Paraneoplastic cerebellar degeneration as a presenting manifestation of non-Hodgkin’s lymphoma

Background

Paraneoplastic Cerebellar degeneration (PCD) is one of the classical paraneoplastic syndromes (PNS) which is characterised by subacute onset, progressive cerebellar ataxia and is usually associated with small cell lung carcinoma, adeno carcinoma of breast and ovary followed by Hodgkin’s lymphoma.

Objective

We herein report a case of subacute onset, progressive cerebellar ataxia in a 37-year-old female, who on evaluation was found to have non-Hodgkin’s lymphoma and experienced good clinical response to treatment.

Discussion

As compared to solid tumours, chances of association of PNS with Lymphomas is quite low and there are only few case reports in the literature showing association of PCD with non-Hodgkin’s lymphoma. As PCD is one of the classical PNS, it is very important to identify subtle cerebellar manifestations in an otherwise apparently normal individual, as early diagnosis and aggressive treatment can immensely improve the mortality and morbidity associated with this syndrome.

Conclusion

This case signifies the importance of suspecting PNS as an important differential diagnosis in a young patient presenting with subacute onset progressive cerebellar ataxia and evaluating her extensively for malignancy in spite of no paraneoplastic antibody been detected as early diagnosis and treatment can lead to gratifying response. We do agree that 2 weeks follow up is a short time interval to determine whether the response was sustained or not, for which a long term follow up is required.

     

Severe motor neuropathy or neuronopathy due to nitrous oxide toxicity after correction of vitamin B12 deficiency

Introduction: Nitrous oxide (N₂O) toxicity can cause a sensory predominant myeloneuropathy identical to subacute combined degeneration caused by vitamin B12 deficiency. We describe a patient with a typical vitamin B12 deficiency syndrome after N₂O abuse who recovered and then developed a severe lower motor neuron syndrome following vitamin B12 correction. This suggests N₂O toxicity independent of functional vitamin B12 deficiency. Methods: Electrophysiological, serological, and clinical evaluations were undertaken in the evaluation of this patient. Results: A 22‐year‐old man abused N₂O and presented with a dorsal column syndrome with low vitamin B12 and high homocysteine serum levels. He recovered with treatment but presented later with profound motor axonal degeneration and normal vitamin B12, homocysteine, and methlymalonic acid levels. Conclusions: This case illustrates that N₂O‐associated severe motor neuropathy or neuronopathy can develop separately from typical vitamin B12 deficiency dorsal column myelopathy. This syndrome can present when functional measures of vitamin B12 deficiency have normalized. Muscle Nerve 51: 614–616, 2015     

Atypical presentation of late‐onset Tay‐sachs disease

Introduction: Late‐onset Tay‐Sachs disease (LOTS) is a lysosomal storage disease caused by deficient Beta‐hexosaminidase A activity. Methods: We describe a 53‐year‐old woman who presented with adult‐onset leg weakness, and whose initial diagnosis was progressive muscular atrophy without identifiable etiology. Development of cerebellar ataxia in mid‐life prompted reassessment. Results: Beta‐hexosaminidase A quantification assay demonstrated absence of the isozyme. Genetic testing identified compound heterozygous mutations in the HEXA gene, confirming the diagnosis of LOTS. Conclusions: The phenotypic spectrum of LOTS includes motor neuronopathy, ataxia, choreoathetosis, neuropathy, and psychiatric symptoms in various combinations. This patient highlights the emergence of different clinical features over many years and emphasizes the need to consider LOTS in the differential diagnosis of progressive muscular atrophy. Muscle Nerve 49 : 768–771, 2014     

Abnormal glycosylation of motor neurons withN-acetyl-d-galactosamine in a case of subacute motor neuronopathy associated with lymphoma

Lectins, glycine max (SBA) andVicia villosa (VVA), which identify terminalN-acetyl-d-galactosamine (GaINAc), stained the motor neurons of a patient with sub-acute motor neuronopathy associated with neoplastic angioendotheliosis. In normal controls and in patients with other neurological disorders including amyotrophic lateral sclerosis, neither lectin stained motor neurons. Abnormal glycosylation of motor neurons with terminal galNAc may be associated with the pathogenesis of subacute motor neuronopathy in this patient.     

