Identifying high-risk neurological phenotypes in adult-onset classic monogenic autoinflammatory diseases: when should neurologists consider testing?

BACKGROUND: Monogenic autoinflammatory disorders result in a diverse range of neurological symptoms in adults, often leading to diagnostic delays. Despite the significance of early detection for effective treatment, the neurological manifestations of these disorders remain inadequately recognized. METHODS: We conducted a systematic review searching Pubmed, Embase and Scopus for case reports and case series related to neurological manifestations in adult-onset monogenic autoinflammatory diseases. Selection criteria focused on the four most relevant adult-onset autoinflammatory diseases-deficiency of deaminase 2 (DADA2), tumor necrosis factor receptor associated periodic fever syndrome (TRAPS), cryopyrin associated periodic fever syndrome (CAPS), and familial mediterranean fever (FMF). We extracted clinical, laboratory and radiological features to propose the most common neurological phenotypes. RESULTS: From 276 records, 28 articles were included. The median patient age was 38, with neurological symptoms appearing after a median disease duration of 5 years. Headaches, cranial nerve dysfunction, seizures, and focal neurological deficits were prevalent. Predominant phenotypes included stroke for DADA2 patients, demyelinating lesions and meningitis for FMF, and meningitis for CAPS. TRAPS had insufficient data for adequate phenotype characterization. CONCLUSION: Neurologists should be proactive in diagnosing monogenic autoinflammatory diseases in young adults showcasing clinical and laboratory indications of inflammation, especially when symptoms align with recurrent or chronic meningitis, small vessel disease strokes, and demyelinating lesions.

Marked neuropsychiatric involvement and dysmorphic features in nemaline myopathy.

BACKGROUND: Inherited nemaline myopathy is one of the most common congenital myopathies. This genetically heterogeneous disease is defined by the presence of nemaline bodies in muscle biopsy. The phenotypic spectrum is wide and cognitive involvement has been reported, although not extensively evaluated. METHODS: We report two nemaline myopathy patients presenting pronounced central nervous system involvement leading to functional compromise and novel facial and skeletal dysmorphic findings, possibly expanding the disease phenotype. RESULTS: One patient had two likely pathogenic NEB variants, c.2943G > A and c.8889 + 1G > A, and presented cognitive impairment and dysmorphic features, and the other had one pathogenic variant in ACTA1, c.169G > C (p.Gly57Arg), presenting autism spectrum disorder and corpus callosum atrophy. Both patients had severe cognitive involvement despite milder motor dysfunction. CONCLUSION: We raise the need for further studies regarding the role of thin filament proteins in the central nervous system and for a systematic cognitive assessment of congenital myopathy patients.

Pompe disease misdiagnosed as polymyositis.

Late-onset Pompe disease manifests predominantly in the proximal lower limbs and may be mistaken for an inflammatory myopathy. A 46-year-old man with acromegaly had an 8-year history of progressive weakness. His myopathy was initially attributed to the acromegaly, but severe progression prompted a muscle biopsy, which suggested an inflammatory myopathy. However, his weakness progressed despite treatment for polymyositis. His muscle ultrasound scan pattern was more suggestive of Pompe disease than polymyositis, and Pompe disease was confirmed by genetic and enzymatic testing. Patients with apparent polymyositis, which persists despite treatment, require reconsideration of the diagnosis, with particular attention to treatable genetic causes.

Translation, Cross-Cultural Adaptation, and Validation to Brazilian Portuguese of the Cerebellar Cognitive Affective/Schmahmann Syndrome Scale.

Cerebellar cognitive affective syndrome (CCAS) is characterized by deficits in executive functions, language processing, spatial orientation, and affect regulation in patients with cerebellar disease. The symptoms can occur isolated or along with motor and coordination symptoms. The aim of our study was to translate and culturally adapt the CCAS scale to Brazilian Portuguese and validate the scale in our population. We performed a cross-sectional study with patients with primary and secondary ataxia. The study included 111 individuals, aged between 20 and 80 years, of both genders, 20 without cognitive and/or affective complaints who participated in the pre-test phase, 40 with cerebellar disease (hereditary/neurodegenerative ataxia or acquired/secondary cerebellar ataxia), and 51 healthy controls with no evidence of cognitive impairment and no affective symptoms matched for sex, age, and educational level. The scale was translated, culturally adapted, and validated. Statistical analysis of the data was performed, with association tests, mean comparison, and ROC curve analysis. Based on the analysis of the ROC curve, optimal cutoff values ​were found for each subitem of the scale. The translated and adapted scale has good internal consistency, is reproducible, has good reliability, and has the potential to be a reliable tool for screening cognitive symptoms in patients with cerebellar disease.

Nutritional status and eating habits of patients with hereditary ataxias: a case-control study.

