Clinical examinations and eye movement recordings of 91 consecutive patients with DBN were analyzed to describe the characteristics of DBN and to localize the lesions producing this abnormality. Horizontal and vertical eye movement recordings were made with EOG and/or magnetic search coil. The most frequent causes were infarction, cerebellar and spinocerebellar degeneration syndromes, MS and developmental anomalies affecting the pons and cerebellum. Toxicity from anticonvulsant drugs probably caused nystagmus in a few patients. Clinical examinations, excluding electronic eye movement recordings, were used to localize lesions. Localizations included the cerebellum in 88% of the patients. However, localizations to structures outside of the cerebellum were made in several patients. The effects of DBN of gaze position, convergence, blockage of fixation, and positioning of the head and body were observed. Almost all patients had DBN in some position of gaze while sitting and fixating a distant target. A few patients demonstrated DBN only with convergence, in the dark, or with positioning of the head and body. Horizontal gaze increased DBN in most patients. The nystagmus slow components usually had constant-velocity or increasing-velocity waveforms. The effects of vertical gaze on DBN were variable. In general, statistically significant differences in the frequencies of these effects among the various causes and localizations of lesions were not found. Horizontal eye movements were electronically recorded in DBN patients, in a group of normal subjects, and in a group of patients with isolated cerebellar atrophy who did not have DBN. The pattern of abnormal horizontal eye movements characteristic of damage to the midline structures of the cerebellum (impaired pursuit, impaired OKN, and inability to suppress VOR) was found in almost all DBN patients (99%), including patients with lesions localized to structures outside the cerebellum by clinical examination. DBN is usually produced by lesions in the cerebellum that also damage pathways that control horizontal tracking and visual-vestibulo-ocular interactions.
Eye movements are clinically normal in most patients with motor neuron disorders until late in the disease course. Rare patients are reported to show slow vertical saccades, impaired smooth pursuit, and gaze-evoked nystagmus. We report clinical and oculomotor findings in three patients with motor neuronopathy and downbeat nystagmus, a classic sign of vestibulocerebellar disease.
All patients had clinical and electrodiagnostic features of anterior horn cell disease. Involvement of finger and wrist extensors predominated, causing finger and wrist drop. Bulbar or respiratory dysfunction did not occur. All three had clinically evident downbeat nystagmus worse on lateral and downgaze, confirmed on eye movement recordings using the magnetic search coil technique in two patients. Additional oculomotor findings included alternating skew deviation and intermittent horizontal saccadic oscillations, in one patient each. One patient had mild cerebellar atrophy, while the other two had no cerebellar or brainstem abnormality on neuroimaging. The disorder is slowly progressive, with survival up to 30 years from the time of onset.
The combination of motor neuronopathy, characterized by early and prominent wrist and finger extensor weakness, and downbeat nystagmus with or without other cerebellar eye movement abnormalities may represent a novel motor neuron syndrome.
Purpose of review
The most relevant advances in immune-mediated movement disorders are described, with emphasis on the clinical–immunological associations, novel antigens, and treatment.
Many movement disorders previously considered idiopathic or degenerative are now recognized as immune-mediated. Some disorders are paraneoplastic, such as anti-CRMP5-associated chorea, anti-Ma2 hypokinesis and rigidity, anti-Yo cerebellar ataxia and tremor, and anti-Hu ataxia and pesudoathetosis. Other disorders such as Sydenham's chorea, or chorea related to systemic lupus erythematosus and antiphospholipid syndrome occur in association with multiple antibodies, are not paraneoplastic, and are triggered by molecular mimicry or unknown mechanisms. Recent studies have revealed a new category of disorders that can be paraneoplastic or not, and associate with antibodies against cell-surface or synaptic proteins. They include anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, which may cause dyskinesias, chorea, ballismus or dystonia (NMDAR antibodies), the spectrum of Stiff-person syndrome/muscle rigidity (glutamic acid decarboxylase, amphiphysin, GABAA-receptor-associated protein, or glycine receptor antibodies), neuromyotonia (Caspr2 antibodies), and opsoclonus–myoclonus–ataxia (unknown antigens).