Extranodal NK/T‐cell lymphoma,nasal type,manifesting as rapidly progressive dementia without any mass or enhancing brain lesion

Among the many potential etiologies for rapidly progressive dementia (RPD), primary central nervous system extranodal NK/T‐cell lymphoma, nasal‐type (ENKL) is a rare entity. We present the first reported case of autopsy‐proven RPD due to ENKL without any mass or enhancing lesion of the brain. A 54‐year‐old immunocompetent man presented with RPD, myoclonus and ataxia. The mini‐mental state examination (MMSE) score was 22/30. His brain MRI revealed progressive brain atrophy without gadolinium enhancement or mass lesion. Five months after the initial evaluation, cognitive impairment further worsened with an MMSE score of 3/30. At the advanced stage, lumbar MRI showed swollen cauda equina with gadolinium enhancement. The number of Epstein‐Barr virus (EBV) DNA in cerebrospinal fluid had gradually increased. Twelve months after onset, the patient died of respiratory failure. Pathological findings revealed that lymphoma cells had diffusely invaded the meninges, parenchyma of the brain, spinal cord and cauda equina. Cells were positive for CD3, CD56 and EBV‐encoded small RNAs and negative for CD20. No evidence of malignancy was identified in the visceral organs. This report indicates that ENKL should be recognized as one of the rare causes of RPD. Early testing for EBV‐DNA in cerebrospinal fluid and imaging of cauda equina would be useful diagnostic tools.     

Atypical parkinsonian syndromes: a general neurologist's perspective

The differential diagnosis of atypical parkinsonian syndromes is challenging. These severe and often rapidly progressive neurodegenerative disorders are clinically heterogeneous and show significant phenotypic overlap. Here, clinical, imaging, neuropathological and genetic features of multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration and frontotemporal lobar degeneration (FTLD) are reviewed. The terms corticobasal degeneration and FTLD refer to pathologically confirmed cases of corticobasal syndrome and frontotemporal dementia (FTD). Frontotemporal lobar degeneration clinically presents as the behavioral variant FTD, semantic variant primary progressive aphasia (PPA), non‐fluent agrammatic variant PPA, logopenic variant PPA and FTD associated with motor neuron disease. While progressive supranuclear palsy and corticobasal syndrome have been called Parkinson‐plus syndromes in the past, they are now classified as FTD‐related disorders, reflecting that they pathologically differ from α‐synucleinopathies like multiple system atrophy and Parkinson disease. The contribution of genetic factors to atypical parkinsonian syndromes is increasingly recognized. Genes involved in the etiology of FTLD include MAPT, GRN and C9orf72. Novel neuroimaging techniques, including tau positron emission tomography imaging, are being investigated. Multimodal magnetic resonance imaging approaches and automated magnetic resonance imaging volume segmentation techniques are being evaluated for optimized differential diagnosis. Current treatment options are symptomatic, and disease modifying therapies are under active investigation.     

Paraneoplastic progressive supranuclear palsy syndrome in a patient with B-cell lymphoma

An important component in the diagnosis of atypical parkinsonian disorders is the exclusion of secondary causes. Paraneoplastic causes of parkinsonism are extremely rare. We describe a case which presented initially as probable progressive supranuclear palsy (PSP) but on follow-up displayed a rapidly progressive course, unexplained fever, peripheral neuropathy and an abnormal CSF. We highlight the difficulties faced in formulating a diagnosis for this unusual case prior to the discovery of an occult B-cell lymphoma, and discuss its relevance in the exclusion criteria for PSP. A paraneoplastic cause should be considered if disease progression is unusually rapid.     

Paraneoplastic motor neuron disease with type 1 Purkinje cell antibodies

Autoimmune serological testing is a useful aid for identifying a paraneoplastic basis for sporadic motor neuron disease. A 67-year-old woman with ovarian carcinoma presented with progressive weakness. Neurological examination was suggestive of motor neuron disease with signs of upper motor neuron disorder. Electromyography revealed severe motor neuronopathy of the upper extremities. Characteristic type 1 Purkinje cell antibodies (anti-Yo antibody) was detected in the serum diluted at 1:61,400. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:943–945, 1998.     

Motor unit number index and neurophysiological index as candidate biomarkers of presymptomatic motor neuron loss in amyotrophic lateral sclerosis

Introduction: Our objective was to determine the utility of motor unit number index (MUNIX) and neurophysiological index (NI) as surrogate biomarkers of disease progression in limbs without clinical signs of lower motor neuron (LMN) involvement from patients with slowly progressive amyotrophic lateral sclerosis (ALS). Methods: Patients with slowly progressive ALS and at least 1 clinically unaffected limb were prospectively enrolled. Clinical signs of LMN loss and results from hand‐held dynamometer (HHD), revised ALS Functional Rating Scale (ALSFRS‐R), mean‐MUNIX (from 3 different muscles), and NI were longitudinally recorded. Results: Eighteen patients with 43 presymptomatic muscles were evaluated. Twenty‐seven muscles remained clinically unaffected during study, with stable ALSFRS‐R subscores and HHD measures. However, a significant decline in mean‐MUNIX and NI was detected. Discussion: Mean‐MUNIX and NI were more sensitive than clinical measures at detecting LMN loss in presymptomatic limbs from patients with slowly progressive ALS. Therefore, these electrophysiological biomarkers should be included in early study phases as meaningful outcome measures. Muscle Nerve 58 : 204–212, 2018     

