to levodopa and were frequently confused with Parkinson's disease (PSP-P). Fourteen cases (14%) could not be separated according to these criteria. In RS, two-thirds of cases were men, whereas the sex distribution in PSP-P was even. Disease duration in RS was significantly shorter (5.9 versus 9.1 years, P < 0.001) and age at death earlier (72.1 versus 75.5 years, P = 0.01) than in PSP-P. The isoform composition of insoluble tangle-tau isolated from the basal pons also differed significantly. In RS, the mean four-repeat:three-repeat tau ratio was 2.84 and in PSP-P it was 1.63 (P < 0.003). The effect of the H1,H1 PSP susceptibility genotype appeared stronger in RS than in PSP-P (odds ratio 13.2 versus 4.5). The difference in genotype frequencies between the clinical subgroups was not significant. There were no differences in apolipoprotein E genotypes. The classic clinical description of PSP, which includes supranuclear gaze palsy, early falls and dementia, does not adequately describe one-third of cases in this series of pathologically confirmed cases. We propose that PSP-P represents a second discrete clinical phenotype that needs to be clinically distinguished from classical PSP (RS). The different tau isoform deposition in the basal pons suggests that this may ultimately prove to be a discrete nosological entity.

Discrepancy between clinical and pathological diagnoses of CBD and PSP

Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are often clinically confused with each other. Moreover, the discrepancy between clinical and pathological diagnoses of CBD and PSP are still controversial. We report here two atypical cases of PSP and CBD. A 73-year old woman was admitted with right hand rigidity, limb kinetic apraxia and cortical sensory loss. Brain atrophy, hypoperfusion and hypometabolism predominantly in the left frontoparietal lobes indicated CBD clinically. Pathological studies revealed neuronal loss and spongy change without ballooned neurons (BN) in the cerebral cortex. Modified Gallyas-Braak (G-B) staining revealed neurofibrillary tangles (NFTs) and tufted astrocytes, indicating pathological diagnosis of PSP. A 75-year-old man admitted with vertical gaze palsy, neck dystonia, parkinsonism and dementia. Atrophy of the frontal lobes and tegmentum of the midbrain and symmetrical frontal hypoperfusion in SPECT indicated PSP. However, neuronal loss and BN in the frontal lobes and clusters of astrocytic plaques indicated CBD pathologically. The G-B staining was useful for differentiating between CBD and PSP, but our atypical cases bring up a new issue about differential diagnosis of CBD and PSP.

Troubles psychiatriques révélateurs d’une maladie de Niemann-Pick de type C à l’âge adulte

Niemann-Pick Type C disease (NPC) is an autosomal recessive neurovisceral lysosomal lipid storage disorder. A 31-year-old right-handed woman had suffered from schizophrenia for 13 years. At 25 years of age, she developed a gait disorder with a static and kinetic cerebellar syndrome, dysarthria, vertical supranuclear gaze palsy and cognitive impairment. Brain MRI was normal. Abdominal ultrasonography was performed because of hypercholesterolemia and elevated transaminases and revealed hepatosplenomegaly, which in conjunction with other signs and symptoms, suggested the diagnosis of NPC. The diagnosis was confirmed by demonstration of lysosomal storage of unesterified cholesterol (filipin staining) and of a reduced rate of LDL-induced cholesterol esterification. Implication of the NPC1 gene was assessed by genetic complementation analysis. The phenotypic presentation of NPC is remarkably variable. The rarer adult-onset form has a slowly progressive course. Psychotic manifestations are often prominent and may precede neurologic symptoms. Exposure to neuroleptics delays the diagnosis of NPC. Psychotic manifestations associated with cerebellar syndrome, vertical supranuclear gaze palsy, and splenomegaly are very suggestive of NPC disease which can be reliably diagnosed on cultured skin fibroblasts by filipin staining.

Introduction to Anatomy and Neural Pathways

This review of the anatomy and neural pathways of motility has focused on the supranuclear pathways for eye movement, because these are the pathways that are responsible for misalignments that are often unfamiliar to the ophthalmologist. In these cases, the pattern of ocular misalignment does not seem to fit a cranial nerve palsy nor seem attributable to myasthenia gravis or orbital causes. When the motility pattern on exam does not seem to fit the distribution of the third, fourth, or sixth cranial nerve, myasthenia, or orbital causes, then supranuclear disorders of gaze should be considered. The most common supranuclear disorders encountered are internuclear ophthalmoplegia, skew deviation, dissociated vertical deviation (DVD), dorsal midbrain syndrome, and horizontal and vertical gaze palsies. The motility examination with prism measurements in different gaze positions in conjunction with neuroimaging usually points the diagnosis toward a supranuclear cause.

