Vertical Gaze Palsy Research Articles

Central cholinergic dysfunction in the adult form of Niemann Pick disease type C: a further link with Alzheimer’s disease?

Adult patients with Niemann-Pick disease type C (NPC) usually develop cognitive impairment progressing to dementia, whose pathophysiology remains still unclear. Noteworthy parallels exist in cognitive impairment and cellular pathology of NPC and Alzheimer's disease (AD). In particular, alterations of cholinergic system, which represent one of the pathological hallmarks and contribute to cognitive deterioration in AD, have recently been demonstrated in a human brain autopsy and in an experimental model of NPC. This finding raised the issue that central cholinergic circuits dysfunction may contribute to pathophysiology of cognitive impairment in NPC as well, and prompted us to evaluate the cholinergic functional involvement in NPC patients by applying a neurophysiologic technique, named short-latency afferent inhibition (SAI). We describe clinical, biochemical, molecular and neuropsychological features, and SAI findings in three patients affected by NPC. Diagnosis of NPC was assessed by molecular analysis of the NPC1 gene in all patients. In two of them, biochemical analysis of intracellular accumulation of unesterified cholesterol was also performed. The main clinical features were cerebellar ataxia, vertical supranuclear gaze palsy and a variable degree of cognitive impairment ranging from only memory impairment to severe dementia. Electrophysiological evaluation revealed a reduced SAI in all three patients. Our SAI findings provide evidence of cholinergic dysfunction in patients with the adult form of NPC, supporting that cholinergic alterations may play a role in cognitive impairment in NPC, and strengthening the similarities between NPC and AD.

Concomitant progressive supranuclear palsy and chronic traumatic encephalopathy in a boxer

We report the case of a 75-year-old ex-professional boxer who developed diplopia and eye movement abnormalities in his 60’s followed by memory impairment, low mood and recurrent falls. Examination shortly before death revealed hypomimia, dysarthria, vertical supranuclear gaze palsy and impaired postural reflexes. Pathological examination demonstrated 4-repeat tau neuronal and glial lesions, including tufted astrocytes, consistent with a diagnosis of progressive supranuclear palsy. In addition, neurofibrillary tangles composed of mixed 3-repeat and 4-repeat tau and astrocytic tangles in a distribution highly suggestive of chronic traumatic encephalopathy were observed together with limbic TDP-43 pathology. Possible mechanisms for the co-occurrence of these two tau pathologies are discussed.

Progression of feeding skills in infantile Pompe disease - the GOSH experience

were commonly seen in this group. Juvenile patients, on the other hand, presented mostly with progressive psychiatric changes and extrapyramidal features. Adult patients showed peculiar combination of dystonia (especially oromandibular dystonia), eyelid apraxia (“blepharospasm-like”) and cognitive decline/dementia. Ocular abnormalities were seen in 36 patients (mostly, vertical supranuclear gaze paralysis). Leukoencephalopathy and progressive cerebral/cerebellar atrophy were the main MRI features. Gelastic cataplexy, although present only in a subset of the infantile/juvenile patients, is a relatively specific finding for NPC. Conclusions: Neurological manifestations in NPC patients are extremely variable, even in the same sibship. Better understanding of the natural history of the disease is crucial for evaluation of potential therapeutic approaches in such a devastating disorder.

Responsiveness of dysphagia to acute l-Dopa challenge in progressive supranuclear palsy