Neurologists should be aware that many movement disorders are immune-mediated. Recognition of these disorders is important because it may lead to the diagnosis of an occult cancer, and a substantial number of patients, mainly those with antibodies to cell-surface or synaptic proteins, respond to immunotherapy.
antibodies; ataxia; autoimmune; chorea; dyskinesia; dystonia; encephalitis; immunotherapy; movement disorders; paraneoplastic
A child with opsoclonus associated with occult neuroblastoma is presented, in whom regression of the eye movement disorder through phases of flutter and dysmetria was observed. It is speculated that these ocular motor abnormalities represent a continuum of cerebellar dysfunction. A peculiar dysmetric head movemment not related to saccadic palsy is documented.
The GABAergic drug baclofen and the cholinergic drug physostigmine were administered to patients with upbeat and downbeat nystagmus. Baclofen (orally, 5 mg three times daily) reduced nystagmus slow phase velocity and distressing oscillopsia by 25-75% in four out of five patients (two upbeat nystagmus; two downbeat nystagmus). Physostigmine (1 mg single intravenous injection) increased nystagmus in five additional patients with downbeat (1) or positional downbeat nystagmus (4) for a duration of 15-20 minutes. The different interactions of baclofen and physostigmine on neurotransmission subserving vertical vestibulo-ocular reflex could account for these effects. The response to baclofen appears to be a GABA-B-ergic effect with augmentation of the physiological inhibitory influence of the vestibulo-cerebellum on the vestibular nuclei. Similarly baclofen has an inhibitory effect on the velocity storage mechanism. Cholinergic action may cause the increment of nystagmus by physostigmine.
Purpose of review
This review describes relevant advances in paraneoplastic neurological syndromes (PNS) with emphasis on particular syndromes and the impact of antibodies against surface antigens in their management.
PNS may present with symptoms that do not raise the suspicion of a paraneoplastic origin. The best example is anti-N-methyl-D-aspartate receptor encephalitis that in adult women frequently associates with ovarian teratoma. An electroencephalogram pattern described as ‘extreme delta brush’ was recently identified in 30% of patients with this disorder. Isolated myelopathy may have a paraneoplastic origin associated with amphiphysin or CV2 (CRMP5) antibodies. Jaw dystonia and laryngospasm can be the predominant symptom of the brainstem encephalitis associated with Ri antibodies. γ-Aminobutyric acid (GABA)B receptor antibodies are the most common antibodies found in patients with limbic encephalitis and small cell lung cancer, and contactin-associated protein 2 antibodies in patients with Morvan’s syndrome and thymoma. Lastly, a recent study identified delta/notch-like epidermal growth factor-related receptor (DNER) as the target antigen of Tr antibodies, a marker of cerebellar ataxia and Hodgkin’s lymphoma.
The number of antibodies relevant to PNS is now expanded to those against surface antigens. These antibodies do not confirm the paraneoplastic origin of the syndrome but predict a better response to immunotherapy.
antibodies; cancer; cerebellar degeneration; Lambert–Eaton myasthenic syndrome; limbic encephalitis; paraneoplastic
Paraneoplastic neurological syndromes (PNSs) cover a wide range of diseases and
involve both the central nervous system (CNS) and peripheral nervous system.