Midbrain Ischemia Presenting as Vertical Gaze Palsy: Value of Diffusion-Weighted Magnetic Resonance Imaging

Background: Conventional magnetic resonance imaging may fail to identify very small but clinically relevant acute subcortical brain infarcts. Diffusion-weighted magnetic resonance imaging (DWI) is very sensitive and specific for acute cerebral ischemia and should contribute to the early detection of such lesions. Methods: We analyzed 6 patients who presented with acute vertical gaze palsy and in whom DWI was performed within 1–6 days from symptom onset. Results: DWI accurately identified ischemia in an area supplied by the posterior thalamosubthalamic paramedian artery in all patients. T₂-weighted and FLAIR imaging failed to identify the clinically relevant lesion in 2 and 3 patients, respectively. Conclusion: DWI improves the clinicoanatomical correlation in patients presenting with supranuclear oculomotor disturbances.

Assessment of paramedian thalamic infarcts: MR imaging, clinical features and prognosis

Considering the highly variable vascular supply of the thalamic nuclei, MRI and clinical syndromes can be heterogeneous in ischemic diseases. We attempt to determine MRI pattern and to analyse neurological features and prognosis of paramedian infarcts. In a prospective case series within 5 years from 1999 to 2003, MRI, MRA and clinical symptoms of 38 consecutive patients were analysed. The inferomedial (posterior thalamoperforating artery) territory was affected in 89%, and lesions in the anterolateral (tuberothalamic artery) territory occurred in 42%. However, definite attribution to anterolateral or inferomedial territories was not possible in 13%. Neurological manifestations were somnolence (87%), hemisyndromes (79%), cognitive deficits (58%), oculomotor nerve palsies (53%) and vertical gaze palsies (39%). The most common aetiologies were cardiac embolism (42%), intraarterial embolism (16%), small vessel disease (13%) and large artery arteriosclerosis (13%). Pathological MRA findings were encountered in 55%, and in 18%, lesions were only visible on diffusion-weighted imaging. Correlation of MRI pattern and neurological symptoms points out anterolateral thalamic lesions as the cause of amnestic deficits. Intracranial MRA allows a non-invasive prediction of basilar tip occlusion. Our results underline the necessity of additional diffusion-weighted imaging in detecting small thalamic and midbrain lesions.

Neuro-ophthalmology and paraneoplastic syndromes.

To describe the neuro-ophthalmological manifestations of paraneoplastic syndromes and their immunological associations. Neuro-ophthalmological signs and symptoms are usually present in paraneoplastic syndromes of the central nervous system. Unlike opsoclonus, less characteristic eye movement abnormalities are difficult to recognize as presenting symptoms of paraneoplastic syndromes. In this setting, the detection of several antibodies, including anti-Hu, Yo, Ma2, Ri, Tr, CV2/CRMP5 or voltage-gated calcium channel antibodies may help to establish that the neuro-ophthalmological disorder is paraneoplastic. Among the recently characterized antibodies, those against the Ma proteins often associate with brainstem encephalitis and vertical gaze paralysis. A small subset of patients with opsoclonus and ataxia harbor anti-Ri antibodies. In other patients, there is preliminary evidence that the autoantigens of opsoclonus reside in the postsynaptic density, but no dominant antibody marker has been identified. Uveitis and optic neuritis are rare accompaniments of paraneoplastic encephalomyelitis; some of these patients harbor anti-CV2/CRMP5 in association with other antibodies. Studies on paraneoplastic retinopathy indicate that immunity to retinal proteins other than recoverin can result in a similar syndrome to that associated with recoverin antibodies, and that melanoma-associated retinopathy may associate with several retinal antibodies. There is increasing recognition of an extensive variety of neuro-ophthalmological abnormalities as manifestations of paraneoplastic syndromes and of several antineuronal antibodies as clinical markers of these disorders. Basic immunological studies support the pathogenic role of some of these antibodies, and are elucidating the pathogenic mechanisms that underlie these and other antibody-associated paraneoplastic syndromes.

