Alberto Rolim Muro Martinez

Sensory Neuronopathy and Autoimmune Diseases

Sensory neuronopathies (SNs) are a specific subgroup of peripheral nervous system diseases characterized by primary degeneration of dorsal root ganglia and their projections. Multifocal sensory symptoms often associated to ataxia are the classical features of SN. Several different etiologies have been described for SNs, but immune-mediated damage plays a key role in most cases. SN may herald the onset of some systemic autoimmune diseases, which further emphasizes how important the recognition of SN is in clinical practice. We have thus reviewed available clinical, neurophysiological, and therapeutic data on autoimmune disease-related SN, namely, in patients with Sjögrens syndrome, autoimmune hepatitis, and celiac disease.

Clinical features and management of hereditary spastic paraplegia

Hereditary spastic paraplegia (HSP) is a group of genetically-determined disorders characterized by progressive spasticity and weakness of lower limbs. An apparently sporadic case of adult-onset spastic paraplegia is a frequent clinical problem and a significant proportion of cases are likely to be of genetic origin. HSP is clinically divided into pure and complicated forms. The later present with a wide range of additional neurological and systemic features. To date, there are up to 60 genetic subtypes described. All modes of monogenic inheritance have been described: autosomal dominant, autosomal recessive, X-linked and mitochondrial traits. Recent advances point to abnormal axonal transport as a key mechanism leading to the degeneration of the long motor neuron axons in the central nervous system in HSP. In this review we aim to address recent advances in the field, placing emphasis on key diagnostic features that will help practicing neurologists to identify and manage these conditions.

Multimodal MRI-Based Study in Patients with SPG4 Mutations

Mutations in the SPG4 gene (SPG4-HSP) are the most frequent cause of hereditary spastic paraplegia, but the extent of the neurodegeneration related to the disease is not yet known. Therefore, our objective is to identify regions of the central nervous system damaged in patients with SPG4-HSP using a multi-modal neuroimaging approach. In addition, we aimed to identify possible clinical correlates of such damage. Eleven patients (mean age 46.0 ± 15.0 years, 8 men) with molecular confirmation of hereditary spastic paraplegia, and 23 matched healthy controls (mean age 51.4 ± 14.1years, 17 men) underwent MRI scans in a 3T scanner. We used 3D T1 images to perform volumetric measurements of the brain and spinal cord. We then performed tract-based spatial statistics and tractography analyses of diffusion tensor images to assess microstructural integrity of white matter tracts. Disease severity was quantified with the Spastic Paraplegia Rating Scale. Correlations were then carried out between MRI metrics and clinical data. Volumetric analyses did not identify macroscopic abnormalities in the brain of hereditary spastic paraplegia patients. In contrast, we found extensive fractional anisotropy reduction in the corticospinal tracts, cingulate gyri and splenium of the corpus callosum. Spinal cord morphometry identified atrophy without flattening in the group of patients with hereditary spastic paraplegia. Fractional anisotropy of the corpus callosum and pyramidal tracts did correlate with disease severity. Hereditary spastic paraplegia is characterized by relative sparing of the cortical mantle and remarkable damage to the distal portions of the corticospinal tracts, extending into the spinal cord.

Dystonia in Machado-Joseph disease: Clinical profile, therapy and anatomical basis.

INTRODUCTION Dystonia is frequent in Machado-Joseph disease, but several important aspects are not yet defined, such as the detailed clinical profile, response to treatment and anatomical substrate. METHODS We screened 75 consecutive patients and identified those with dystonia. The Burke-Marsden-Fahn Dystonia Rating Scale was employed to quantify dystonia severity. Patients with dystonia received levodopa 600 mg/day for 2 months and were videotaped before and after treatment. A blinded evaluator rated dystonia in the videos. Patients with disabling dystonia who failed to respond to levodopa treatment received botulinum toxin. Finally, volumetric T1 and diffusion tensor imaging sequences were obtained in the dystonic group using a 3T-MRI scanner to identify areas of gray and white matter that were selectively damaged. RESULTS There were 21 patients with dystonia (28%): 9 classified as generalized and 12 as focal/segmental. Patients with dystonia had earlier onset and larger (CAG) expansions (28.9 ± 11.7 vs 40.6 ± 11.4; p < 0.001 and 75 vs 70; p < 0.001, respectively). Although group analyses failed to show benefit on levodopa (p = 0.07), some patients had objective improvement. In addition, ten patients received botulinum toxin resulting in a significant change in dystonia scores after 4 weeks (p = 0.03). Patients with dystonia had atrophy at pre- and paracentral cortices; whereas, non-dystonic patients had occipital atrophy. Basal ganglia volume was reduced in both groups, but atrophy at the thalami, cerebellar white matter and ventral diencephali was disproportionately higher in the dystonic group. CONCLUSION Dystonia in Machado-Joseph disease is frequent and often disabling, but may respond to levodopa. It is associated predominantly with structural abnormalities around the motor cortices and in the thalami.