Paraneoplastic encephalitis comprises several diseases such as paraneoplastic
cerebellar degeneration (PCD), limbic encephalitis (LE), paraneoplastic
encephalomyelitis (PEM), brainstem encephalitis, opsomyoclonus syndrome, in
addition to other even less frequently occurring entities. LE was the first
historically identified CNS PNS, and similarities between other temporal lobe
diseases such as herpes encephalitis have been elucidated. In the past few
decades several autoantibodies have been described in association with LE. These
encompass the classical ‘onconeuronal’ antibodies (abs) such as Hu, Yo, Ri and
others, and now additionally abs towards either ion channels or surface
antigens. The clinical core findings in LE are various mental changes such as
amnesia or confusion, often associated with seizures. Careful characterization
of psychiatric manifestations and/or associated neurological signs can help to
characterize the syndrome and type of ab. The treatment options in LE depend on
the aetiology. In LE caused by onconeuronal abs, the treatment options are poor.
In two types of abs associated with LE, abs against ion channels and surface
antigens (e.g. NMDA), immunomodulatory treatments seem effective, making these
types of LE treatable conditions. However, LE can also occur without being
associated with cancer, in which case only immunomodulation is required. Despite
effective treatments, some patients’ residual deficits remain, and recurrences
have also been described.
cancer; ion channel antibodies; limbic encephalitis; NMDA; onconeuronal antibodies; paraneoplastic disease; paraneoplastic encephalitis; surface antibodies
Opsoclonus–myoclonus syndrome (OMS) is a rare condition that includes chaotic multidirectional saccadic eye movements associated with myoclonus and ataxia. In adults, it is usually considered to be an autoimmune disease occurring either in a paraneoplastic context or after central nervous system infection. We report the case of a patient who presented with the classic features of OMS as a manifestation of acute Borrelia burgdorferi infection that was shown both on serum and cerebrospinal fluid examination. The outcome was favourable after prolonged antibiotic treatment. Lyme disease could be added to the list of aetiologies to be screened in OMS, as it would allow effective treatment and avoidance of unnecessary investigations.
Opsoclonus-myoclonus may be caused by various neurological conditions and toxic-metabolic states, but typically occurs as a parainfectious or paraneoplastic manifestation. The development of opsoclonus-myo-clonus has been variably attributed to lesions in the pons or cerebellum. Herein the authors describe a case of opsoclonus-myoclonus due to posterior reversible encephalopathy syndrome in which magnetic resonance imaging revealed lesions in the region of the cerebellar dentate nuclei. Clinical and radiological resolution of the opsoclonus-myoclonus and of the posterior reversible encephalopathy syndrome followed antihyperten-sive therapy.
Cerebellum; Dentate; Myoclonus; Opsoclonus; PRES
Anti–N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis has been recently reported as autoimmune/paraneoplastic encephalitis, affecting mostly young females.
To describe opsoclonus-myoclonus syndrome in association with anti-NMDAR antibodies.
Geneva University Hospital.
A 23-year-old woman with opsoclonus-myoclonus syndrome.
Two weeks after an episode of gastroenteritis, the patient developed symptoms of depression associated with psychomotor slowing, progressive gait instability, and opsoclonus-myoclonus. Cerebrospinal fluid examination showed mild lymphocytic pleocytosis and intrathecal IgG synthesis with oligoclonal bands. The patient’s condition worsened rapidly to an akinetic mutism, followed by a period of agitation, delirium, and hallucinations. These gradually subsided; however, a frontal behavior and executive dysfunction persisted 5 months after symptom presentation. No tumor was found. Anti-NMDAR antibodies were found in the cerebrospinal fluid.
Opsoclonus-myoclonus may occur in patients with anti-NMDAR encephalitis. Prompt diagnosis of this disorder is important because after tumor removal and immunomodulatory therapies it has a relatively good prognosis.
Paraneoplastic cerebellar degeneration is a rare non-metastatic manifestation of malignancy. In this report, to the best of our knowledge we describe for the first time a diagnosis of paraneoplastic cerebellar degeneration several months prior to the diagnosis of clear carcinoma of the uterus.