Posterior canal-type ocular tilt reaction caused by unilateral rostral midbrain hemorrhage

A 56-year-old man receiving treatment for hypertension experienced sudden-onset dizziness and was admitted to our hospital. Computed tomography of the brain revealed a small high-density lesion in the right rostral midbrain. Subsequent magnetic resonance imaging revealed a small hemorrhagic lesion in the same position. The patient complained of double vision affecting the right side when viewing a horizontal linear target. Vergence was intact, but vertical gaze was severely restricted downward and moderately restricted upward. Vestibulo-ocular reflex maneuvers did not alleviate the patient's vertical gaze palsy. By 40 days after the incident, his motility had recovered and he could begin to tilt his head to the left. Consecutive Hess tests demonstrated a skew deviation of right hypertropia, which continued for over two years. Funduscopic examination revealed left extorsion but no right intorsion. A diagnosis of posterior canal-type ocular tilt reaction (OTR) was made from these signs. The patient's course indicated that periaqueductal syndrome dominated in the acute stage whilst unilateral symptoms became more apparent in the chronic stage. The rostral interstitial nucleus of the medial longitudinal fasciculus and the posterior commissure were estimated to contain the main causative lesion for the acute symptoms, whereas the interstitial nucleus of Cajal (INC) was implicated in the chronic stage. Posterior canal-type OTR caused by unilateral INC lesion has been reported only rarely.

A riddle wrapped in a mystery: understanding Niemann-Pick disease, type C.

Niemann-Pick disease, type C (NPC), is a lipid storage disease that may present at any age from fetal life to the seventh decade. Its protean manifestations include hepatic and pulmonary failure, as well as a range of progressive neuropsychiatric phenotypes. Late onset disease has been increasingly recognized as the biochemical diagnosis of NPC has been more widely applied. The phenotypes, biochemical, and molecular bases of NPC are reviewed. Indistinguishable phenotypes are produced by mutations in two distinct genes, designated NPC 1 and NPC 2, that play key roles in the intracellular trafficking of lipids. The diagnosis of NPC is challenging as the characteristic vertical supranuclear gaze palsy is difficult to recognize, organomegaly is often absent, and standard biochemical screening studies are usually normal. Definitive diagnosis requires demonstration of the trafficking defect in cultured fibroblasts, supplemented in selected cases by genotyping. Animal studies have shown that inhibition of glycosphingolipid synthesis may delay the onset of disease and prolong survival; a human trial of this approach is underway. NPC is a model for inborn errors of metabolism whose gene product mediates molecular trafficking rather than catabolizing macromolecules, as in classic lipid storage diseases. NPC should be considered in the differential diagnosis of progressive neurodegenerative disorders at any age. The astute clinician can provide great comfort to families afflicted by NPC by making an accurate diagnosis, notwithstanding the absence of definitive treatment.

An autopsied case of dementia with Lewy bodies with supranuclear gaze palsy

A 66-year-old man had suffered from a slow and steady decline in both physical and cognitive function for four years. He showed bradykinesia and small step gait with supranuclear vertical gaze palsy, especially upward gaze palsy. He was started on levodopa therapy but without response. A diagnosis of progressive supranuclear palsy was clinically suspected. He died at age 69. Pathologically, many α-synuclein positive inclusions were detected both in the brain stem and cerebral cortices, and the diagnosis of dementia with Lewy bodies was made. Scattered α-synuclein-positive inclusions and threads, which may be a pathological substrate for supranuclear gaze palsy, were identified in the rostal midbrain. From a review of five cases of dementia with Lewy bodies with supranuclear gaze palsy including this case, the absence of falls in the early stage of the disease, fluctuation of cognition, hallucination and vertical gaze palsy with a more severe defect in the upward direction distinguished dementia with Lewy bodies with vertical gaze palsy from progressive supranuclear palsy. In the differential diagnosis of parkinsonism with gaze palsy, clinicians should consider dementia with Lewy bodies with gaze palsy as well as progressive supranuclear palsy.

Niemann-pick type C disease associated with peripheral neuropathy

Niemann-Pick type C disease is an autosomal-recessive, inherited neurovisceral lipid storage disorder. This disease results from either protein NPC1 or HE1 deficiency, which leads to cholesterol metabolism disturbance and is characterized by early hepatosplenomegaly and progressive ataxia, dystonia, cataplexy, dysarthria, and dementia. We describe a 3 1/2-year-old patient with Niemann-Pick type C disease, who presented with regression in both cognitive and motor domains. Almost 10 months before admission to the hospital, the child developed progressive speech and behavioral changes, as well as gait disturbances with frequent falls. The examination demonstrated hepatosplenomegaly, ataxia, and vertical gaze palsy. Nerve conduction velocities demonstrated mild demyelinating peripheral neuropathy. Bone marrow examination revealed foam cells, and cholesterol esterification studies found massive accumulation of unesterified cholesterol and very low intracellular esterification of exogenous lipoprotein-derived cholesterol. These results indicate Niemann-Pick type C disease. Peripheral neuropathy is a rare complication in patients with Niemann-Pick type C disease, which certainly contributes to their neurologic deterioration.