Dysphagia occurs in up to 80 % of patients with progressive supranuclear palsy (PSP) [1], and may result in aspiration pneumonia, which is the leading cause of death in PSP [2]. We report the improvement of dysphagia following L-Dopa challenge in three patients diagnosed with probable PSP [3] and evaluated for enteral nutrition. All patients showed MRI signs suggestive of PSP [4] and had the specific finger tap pattern of ‘‘hypokinesia without decrement’’ [5]. None of them had prior or concomitant history of REM Sleep Behaviour Disorder. Disease severity was rated through the Progressive Supranuclear Palsy Rating Scale and Staging System (PSPRS) [6]. Dysphagia was evaluated by a trained Speech and Language Therapist through the Dysphagia Rating Scale (DRS), a recently developed tool able to predict the risk of complications of dysphagia [7] (Table 1). Case 1: 78-year-old male with PSP history of 5 years, treated with L-Dopa 300 mg/day. He showed complete supranuclear upward and downward gaze palsy, increased latency onset of horizontal saccades, square wave jerks, positive applause sign, moderate dysarthria, moderate rigidity in the upper and lower limbs, mild dystonia and akinesia in the right arm and hand, trunk apraxia and inability to walk unassisted. Mild oral apraxia associated with oromandibular dystonia resulted in prolonged oropharyngeal phase, food accumulation, and coughing. L-Dopa was increased up to 600 mg in 2 days, leading to less frequent episodes of oral apraxia and decreased latency of the oropharyngeal phase, with significant reduction of dysphagia risks. He received logopedic training, and for the following 3 months his condition was stable. Case 2: 66-year-old male diagnosed with PSP at the age of 61 following the onset of gaze abnormalities, tremor, falls, and bradykinesia and treated with low doses of L-Dopa to mild benefit. At the time of L-Dopa challenge he showed complete vertical and partial horizontal supranuclear gaze palsy, positive applause sign, severe dysarthria, neck dystonia, severe axial and limb rigidity, dystonia, and akinesia of the right hand. He was wheelchair-bound and unable to stand unassisted. Prolonged oropharyngeal phase due to oral dystonia and oral apraxia was observed. L-Dopa was increased up to 1,200 mg/day, with improvement of swallowing. He received logopedic training, and at 6 months’ follow-up his condition was stable. Case 3: 69-year-old female with a PSP history of 4 years, treated with L-Dopa 400 mg/day. She came to our observation after progressive worsening of her general conditions such as severe axial and limb rigidity, severe dystonia and akinesia in her left arm and leg, akinetic mutism, complete vertical supranuclear gaze palsy, and severe oral apraxia and oromandibular dystonia that made her almost unable to open her mouth or push food behind. She showed signs of malnutrition and dehydration. L-Dopa was increased to 1,000 mg in 4 days. By the second day, the patient showed a reduction of body stiffness and spontaneous mouth opening at food presentation. After a S. Varanese (&) P. Di Ruscio L. Ben M’ Barek Casa di cura Villa Pini d’Abruzzo, Policlinico Abano Terme, Via dei Frentani 124, 66100 Chieti, Italy e-mail: sara78_96@yahoo.it

Parinaud Syndrome in Association with Thalamic Infarct in a Young Person

Aim: We report a case of Parinaud syndrome secondary to an acute left posteromedial thalamic infarct in a young person. Presentation of Case:Patient's main presenting complaint s were blurring of vision and diplopia. The main clinical manifestations were that of a severe restriction in upward gaze, and convergence-retraction nystagmus. Discussion: Vertical gaze palsies have been well associated with midbrain lesions but more rarely associated with seemingly isolated thalamic lesions. This case report further supports current limited literature that suggests that thalamic lesions may also manifest as vertical gaze palsies. In addition, cases of cerebrovascular events are usually first seen in the Emergency Department where diagnoses are made and acute management is given. In this case, the patient was referred to the Eye clinic from the Emergency Department for visual symptoms. Parinaud syndrome was promptly recognised by the opht halmologist upon examination and the decision for urgent brain imaging with referral to the neurologist was quickly made. Timely management of patient likely contributed to his favourable outcome. Conclusion: This is a case of Parinaud syndrome secondary t o an acute left posteromedial thalamic infact in a young person without obvious midbrain involvement. This case highlights the important role of ophthalmologists in the early recognition of Parinaud syndrome, which can allow for prompt diagnosis and manage ment. Timely

Vertical gaze palsy in Parkinsonism: An alternative diagnosis to progressive supranuclear palsy

Vertical gaze palsy is a highly relevant clinical sign in Parkinsonian syndromes. As the eponymous sign of progressive supranuclear palsy (PSP), it is a core feature of this disease. However, the differential diagnosis of vertical gaze palsy in patients with Parkinsonism is rarely considered. We present the case of a 65-year-old gentleman with Parkinsonism who presented with diplopia secondary to oculomotor dysfunction and vertical gaze palsy. Computed tomography (CT) sacn demonstrated a thalamic haemorrhage with intraventricular extension. Neurosurgical intervention was not required. The patients spectacles were fitted with a temporary Fresnel prism over the left lens to relieve diplopia. This progressively improved without the need for strabismus surgery. Vertical gaze dysfunction occurs in patients with thalamic haemorrhage and is an important differential diagnosis of vertical gaze palsy in Parkinsonism.