Autoimmune neuropathies associated to rheumatic diseases

Systemic manifestations are frequent in autoimmune rheumatic diseases and include peripheral nervous system damage. Neuron cell body, axons and myelin sheath may all be affected in this context. This involvement results in severe and sometimes disabling symptoms. Sensory, motor and autonomic features may be present in different patterns that emerge as peculiar clinical pictures. Prompt recognition of these neuropathies is pivotal to guide treatment and reduce the risks of long term disability. In this review, we aim to describe the main immune-mediated neuropathies associated to rheumatic diseases: sensory neuronopathies, multiple mononeuropathies and chronic inflammatory demyelinating polyradiculoneuropathy, with an emphasis on clinical features and therapeutic options.

Neuroimaging in Sensory Neuronopathy

Sensory neuronopathies (SN) are a group of disorders characterized by primary damage to the dorsal root ganglia neurons. Clinical features include multifocal areas of hypoaesthesia, pain, dysautonomia, and sensory ataxia, which is the major source of disability. Diagnosis relies upon clinical assessment and nerve conductions studies, but sometimes it is difficult to distinguish SN from similar conditions, such as axonal polyneuropathies and some myelopathies. In this scenario, underdiagnosis is certainly an important issue for SN patients and additional diagnostic tools are needed. MRI is able to evaluate the dorsal columns of the spinal cord and has proven useful in the workup of SN patients. Although T2 weighted hyperintensity restricted to the posterior fasciculi without contrast enhancement is the typical finding, additional abnormalities have been recently reported. The aim of this review is to gather available information on neuroimaging findings of SN, discuss their clinical correlates and the potential impact of novel MRI‐based techniques.

Misdiagnosis of hemifacial spasm is a frequent event in the primary care setting

UNLABELLED Primary hemifacial spasm (HFS) is characterized by irregular and involuntary contraction of the muscles innervated by the ipsilateral facial nerve. Treatment controls symptoms and improves quality of life (QoL). OBJECTIVE Evaluate the initial diagnosis and treatment of HFS prior to referral to a tertiary center. METHOD We interviewed through a standard questionnaire 66 patients currently followed in our center. RESULTS Mean age: 64.19±11.6 years, mean age of symptoms onset: 51.9±12.5 years, male/female ratio of 1:3. None of the patients had a correct diagnosis in their primary care evaluation. Medication was prescribed to 56.8%. Mean time from symptom onset to botulinum toxin treatment: 4.34 ±7.1 years, with a 95% satisfaction. Thirty percent presented social embarrassment due to HFS. CONCLUSION Despite its relatively straightforward diagnosis, all patients had an incorrect diagnosis and treatment on their first evaluation. HFS brings social impairment and the delay in adequate treatment negatively impacts QoL.

Misdiagnosis Of Hemifacial Spasm Is A Frequent Event In The Primary Care Setting.

UNLABELLED Primary hemifacial spasm (HFS) is characterized by irregular and involuntary contraction of the muscles innervated by the ipsilateral facial nerve. Treatment controls symptoms and improves quality of life (QoL). OBJECTIVE Evaluate the initial diagnosis and treatment of HFS prior to referral to a tertiary center. METHOD We interviewed through a standard questionnaire 66 patients currently followed in our center. RESULTS Mean age: 64.19±11.6 years, mean age of symptoms onset: 51.9±12.5 years, male/female ratio of 1:3. None of the patients had a correct diagnosis in their primary care evaluation. Medication was prescribed to 56.8%. Mean time from symptom onset to botulinum toxin treatment: 4.34 ±7.1 years, with a 95% satisfaction. Thirty percent presented social embarrassment due to HFS. CONCLUSION Despite its relatively straightforward diagnosis, all patients had an incorrect diagnosis and treatment on their first evaluation. HFS brings social impairment and the delay in adequate treatment negatively impacts QoL.