INTRODUCTION: Hereditary Ataxias (HAs) comprise a wide spectrum of genetically determined neurodegenerative diseases with progressive ataxia as the main symptom. Few studies have evaluated nutritional profile in HA patients and most of these focused on specific ataxia subtypes. The objectives of this study were: (1) to investigate whether hereditary ataxias were associated with changes in energy expenditure, body composition and dietary intake; (2) to verify differences in these variables according to ataxia subtype, sex, age, and disease severity. METHODS: Thirty-eight hereditary ataxia patients from two neurology centers in Northeastern Brazil and 38 controls were evaluated. Body composition was assessed with bio-impedance analysis and dietary intake was estimated with a validated questionnaire (24-hour dietary recall). RESULTS: Mean body mass index (BMI) was lower in HA compared to controls (p = 0.032). Hereditary ataxia patients showed lower protein intake, higher frequency of dysphagia and higher incidence of nausea and diarrhea. The difference in average estimated caloric intake did not reach statistical significance (2359kcal ± 622 in patients × 2713kcal ± 804 in controls, p = 0.08). Disease severity measured by the SARA scale was not associated with BMI, nor was ataxia subtype (autosomal dominant × non-autosomal dominant ataxias). CONCLUSION: Hereditary ataxia patients have lower BMI compared to healthy controls. There was no difference in this cohort between dominant or non-dominant ataxia regarding BMI. Weight loss may be a common finding among hereditary ataxias and may affect the quality of life in these patients.

Persistent psychosis associated with extreme delta brush in anti-NMDA receptor encephalitis: a case report.

BACKGROUND: Anti-NMDAR encephalitis is an emerging differential diagnosis of first episode and persistent psychosis in the psychiatric community, as clinical manifestations include psychiatric symptoms, cognitive dysfunction, seizures, decreased consciousness, and dyskinesias. This disease is associated with extreme delta brush (EDB), but the significance and temporal course of this EEG pattern still needs to be determined. Herein, we report a case of anti-NMDAR encephalitis with persistent psychosis associated with EDB occurrence on multiple occasions during a 5-year disease course. CASE PRESENTATION: A 15-year-old girl was diagnosed with anti-NMDAR encephalitis and treated with progressive improvement. Four years after initial manifestations, an EDB pattern was seen on electroencephalogram (EEG) without new neurological symptoms. She had residual symptoms of episodic auditory hallucinations and impulsivity. One year later, the patient had a recurrence of neurological symptoms (seizures, dyskinesias and impaired attention), persisting with EDB on EEG. Clinical symptoms and EDB resolved after second-line treatment with rituximab. CONCLUSION: We describe the first case of persistent psychosis in anti-NMDAR encephalitis associated with extreme delta brush on multiple EEGs on prolonged follow-up. Electroencephalographic patterns such as EDB may serve as markers of residual disease activity, including psychiatric symptoms. Further studies with prolonged EEG monitoring are needed to better understand these findings.

New observations on minifascicular neuropathy with sex-dependent gonadal dysgenesis: a case series with nerve ultrasound assessment.

BACKGROUND: Gonadal dysgenesis with minifascicular neuropathy (GDMN) is a rare autosomal recessive condition associated with biallelic DHH pathogenic variants. In 46, XY individuals, this disorder is characterized by an association of minifascicular neuropathy (MFN) and gonadal dysgenesis, while in 46, XX subjects only the neuropathic phenotype is present. Very few patients with GDMN have been reported so far. We describe four patients with MFN due to a novel DHH likely pathogenic homozygous variant and the results of nerve ultrasound assessment. METHODS: This retrospective observational study included 4 individuals from 2 unrelated Brazilian families evaluated for severe peripheral neuropathy. Genetic diagnosis was performed with a peripheral neuropathy next-generation sequencing (NGS) panel based on whole exome sequencing focused analysis that included a control SRY probe to confirm genetic sex. Clinical characterization, nerve conduction velocity studies, and high-resolution ultrasound nerve evaluation were performed in all subjects. RESULTS: Molecular analysis disclosed in all subjects the homozygous DHH variant p.(Leu335Pro). Patients had a striking phenotype, with marked trophic changes of extremities, sensory ataxia, and distal anesthesia due to a sensory-motor demyelinating polyneuropathy. One 46, XY phenotypically female individual had gonadal dysgenesis. High-resolution nerve ultrasound showed typical minifascicular formation and increased nerve area in at least one of the nerves assessed in all patients. CONCLUSION: Gonadal dysgenesis with minifascicular neuropathy is a severe autosomal recessive neuropathy characterized by trophic alterations in limbs, sensory ataxia, and distal anesthesia. Nerve ultrasound studies are very suggestive of this condition and may help to avoid invasive nerve biopsies.