Degeneration of corpus callosum and recovery of motor function after stroke: A multimodal magnetic resonance imaging study

Animal models of stroke demonstrated that white matter ischemia may cause both axonal damage and myelin degradation distant from the core lesion, thereby impacting on behavior and functional outcome after stroke. We here used parameters derived from diffusion magnetic resonance imaging (MRI) to investigate the effect of focal white matter ischemia on functional reorganization within the motor system. Patients (n = 18) suffering from hand motor deficits in the subacute or chronic stage after subcortical stroke and healthy controls (n = 12) were scanned with both diffusion MRI and functional MRI while performing a motor task with the left or right hand. A laterality index was employed on activated voxels to assess functional reorganization across hemispheres. Regression analyses revealed that diffusion MRI parameters of both the ipsilesional corticospinal tract (CST) and corpus callosum (CC) predicted increased activation of the unaffected hemisphere during movements of the stroke‐affected hand. Changes in diffusion MRI parameters possibly reflecting axonal damage and/or destruction of myelin sheath correlated with a stronger bilateral recruitment of motor areas and poorer motor performance. Probabilistic fiber tracking analyses revealed that the region in the CC correlating with the fMRI laterality index and motor deficits connected to sensorimotor cortex, supplementary motor area, ventral premotor cortex, superior parietal lobule, and temporoparietal junction. The results suggest that degeneration of transcallosal fibers connecting higher order sensorimotor regions constitute a relevant factor influencing cortical reorganization and motor outcome after subcortical stroke. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Effects of aripiprazole and haloperidol on neural activation during a simple motor task in healthy individuals: A functional MRI study

The dopaminergic system plays a key role in motor function and motor abnormalities have been shown to be a specific feature of psychosis. Due to their dopaminergic action, antipsychotic drugs may be expected to modulate motor function, but the precise effects of these drugs on motor function remain unclear. We carried out a within‐subject, double‐blind, randomized study of the effects of aripiprazole, haloperidol and placebo on motor function in 20 healthy men. For each condition, motor performance on an auditory‐paced task was investigated. We entered maps of neural activation into a random effects general linear regression model to investigate motor function main effects. Whole‐brain imaging revealed a significant treatment effect in a distributed network encompassing posterior orbitofrontal/anterior insula cortices, and the inferior temporal and postcentral gyri. Post‐hoc comparison of treatments showed neural activation after aripiprazole did not differ significantly from placebo in either voxel‐wise or region of interest analyses, with the results above driven primarily by haloperidol. We also observed a simple main effect of haloperidol compared with placebo, with increased task‐related recruitment of posterior cingulate and precentral gyri. Furthermore, region of interest analyses revealed greater activation following haloperidol compared with placebo in the precentral and post‐central gyri, and the putamen. These diverse modifications in cortical motor activation may relate to the different pharmacological profiles of haloperidol and aripiprazole, although the specific mechanisms underlying these differences remain unclear. Evaluating healthy individuals can allow investigation of the effects of different antipsychotics on cortical activation, independently of either disease‐related pathology or previous treatment. Hum Brain Mapp 38:1833–1845, 2017. © 2017 Wiley Periodicals, Inc.     

Paraneoplastic encephalomyelitis/sensory motor peripheral neuropathy - an autopsy case study

Paraneoplastic neurological anti-Hu syndrome is one of the most frequent remote effects of cancer and usually manifests as encephalomyelitis combined with peripheral neuropathy. Subacute sensory neuronopathy, which results from the inflammatory destruction of sensory neurone cell bodies in the dorsal root ganglia, is thought to be the principal presentation of peripheral neuropathy. In addition to sensory involvement, evidence of motor nerve involvement is frequently found. The mechanisms of motor involvement remain largely unclear and there have been only a limited number of pathological studies. We present an autopsy case study of anti-Hu paraneoplastic encephalomyelitis/sensory-motor neuropathy, which confirms an inflammatory paraneoplastic destruction of sensory neuron cell bodies in the dorsal root ganglia and lower motor neurons in the spinal cord, as a cause of clinically rapidly progressive peripheral sensory-motor neuropathy.     

Multifocal motor neuropathy with high titers of anti‐MAG antibodies

Multifocal motor neuropathy (MMN) and anti‐myelin‐associated glycoprotein (anti‐MAG)‐associated neuropathy are clinically and electrophysiologically distinct entities. We describe a patient with characteristic features of both neuropathies, raising the possibility of an overlap syndrome. A 49‐year‐old patient reported a history of slowly progressive predominantly distal tetraparesis, with mild sensory deficits. Nerve conduction studies demonstrated persistent motor conduction blocks outside compression sites, typical of MMN. Laboratory findings revealed persistently high titers of anti‐MAG immunoglobulin Mλ (IgMλ) paraprotein in the context of a monoclonal gammapathy of unknown significance. Skin biopsy of distal lower limb revealed IgM positive terminal nerve perineurium deposits. This case suggests that the distinction between subtypes of chronic inflammatory neuropathies may not be as clear as initially thought, and that the pattern of pathogenicity of anti‐MAG antibodies may vary.     