A novel phenotype of ZIKV-related neurological disease: Sensory neuronopathy

Zika virus (ZIKV) infection has become a major health problem in Latin America in the past few years. Peripheral nervous system involvement is one of the major complications related to this arbovirus. This was particularly highlighted after the outbreaks of Guillain-Barre syndrome (GBS) in French Polynesia and Latin America soon after ZIKV epidemics. Most reported patients had a rather typical GBS presentation with rapidly ascending paralysis, diffuse areflexia, and facial diplegia. Recently, atypical phenotypes have been also reported, including Miller-Fisher syndrome (MFS) and small-fiber neuropathy. We now report a Brazilian patient with typical clinical and electrophysiological findings of a sensory neuronopathy (SN) that developed weeks after ZIKV infection. This description broadens the clinical profile of ZIKV-related neurological disease.

A new phenotype associated with homozygous GRN mutations: complicated spastic paraplegia.

Sirs, GRN heterozygous mutations are among the most common causes of autosomal dominant frontotemporal lobar degeneration (FTLD) [1]. In 2012, Smith et al. [2] described homozygous GRN mutations causing a novel type of progressive myoclonus epilepsy ceroid neuronal lipofuscinosis type 11 (CLN11). The key initial manifestations were early adulthood visual loss and generalized epilepsy. We report a patient with homozygous GRN mutations who had spastic paraplegia (SPG) as the first manifestation of disease. A 25-year-old female came for evaluation with a 4-year history of progressive gait impairment and urinary incontinence. Over the last year she had developed mood lability and delusional thoughts. Recently she had been experiencing photosensitive seizures which were preceded by visual aura. She had low scholar performance since early childhood. Consanguinity was suspected since her parents came from the same small village. Parents and brother were all reported to be healthy but unfortunately were unavailable for evaluation. During interview, family members reported that the proband’s father and mother are now in their 50s and deny significant cognitive or behavioral complaints (Fig. 1a). Neurological examination revealed high arched feet, appendicular ataxia, lower limb spasticity, widespread hyperreflexia and upgoing toes. Her gait was spastic, but she also presented widened base indicating concomitant axial ataxia. Magnetic resonance imaging revealed global and severe cerebellar atrophy (Fig. 1b). Serial electroencephalograms revealed a slow wave background activity and epileptiform discharges predominating in posterior regions during photostimulation. Epilepsy was controlled with lamotrigine 400 mg and no myoclonus was ever documented. During the following 2 years gait disturbance progressed and walking was only possible with bilateral support. Her husband mentioned inattention, word-finding difficulty as well as poor task completion and decision making. Frequent crying, suicidal thoughts and aggressive behavior were also evident during consultation. A MOCA test revealed severe cognitive impairment (3/30 points); only time orientation tasks were correctly answered. Ophthalmological investigation was not feasible due to poor cooperation. Considering a diagnosis of complicated SPG and due to the genetic heterogeneity of this group of disorders, we proceeded to wholeexome sequencing performed at the Illumina Hiseq 2500 platform. Variants not present at single-nucleotide polymorphism databases and fitting a recessive model were prioritized for further analysis. A homozygous c.767_768insCC mutation was identified at the GRN gene (Fig. 1c). This new variant is predicted to be pathogenic by in silico analysis (http://www.mutationtaster.org/). It disrupts the open reading frame and leads to premature termination of the transcript. This case highlights the pleiotropic effects of progranulin deficiency according to each specific genotype. Heterozygous individuals present with late-onset cognitive and behavioral deficits. In a homozygous state, an almost complete absence of progranulin results in a pleomorphic clinical picture (with predominant visual loss and/or epilepsy) beginning in the early 20s [3,4]. Progranulin plays a key role in neuronal survival and different neuronal populations present different vulnerabilities according to the degree of haploinsufficiency. Additionally, significant ethical challenges emerge from the diagnosis of an autosomal recessive disease in a scenario where more than one mode of inheritance is possible. Taking into account the high penetrance of GRN mutations (up to 97.3%), the patient’s first-degree relatives have a high likelihood of developing FTLD [5]. We acknowledge that the phenotypic spectrum associated with homozygous GRN mutations is wide and cerebellar ataxia is often a major finding. Despite that, the unique feature of our case is the gait disorder heralding disease onset. She indeed presented with a mixed gait disturbance (spasticity and ataxia) but spasticity certainly dominated the clinical picture. Homozygous GRN mutations may cause a spastic ataxia phenotype. This gene should be included in the differential diagnosis of complicated SPGs and ataxias, particularly when epilepsy or visual loss is present.