A 75-year-old Caucasian woman manifested a rapidly progressive cerebellar syndrome with nystagmus, past-pointing, dysdiadochokinesis, dysarthria, truncal ataxia and titubation. The paraneoplastic cerebellar degeneration was associated with anti-Yo and anti-glutamic acid decarboxylase antibodies. 14-3-3 protein was detected in the cerebrospinal fluid. She was treated with intravenous immunoglobulin prior to laparotomy, hysterectomy and bilateral salpingoophorectomy. Our patient has survived for three years following diagnosis and treatment.
To the best of our knowledge this is the first report of an association of clear cell carcinoma of the uterus and paraneoplastic cerebellar degeneration with both anti-Yo and anti-glutamic acid decarboxylase antibodies. The findings imply that both antibodies contributed to the fulminating paraneoplastic cerebellar degeneration observed in our patient, and this was of such severity it resulted in the release of 14-3-3 protein in the cerebrospinal fluid, a marker of neuronal death.
14-3-3 proteins; anti-Yo/anti-GAD antibodies; clear cell carcinoma of uterus; paraneoplastic cerebellar degeneration
In a patient with posterior medullary haemorrhage, first upbeat and later downbeat nystagmus occurred in the primary position. The lesion was limited to the posterior and medial part of the medulla. Clinical and electro-oculographic examination first showed upbeat nystagmus in the primary position and upgaze, with downbeat nystagmus in downgaze. Two and a half months later, there was downbeat nystagmus in the primary position and downgaze and upbeat nystagmus in upgaze.
In recent years there is an increasing description of novel anti-neuronal antibodies that are associated with paraneoplastic and non-paraneoplastic neurological syndromes. These antibodies are useful in clinical practice to confirm the immunmediated origin of the neurological disorder and are helpful in tumor search. Currently, anti-neuronal antibodies can be classified according to the location of the recognized antigen into two groups, 1.) intraneuronal antigens and 2.) antigens located in the cell membrane. Different techniques are established for detecting these antibodies: tissue-based assay (TBA), cell-based assay (CBA), immunoblot, immunoprecipitation assay (IP), and ELISA. TBA detect most of the antibodies, however, different pretreatment methods of rat brain are necessary to visualize either Group 1 or 2 antibodies. Higher specificity is provided by immunoblots, applicable for Group 1 antibodies, and CBA, suitable for Group 2 antibodies. IP and ELISA may be useful for the detection of specific antibodies or to solve particular issues such as antibody titers. Diagnosis of paraneoplastic and non-paraneoplastic neurological syndromes has important implications on treatment and follow-up of patients. Selection and proper combination of test systems and appropriate knowledge of the clinical information will provide a maximum of sensitivity and specificity in identifying the associated antibody.
anti-neuronal antibodies; diagnosis; tissue-based assay; cell-based assay; immunoblot; sensitivity; specificity
Adult opsoclonus‐myoclonus (OM), a disorder of eye movements accompanied by myoclonus affecting the trunk, limbs, or head, is commonly associated with an underlying malignancy or precipitated by viral infection.
We present the first two reports of post‐streptococcal OM associated with antibodies against a 56 kDa protein. Two young girls presented with opsoclonus and myoclonus following a febrile illness and pharyngitis. Protein purification techniques were employed. Amino acid sequences of human neuroleukin (NLK) and streptococcal proteins were compared using the protein‐protein BLAST application.
The antigen was identified as NLK (glucose‐6‐phosphate isomerase, GPI). GPI is present on the cell surface of streptococcus making the protein a candidate target for molecular mimicry.
We have identified NLK as an antigenic target in two patients with post‐streptococcal OM. The pathogenicity of the antibodies is uncertain. The potential role of anti‐neuroleukin antibodies in the pathogenesis of OM is discussed. We propose that OM may represent a further syndrome in the growing spectrum of post‐streptococcal neurological disorders. The role of streptococcus in OM and the frequency with which anti‐NLK responses occur in both post‐infectious and paraneoplastic OM should be investigated further.
antibodies; opsoclonus‐myoclonus; post‐infectious; streptococcus
Immunoglobulin G (IgG) antibodies reactive with intracellular neuronal proteins have been described in paraneoplastic and other autoimmune disorders. Because neurons have been thought impermeable to immunoglobulins, however, such antibodies have been considered unable to enter neurons and bind to their specific antigens during life. Cerebellar Purkinje cells - an important target in paraneoplastic and other autoimmune diseases - have been shown in experimental animals to incorporate a number of molecules from cerebrospinal fluid. IgG has also been detected in Purkinje cells studied post mortem. Despite the possible significance of these findings for human disease, immunoglobulin uptake by Purkinje cells has not been demonstrated in living tissue or studied systematically.