Acute bulbar,neck and limb weakness with monospecific anti‐GT1a antibody: A rare localized subtype of Guillain‐Barré sydnrome

Introduction: Acute bulbar, neck, and limb weakness carries several potential differential diagnoses. Although a diagnosis can often be established clinically, investigations such as electrodiagnostic and antibody testing can provide support for the clinical diagnosis and may aid in understanding the pathogenesis. A 65‐year‐old woman presented with acute bulbar, neck, and rapidly progressive bilateral upper limb weakness. Methods: Clinical evaluation, electrophysiological, and serological studies were undertaken. Results: Neurophysiology demonstrated proximal conduction block. A clinical diagnosis of pharyngeal‐cervical‐brachial weakness, a localized variant of Guillain‐Barré syndrome, was made. The patient received treatment with intravenous immunoglobulin and made a remarkable recovery over the next month. She was found to have serum monospecific anti‐GT1a antibodies. Conclusions: We report a case of pharyngeal‐cervical‐brachial weakness with monospecific anti‐GT1a antibodies and discuss the differential diagnosis of acute bulbar, neck, and limb weakness. Muscle Nerve 53 : 143–146, 2016     

New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome

Facial-onset sensory and motor neuronopathy (FOSMN) syndrome represents a rare, slowly progressive, lower motor neuron disease with sensory compromise, involving mainly the face, bulbar region and upper limbs. However, non-motor symptoms and neurogenetic studies have rarely been evaluated in large case series. In the present study, 10 unrelated Brazilian patients with FOSMN syndrome underwent extensive clinical, laboratory, neurophysiological and neurogenetic assessment. Median age at symptom onset was 52.1 years, and men and women were equally affected. Patients presented with hemifacial or bilateral facial paresthesia and weakness, which evolved with dysphagia, dysphonia, and facial and tongue atrophy and, finally, a dropped-head, upper limb weakness and syringomyelia-like sensory disturbances in the upper limbs. All 10 patients showed chronic diffuse neurogenic compromise of bulbar, cervical and thoracic myotomes, and abnormal blink reflex tests. A positive family history of neurodegeneration was identified in six cases, and revealed pathogenic gene variants in three families (involving VCP, TARDBP and CHCHD10). Thus, our case series has revealed new findings regarding FOSMN syndrome: (i) its clinical course is not always benign, with poorer prognoses associated with dropped-head syndrome and early bulbar compromise; (ii) FOSMN syndrome may be part of a complex familial neurodegenerative spectrum; and (iii) a definite genetic basis may be observed in some cases.     

Progressive motor unit loss in the G93A mouse model of amyotrophic lateral sclerosis is unaffected by gender

We examined whether there are gender differences in the progressive loss of functional motor units in SOD1^G93A transgenic mice. Isometric muscle and motor unit twitch contractions were recorded in fast‐ and slow‐twitch muscles in response to stimulation of the sciatic nerve. Using a modified motor unit number estimation technique (ITS‐MUNE), we found that motor unit numbers declined rapidly from 40 to 90 days of age during the asymptomatic phase of ALS in fast‐ but not slow‐twitch hindlimb muscles of both male and female mice. There was a corresponding decline in twitch and tetanic contractile forces of the fast‐twitch muscles. Gender did not affect the progressive loss of motor units and associated decline in force production. We conclude that gender does not alter progressive, muscle‐specific motor unit loss in ALS, even though gender does influence disease onset. Muscle Nerve 39: 318–327, 2009     

Paraneoplastic peripheral neuropathies

Paraneoplastic peripheral neuropathies constitute a heterogeneous group of conditions. A link between the tumor and the neuropathy has been demonstrated in a subgroup only. Definite paraneoplastic neuropathies correspond to neuropathies associated with antibodies reacting with antigens common to the peripheral nervous system and the cancer. Neuropathies associated with anti-Hu antibodies are the most frequent and consist mainly in subacute sensory neuronopathy. Sensory or sensory-motor neuropathies with anti-CV2 antibodies are less frequent. The link between the cancer and the neuropathy is less clear in the other forms. The frequency of cancer in this group varies from 1 to 18 p.cent.These neuropathies include inflammatory demyelinating neuropathies, neuropathy and vasculitis, lower motor neurone diseases, and autonomic neuropathies. Occasionally, the neuropathy improves with treatment of the tumor. Recent data suggest that gangliosides may be the target of the immune process in neuropathies associated with melanoma.