Anti-ma2 paraneoplastic encephalitis in association with recurrent cervical cancer.

BackgroundParaneoplastic neurological syndromes are rare, and although they are frequently associated with gynecological malignancies, cervical cancer is a rare cause. The symptoms of anti-Ma2 encephalitis are diverse and often present prior to the diagnosis of malignancy.Case ReportWe report a case of a 37-year-old woman with a history of cervical cancer presenting with unexplained weight gain and vertical supranuclear gaze palsy. Magnetic resonance imaging of the brain revealed lesions within the bilateral hypothalami and midbrain. Anti-Ma2 antibodies were eventually found in the serum, prompting a search for malignancy. Recurrent metastatic cervical cancer was found in the retroperitoneal lymph nodes.ConclusionsThis is the first report of cervical cancer in association with anti-Ma2 encephalitis, and highlights the need for a high degree of suspicion in patients with a cancer history presenting with neurological symptoms. The symptoms associated with anti-Ma2 encephalitis are diverse and typically precede the diagnosis of cancer in patients, and should trigger a search for an underlying malignancy.

Clinical and genetic characteristics of mexican patients with juvenile presentation of niemann-pick type C disease.

Niemann-Pick type C disease (NPC) is a rare lysosomal disease with a protean presentation, ranging from a fatal neonatal course with visceromegaly to an adult presentation with only neurological or psychiatric symptomatology. In this report we describe the genetic and clinical characteristics of 3 Mexican patients from different families with juvenile presentation of NPC. Clinical examination, imaging of central nervous and gastrointestinal system, and EEG were performed. Genetic studies include sequencing and deletion/duplication analysis of NPC1 and NPC2 genes. All patients presented with cognitive impairment, ataxia, and supranuclear vertical gaze palsy; one case had gelastic cataplexy. Also they developed epilepsy and cortical atrophy and two patients had thinning of corpus callosum. The 3 patients were compound heterozygotes for NPC1 sequence variants, including 5 missense and 1 nonsense mutations: p.P1007A and p.F1087L in Case 1; p.Q921P and p.G992R in Case 2; and p.R348∗ and p.V1165M in case 3. Mexican patients with juvenile NPC presented with a variable clinical phenotype and compound heterozygosity. This suggests a relative high frequency of mutation carriers as it is reported for European population. Consequently, clinicians should consider NPC as a diagnosis possibility in any adolescent or young adult patient with juvenile dementia and/or ataxia, even in absence of gelastic cataplexy and supranuclear vertical gaze palsy.

Polysomnographic findings and respiratory management in leigh syndrome – A case report

Leigh syndrome (LS) is a neurodegenerative disorder with symmetric necrotizing lesions mainly in the basal ganglia, thalamus and brainstem. Respiratory disturbances are a common feature, may have a fluctuating nature and vary from irregular breathing, deep sighing, hyperventilation or hiccups with lethargy to acute respiratory failure. Since this is a rare condition, there are few published descriptions of respiratory symptoms and polysomnographic (PSG) findings. The authors describe clinical and PSG data of a child with LS. Case report with description of the clinical and PSG data of a recently diagnosed LS. The analysis of PSG data was based on the AASM guidelines. Post-sigh apnea (P-S apn) was defined as a pause of chest movements for >= 10 s. preceded by an augmented breath (>= 2x amplitude of the preceding stable respiration). A 4 years-old boy was born uneventfully and developed normally until the age of three. He was admitted in a comatous state due to central hypoventilation during an acute respiratory infection. Five months before he had initiated ataxic gait, motor regression, irregular breathing, hiccups and sighs. On examination he had dysmorphic features, hypertrichosis, vertical gaze paralysis, squint, ataxia and tremor. MRI showed bilateral, symmetric focal hyperdensities in basal ganglia and thalamus. Biochemical study identified a complex IV deficiency in mitochondrial respiratory-chain. After respiratory stabilization, non invasive ventilation (NIV) was initiated during sleep. Some days later, he began to refuse it and, as desaturation and hypercapnia had subsided, NIV was suspended. During follow-up he maintained irregular breathing with periods of apneusis-like breathing, frequent sighs and hiccups. PSG was performed six months after diagnosis. Sleep structure was normal with an arousal index of 7.2. Respiratory rhythm was very irregular, with clustered breathing on stage NREM 1/2. There were no obstructive events or isolated central apneas, sighs were very frequent (11/hour) and 40 P-S apn were observed (5/h). Mean SpO2 was 98 % (92–100), TcCO2 40-46 mmHg. During follow-up he maintained frequent sighs and hiccups. The parents were informed that the child should be admitted if irregular breathing with apnea was noticed. The PSG findings are consistent with those described in the rare literature for LS. The respiratory management in LS is challenging due to the fluctuation of the respiratory symptoms.