To assess Purkinje cell uptake of immunoglobulins, organotypic cultures of rat cerebellum incubated with rat IgGs, human IgG, fluorescein-conjugated IgG, and rat IgM were studied by confocal microscopy in real time and following fixation. An IgG-daunorubicin immunotoxin was used to determine whether conjugation of pharmacological agents to IgG could be used to achieve Purkinje cell-specific drug delivery.
IgG uptake was detected in Purkinje cell processes after 4 hours of incubation and in Purkinje cell cytoplasm and nuclei by 24-48 hours. Uptake could be followed in real time using IgG-fluorochrome conjugates. Purkinje cells also incorporated IgM. Intracellular immunoglobulin did not affect Purkinje cell viability, and Purkinje cells cleared intracellular IgG or IgM within 24-48 hours after transfer to media lacking immunoglobulins. The IgG-daunomycin immunotoxin was also rapidly incorporated into Purkinje cells and caused extensive, cell-specific death within 8 hours. Purkinje cell death was not produced by unconjugated daunorubicin or control IgG.
Purkinje cells in rat organotypic cultures incorporate and clear host (rat) and non-host (human or donkey) IgG or IgM, independent of the immunoglobulin's reactivity with Purkinje cell antigens. This property permits real-time study of immunoglobulin-Purkinje cell interaction using fluorochrome IgG conjugates, and can allow Purkinje cell-specific delivery of IgG-conjugated pharmacological agents. Antibodies to intracellular Purkinje cell proteins could potentially be incorporated intracellularly to produce cell injury. Antibodies used therapeutically, including immunotoxins, may also be taken up and cause Purkinje cell injury, even if they do not recognize Purkinje cell antigens.
In recent years there is an increasing description of novel anti-neuronal antibodies that are associated with paraneoplastic and non-paraneoplastic neurological syndromes. These antibodies are useful in clinical practice to confirm the immunmediated origin of the neurological disorder and are helpful in tumor search. Currently, antineuronal antibodies can be classified according to the location of the recognized antigen into two groups, 1.) intraneuronal antigens and 2.) antigens located in the cell membrane. Different techniques are established for detecting these antibodies: tissue-based assay (TBA), cell-based assay (CBA), immunoblot, immunoprecipitation assay (IP), and ELISA. TBA detect most of the antibodies, however, different pretreatment methods of rat brain are necessary to visualize either Group 1 or 2 antibodies. Higher specificity is provided by immunoblots, applicable for Group 1 antibodies, and CBA, suitable for Group 2 antibodies. IP and ELISA may be useful for the detection of specific antibodies or to solve particular issues such as antibody titers. Diagnosis of paraneoplastic and non-paraneoplastic neurological syndromes has important implications on treatment and follow-up of patients. Selection and proper combination of test systems and appropriate knowledge of the clinical information will provide a maximum of sensitivity and specificity in identifying the associated antibody.
anti-neuronal antibodies; diagnosis; tissue-based assay; cell-based assay; immunoblot; sensitivity; specificity
In two monkeys, we recorded spontaneous eye movements before and after ablation of the cerebellar nodulus and uvula (Nod/Uv). In both monkeys, there was an increase in upward ocular drift (downbeat nystagmus, DBN) in darkness (M1: 1.5 °/s pre, 3.4 °/s post; M2: 1.3 °/s pre, 7.0 °/s post), but not in light. There was little effect of orbital position on drift velocity. These findings suggest that the Nod/Uv may play a role in the bias component of DBN.