Heterogeneity and frequency of movement disorders in juvenile and adult-onset Niemann-Pick C disease

Niemann-Pick type C disease (NPC) is a recessive neurolipidosis. We report five adolescent and adult NPC cases to underscore the frequency and heterogeneity of movement disorders in NPC. Clinical, morphologic, biochemical and genetic study was performed in the five patients. Disease onset was between 8 and 50 years. Movement disorders were present in all cases, were heterogeneous and often combined [cerebellar ataxia (5/5), myoclonus (3/5), dystonia (2/5), chorea (1/5) and tremor (1/5)] and were the first sign in 4/5. Two patients were reported to have no vertical supranuclear gaze palsy (VSGP) at the first examination. Two patients experienced acute neuropsychiatric signs leading to death in one case due to myoclonic storm. Filipin staining was always positive. Two NPC1 mutations were identified in three patients, only one in two siblings. NPC should be considered in case of unexplained movement disorders, even when VSGP or cataplexy are not reported. Filipin staining remains a strong support for the diagnosis. Treatment with miglustat should be considered which is currently the only approved disease-specific treatment of NPC in children and adults.

Young Patient With Aphasia, Monoparesis, Facial Drop, Facial Sensory Loss, Diplopia, Dysarthria, and Vertical Gaze Palsy

We present a case of a 40-year-old male without previous medical history and medication who denied tobacco smoking or alcohol abuse. He led a healthy lifestyle, and there were no cardiovascular risk factors in his family history. In October 2012, he experienced acute onset of horizontal diplopia while playing with his child. During the transport to the emergency room, he developed a left-sided facial drop and dysarthria. On arrival, he was immediately moved to the computed tomography (CT) room as a candidate for intravenous thrombolysis and was examined by a stroke neurologist. At that time, the patient’s level of consciousness was slightly drowsy, but he was orientated. His pupils were equal with normal reactions to light. He had horizontal diplopia in either direction, more pronounced on the right side. The right eye was nasally deviated. There was no problem with vertical eye movements. He had facial sensory loss on the left side, left-sided facial drop causing dysarthria, and difficulty with word finding. There were no sensorimotor findings in the upper extremities. He was able to raise his right lower extremity, but could not hold it in the upright position for 5 seconds, and the Babinski sign was present on the right side. The National Institutes of Health Stroke Score was 6. With the suspicion of posterior circulation stroke, a noncontrast computed tomographic head scan and CT angiography were ordered. There was no pathology on noncontrast computed tomographic scan. Before CT angiography findings were available, the patient’s symptoms progressed. He became mute but understood verbal commands and developed a vertical gaze palsy. There was confusion …

Profile of Gaze Dysfunction following Cerebrovascular Accident

Aim. To evaluate the profile of ocular gaze abnormalities occurring following stroke. Methods. Prospective multicentre cohort trial. Standardised referral and investigation protocol including assessment of visual acuity, ocular alignment and motility, visual field, and visual perception. Results. 915 patients recruited: mean age 69.18 years (SD 14.19). 498 patients (54%) were diagnosed with ocular motility abnormalities. 207 patients had gaze abnormalities including impaired gaze holding (46), complete gaze palsy (23), horizontal gaze palsy (16), vertical gaze palsy (17), Parinaud's syndrome (8), INO (20), one and half syndrome (3), saccadic palsy (28), and smooth pursuit palsy (46). These were isolated impairments in 50% of cases and in association with other ocular abnormalities in 50% including impaired convergence, nystagmus, and lid or pupil abnormalities. Areas of brain stroke were frequently the cerebellum, brainstem, and diencephalic areas. Strokes causing gaze dysfunction also involved cortical areas including occipital, parietal, and temporal lobes. Symptoms of diplopia and blurred vision were present in 35%. 37 patients were discharged, 29 referred, and 141 offered review appointments. 107 reviewed patients showed full recovery (4%), partial improvement (66%), and static gaze dysfunction (30%). Conclusions. Gaze dysfunction is common following stroke. Approximately one-third of patients complain of visual symptoms, two thirds show some improvement in ocular motility.

Thalamic hypoperfusion in early stage of progressive supranuclear palsy(Richardson's syndrome): Report of an autopsy-confirmed case

Progressive supranuclear palsy-Richardson's syndrome (PSP-RS) is a neurodegenerative disease characterized by postural instability and vertical gaze palsy, but the clinical diagnosis of PSP-RS is often difficult in the early stage of the disease. A 64-year-old male experienced frequent falls, followed by dysarthria and dysphagia. Neurological examination at age 64 demonstrated vertical gaze palsy, dysarthria, dysphagia, and retropulsion. At that time, while brain MRI demonstrated no apparent abnormalities, SPECT showed the reduction of the cerebral blood flow in the thalamus as well as the medial frontal lobe cortices. The patient was diagnosed with probable PSP-RS, and died at age 70. On postmortem examination, there were abundant tuft-shaped astrocytes, neurofibrillary tangles, coiled bodies, and argyrophilic threads in the brain, establishing the diagnosis of PSP-RS. Our definite PSP-RS case suggests that thalamic hypoperfusion may provide helpful evidence to support a diagnosis of PSP-RS in the early stage of the disease.

P 251. Effects of slow frequency repetitive-transcranial magnetic stimulation in patients with corticobasal syndrome

Corticobasal syndrome (CBS) is characterized by asymmetric cortical sensorimotor dysfunction and parkinsonism diagnosed during life. Transcranial magnetic stimulation (TMS) in CBS has shown many cortical physiological abnormalities, on the whole indicating a reduced inhibition and increased excitability in some cortical circuits and a reduced excitability in other circuits ( Pal et al., 2008 ). Repetitive low-frequency TMS trains (<1 Hz) decrease cortical excitability in the motor cortex when delivered for 5 min or more ( Cincotta et al., 2003 ). To explore in CBS motor cortical excitability and the effects of a single session of LF-rTMS. We studied with TMS two CBS patients: a 70-year-old man, (disease duration 3 years; right alien hand syndrome) and a 56-year-old woman (disease duration 1 year; vertical gaze palsy; postural instability; left hand dystonic posture). We used a Magstim 200 stimulator with figure-of-eight coils at the hot-spot for the FDI muscle. We measured bilaterally: relaxed (rT) and active Threshold (aT); and Contralateral Silent Period (CSP) 1.3xrT, 20% maximum effort. In a random order-active/sham-we used a 10′ low frequency (0,3 Hz) rTMS over the more affected M1. We used two focal coils, which were one above the other, for “active” stimulation, the coil directly contacting the scalp was connected to the stimulator, whereas the other was not. We evaluated immediately after the active/sham treatment (T1) and after 30′ (T2) rT, CSP length and clinical effect. For the statistic we compared with t-test in each of the subject the separately values from individual trials for the less affected side (LA) and more affected side (MA) and before-after rTMS. In CBS CSP was shortened ( Fig. 1 ) and rT/aT were increased especially in the MA. The novel finding was the effects of active LF-rTMS on the contralateral silent period ( Fig. 2 ), although we did not observed any clinical effect, that disappeared after 30 min. In CBS TMS confirmed a decrease of cortical inhibitory phenomenon bilaterally as shown by CSP reduction and increased of cortical excitability. TMS changes differed among our two patients more prominent on the more affected side and in the patient with longer disease duration. A brief LF-rTMS applied on the MA hand prolonged transiently CSP length probably through a GABA-B modulation. This report represents the first experience with slow frequency rTMS in CBS and it might well be that with the same experimental setting with a longer train repeated over the course of several days would be able to induce more pronounced effects on cortical excitability.