Cerebellum; Rhesus; Monkey; Ataxia; Oscillopsia
The concept of antibody mediated CNS disorders is relatively recent. The classical CNS paraneoplastic neurological syndromes are thought to be T cell mediated, and the onconeural antibodies merely biomarkers for the presence of the tumour. Thus it was thought that antibodies rarely, if ever, cause CNS disease. Over the past 10 years, identification of autoimmune forms of encephalitis with antibodies against neuronal surface antigens, particularly the voltage gated potassium channel complex proteins or the glutamate N-methyl-D-aspartate receptor, have shown that CNS disorders, often without associated tumours, can be antibody mediated and benefit from immunomodulatory therapies. The clinical spectrum of these diseases is not yet fully explored, there may be others yet to be discovered and some types of more common disorders (eg, epilepsy or psychosis) may prove to have an autoimmune basis. Here, the known conditions associated with neuronal surface antibodies are briefly reviewed, some general aspects of these syndromes are considered and guidelines that could help in the recognition of further disorders are suggested.
Subjective tinnitus (ST) is a frequent but poorly understood medical condition. Recent studies demonstrated abnormalities in several types of eye movements (smooth pursuit, optokinetic nystagmus, fixation, and vergence) in ST patients. The present study investigates horizontal and vertical saccades in patients with tinnitus lateralized predominantly to the left or to the right side. Compared to left sided ST, tinnitus perceived on the right side impaired almost all the parameters of saccades (latency, amplitude, velocity, etc.) and noticeably the upward saccades. Relative to controls, saccades from both groups were more dysmetric and were characterized by increased saccade disconjugacy (i.e., poor binocular coordination). Although the precise mechanisms linking ST and saccadic control remain unexplained, these data suggest that ST can lead to detrimental auditory, visuomotor, and perhaps vestibular interactions.
asymmetry; cross-modal; interactions; tinnitus; visually guided saccades
Paraneoplastic neurologic disorders (PNDs) offer an uncommon opportunity to study human tumor immunity and autoimmunity. In small cell lung cancer (SCLC), expression of the HuD neuronal antigen is thought to lead to immune recognition, suppression of tumor growth, and, in a subset of patients, triggering of the Hu paraneoplastic neurologic syndrome. Antigen-specific CTLs believed to contribute to disease pathophysiology were described 10 years ago in paraneoplastic cerebellar degeneration. Despite parallel efforts, similar cells have not been defined in Hu patients. Here, we have identified HuD-specific T cells in Hu patients and provided an explanation for why their detection has been elusive. Different Hu patients harbored 1 of 2 kinds of HuD-specific CD8+ T cells: classical IFN-γ–producing CTLs or unusual T cells that produced type 2 cytokines, most prominently IL-13 and IL-5, and lacked cytolytic activity. Further, we found evidence that SCLC tumor cells produced type 2 cytokines and that these cytokines trigger naive CD8+ T cells to adopt the atypical type 2 phenotype. These observations demonstrate the presence of an unusual noncytotoxic CD8+ T cell in patients with the Hu paraneoplastic syndrome and suggest that SCLC may evade tumor immune surveillance by skewing tumor antigen–specific T cells to this unusual noncytolytic phenotype.
'Rotatory nystagmus', in which the visual axis of the eye moves involuntarily in the horizontal and vertical planes describing a closed loop trajectory, was analysed by means of combined video and electro-oculography in a patient with multiple sclerosis having numerous ocular signs of cerebellar disease. The rotations were sporadic, isolated single cycles having stereotyped, crescentiform loop shapes. Each consisted of a combination of a single cycle of vertical ocular flutter, the onset of which was followed 40 to 50 milliseconds later by a single cycle of horizontal ocular flutter. The timing relationship between flutters suggest that the vertical and horizontal systems had become somehow entrained. Rotatory nystagmus is saccadic in nature and arises from a unique timing relationship between vertical and horizontal flutter.
Anti‐glutamic acid decarboxylase (GAD) antibodies are described in stiff‐person syndrome and also in other neurological syndromes, including cerebellar ataxia and epilepsy. This paper reports the case of a patient who had chronic focal epilepsy, upbeat nystagmus and cerebellar ataxia, associated with a polyautoimmune response including anti‐GAD antibodies. Both gait and nystagmus improved markedly after immunosuppressive treatment with corticosteroids and azathioprine. After the introduction of benzodiazepines, previously refractory seizures were completely controlled. Anti‐GAD antibodies should be actively sought out in pharmacoresistant epilepsy, particularly if other neurological abnormalities are present. Combined treatment with immunosuppressants and γhydroxybutyric acidergic agents may be highly effective.
Anti-glutamic acid decarboxylase (GAD) antibodies are described in stiff-person syndrome and also in other neurological syndromes, including cerebellar ataxia and epilepsy. This paper reports the case of a patient who had chronic focal epilepsy, upbeat nystagmus and cerebellar ataxia, associated with a polyautoimmune response including anti-GAD antibodies. Both gait and nystagmus improved markedly after immunosuppressive treatment with corticosteroids and azathioprine. After the introduction of benzodiazepines, previously refractory seizures were completely controlled. Anti-GAD antibodies should be actively sought out in pharmacoresistant epilepsy, particularly if other neurological abnormalities are present. Combined treatment with immunosuppressants and γhydroxybutyric acidergic agents may be highly effective.
Opsoclonus–myoclonus syndrome (OMS) is a rare condition that has been reported from all parts of the world. It is well recognized as a paraneoplastic syndrome in children with neuroblastoma and in adults with small-cell carcinoma of lung and some other cancers. It may also occur in association with various central nervous system infections. We report a case of OMS in a patient with varicella zoster virus infection. IgM antibody for varicella-zoster virus was detected in the serum and the cerebrospinal fluid. The patient improved after treatment with clonazepam and was asymptomatic at 1-month follow-up.
Opsoclonus; myoclonus; varicella-zoster virus
Background and Purpose
The mechanism of upbeat nystagmus is unknown and clinicoanatomical correlative studies in series of patients with upbeat nystagmus are limited.
Fifteen patients with upbeat nystagmus received full neuro-ophthalmological evaluation by the senior author. Nystagmus was observed using video Frenzel goggles and recorded with video-oculography. Brain lesions were documented with MRI.
Lesions responsible for nystagmus were found throughout the brainstem, mainly in the paramedian area: in the medulla (n=8), pons (n=3), pons and midbrain with or without cerebellar lesions (n=3), and midbrain and thalamus (n=1). Underlying diseases comprised cerebral infarction (n=10), multiple sclerosis (n=2), cerebral hemorrhage (n=1), Wernicke encephalopathy (n=1), and hydrocephalus (n=1). Upbeat nystagmus was mostly transient and showed occasional evolution during the acute phase. In one patient with a bilateral medial medullary infarction, the upbeat nystagmus changed into a hemiseesaw pattern with near complete resolution of the unilateral lesion. Gaze and positional changes usually affected both the intensity and direction of the nystagmus. A patient with a cervicomedullary lesion showed a reversal of upbeat into downbeat nystagmus by straight-head hanging and leftward head turning while in the supine position. Gaze-evoked nystagmus (n=7), ocular tilt reaction (n=7), and internuclear ophthalmoplegia (n=4) were also commonly associated with upbeat nystagmus.
In view of the responsible lesions and associated neuro-ophthalmological findings, upbeat nystagmus may be ascribed to damage to the pathways mediating the upward vestibulo-ocular reflex or the neural integrators involved in vertical gaze holding.
Upbeat nystagmus; Vestibulo-ocular reflex; Neural integrator