Leukodystrophies in idiopathic adult‐onset ataxia: Frequency and phenotype in 105 patients

Here, we systemati-cally screened a representative cohort of patients with adult-onset ataxia for underlying leukodystrophies and analyzedits phenotypic presentation.One hundred five ataxia patients from independent fami-lies were recruited as a continuous series from the ataxiaclinic in T€ubingen according to the following inclusion crite-ria: (1) age of onset of ataxia 16 years, (2) family historyconsistent with autosomal-recessive inheritance, and (3)prior exclusion of Friedreich ataxia in patients with age ofonset 25 years and prior exclusion of common subtypesof spinocerebellar ataxia (SCA1, -2, -3, -6, -7, -17) inpatients with onset 25 years. All patients underwent abasic screening that included serum levels of very-long-chainfatty acids for X-linked adrenoleukodystrophy/adrenomyelo-neuropathy (ALD/AMN) and enzyme activities for meta-chromatic leukodystrophy (MLD), GM1 gangliosidosis,GM2 gangliosidosis variants (Tay-Sachs disease [TS] andSandhoff disease [SD]), and Krabbe disease (KD) in culturedleukocytes. If phenotypic evidence or MR imaging was sug-gestive of other types of neurometabolic disorders, we alsoperformed the respective genetic or biochemical testing, forexample, screening for Niemann-Pick disease type C (NPC)in patients with vertical-gaze palsy, for cerebrotendinousxanthomatosis (CTX) in cases of cognitive dysfunction, andfor leukencephalopathy with brainstem and spinal cordinvolvement and lactate elevation (LBSL) or vanishing whitematter disease (VWMD).Standardized clinical characterization included signs ofcorticospinal tract affection, dystonia, peripheral polyneu-ropathy (muscular atrophy or absent reflexes in combinationwith pallhypesthesia), or psychiatric comorbidities (exceptfor depression, as it is a common and unspecific feature ofchronic progressive disease

Early clinical features of patients with progressive supranuclear palsy with predominant cerebellar ataxia

BackgroundPatients who develop progressive supranuclear palsy with predominant cerebellar ataxia (PSP-C) develop cerebellar ataxia as the initial and principal symptom, may be misdiagnosed as having multiple system atrophy with predominant cerebellar features (MSA-C). Therefore, we investigated the clinical signs and symptoms between PSP-C and MSA-C early in their disease course. MethodsWe reviewed the medical records of 15 consecutive patients with pathologically proven PSP-C (4) and MSA-C (11). We recorded the presence or absence of clinical features that developed within 2 years of disease onset. ResultsThe age at onset of PSP-C patients was older than that of MSA-C patients (p = 0.009). The frequencies of falls were higher in PSP-C patients than in MSA-C patients (p = 0.026). Additionally, the development of supranuclear vertical gaze palsy was higher in PSP-C patients than in MSA-C patients (p = 0.011), whereas the frequency of dysautonomia was lower in PSP-C patients than in MSA-C patients (p = 0.035). ConclusionsOlder onset, early falls, and supranuclear vertical gaze palsy without dysautonomia may predict the diagnosis of PSP-C in patients with late-onset sporadic cerebellar ataxia.

Niemann–Pick type C: a potentially treatable disorder?

Niemann–Pick disease refers to a group of autosomal recessive lipid storage disorders associated with a variable degree of neurological manifestations in addition to other organ involvement. Niemann–Pick disease is divided...

“Atypical” atypical parkinsonism: New genetic conditions presenting with features of progressive supranuclear palsy, corticobasal degeneration, or multiple system atrophy—A diagnostic guide

Recently, a number of genetic parkinsonian conditions have been recognized that share some features with the clinical syndromes of progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and multiple system atrophy (MSA), the classic phenotypic templates of atypical parkinsonism. For example, patients with progranulin, dynactin, or ATP13A gene mutations may have vertical supranuclear gaze palsy. This has made differential diagnosis difficult for practitioners. In this review, our goal is to make clinicians aware of these genetic disorders and provide clinical clues and syndromic associations, as well as investigative features, that may help in diagnosing these disorders. The correct identification of these patients has important clinical, therapeutic, and research implications. © 2013 Movement Disorder Society.

Commentary for “Progressive ataxia associated with scarring skin lesions and vertical gaze palsy”

Commentary for “Progressive ataxia associated with scarring skin lesions and vertical gaze palsy”

Progressive ataxia associated with scarring skin lesions and vertical gaze palsy

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