Aseptic meningitis in Fabry disease due to a novel GLA variant: an expanded phenotype?

BACKGROUND: F abry disease (FD) is an X-linked lysosomal storage disorder with accumulation of globotriosylceramide, causing neurologic involvement mainly as acroparesthesias and cerebrovascular disease. Aseptic meningitis has been reported in 11 patients with FD, but no prior study has correlated alpha-galactosidase (GLA) specific variants with meningitis. We present in this manuscript a family in which a novel GLA pathogenic variant was associated with aseptic meningitis in 2 of 5 family members. METHODS: This study began with identifying the proband, then screening family members for FD symptoms and evaluating symptomatic individuals for genetic and biochemical status. All patients underwent magnetic resonance imaging, and those with headache underwent cerebrospinal fluid (CSF) analysis. RESULTS: Five patients (3 females) from a single family were included in this study. Mean age at diagnosis was 20.6 years. Two patients (40%) had aseptic meningitis; one of them also had cerebrovascular events. C-reactive protein and erythrocyte sedimentation rate were elevated during aseptic meningitis episodes. Both patients responded to intravenous methylprednisolone with resolution of fever, headache, and vomiting. One of them recurred and needed chronic immunosuppression with azathioprine. CONCLUSION: We described aseptic meningitis in a family with a novel GLA variant. Meningitis might be a common phenomenon in FD and not a particularity of this variant. Understanding the mechanisms underlying meningitis and its association with cerebrovascular events may lead to a new paradigm of treatment for stroke in these patients. Further prospective studies with CSF collection in patients with FD and recurrent headache could help to elucidate this question.

Controversies in immunotherapy for anti-NMDA receptor encephalitis: a scoping review with a proposal of operational definitions.

Anti-NMDA receptor encephalitis (NMDARE), an autoimmune encephalitis associated with autoantibodies against the N-methyl-D-aspartate (NMDA) receptor, affects predominantly young women and is associated with psychiatric symptoms, seizures, movement disorders, and autonomic instability. Traditional treatments of anti-NMDA receptor encephalitis involve corticosteroids, intravenous immunoglobulin, plasmapheresis, cyclophosphamide, and rituximab. However, many controversies remain in the treatment for NMDA receptor encephalitis, such as optimal timing and combination of different immunotherapies, the role of newer strategies (e.g., bortezomib or tocilizumab) for severe and refractory patients, and the need or not for long-term immunosuppression. Our goal was to perform a scoping review to discuss the controversial topics of immunotherapy for NMDA receptor encephalitis and propose operational definitions to guide clinical practice and future research in the field.

Incidental magnetic resonance imaging findings leading to an unusual diagnosis: Adult onset Krabbe disease.

BACKGROUND AND PURPOSE: Krabbe disease (KD), or globoid cell leukodystrophy (Online Mendelian Inheritance in Man #245200), is an autosomal recessive lysosomal storage disease caused by mutations in GALC leading to galactocerebrosidase deficiency. Age at onset can vary from early infancy (3-6 months of age) to adulthood, which has rarely been reported. Little is known about the natural history and early manifestations of adult onset KD (AOKD). METHODS: Here, we report a patient with an incidental diagnosis of AOKD and discuss management options in this scenario. RESULTS: A 32-year-old woman came to medical attention because of headache and had brain magnetic resonance imaging findings compatible with AOKD, two pathogenic variants in GALC, and reduced activity of galactocerebrosidase. The jury is still out about the best management of such cases, and clinicians should be aware of this diagnosis, as AOKD is a potentially treatable condition. CONCLUSIONS: AOKD is a rare and potentially treatable condition. More studies on natural history of AOKD are urgently needed to guide the best management of this disease.

Central hypersomnia and chronic insomnia: expanding the spectrum of sleep disorders in long COVID syndrome - a prospective cohort study.

INTRODUCTION: Long-onset COVID syndrome has been described in patients with COVID-19 infection with persistence of symptoms or development of sequelae beyond 4 weeks after the onset of acute symptoms, a medium- and long-term consequence of COVID-19. This syndrome can affect up to 32% of affected individuals, with symptoms of fatigue, dyspnea, chest pain, cognitive disorders, insomnia, and psychiatric disorders. The present study aimed to characterize and evaluate the prevalence of sleep symptoms in patients with long COVID syndrome. METHODOLOGY: A total of 207 patients with post-COVID symptoms were evaluated through clinical evaluation with a neurologist and specific exams in the subgroup complaining of excessive sleepiness. RESULTS: Among 189 patients included in the long COVID sample, 48 (25.3%) had sleep-related symptoms. Insomnia was reported by 42 patients (22.2%), and excessive sleepiness (ES) was reported by 6 patients (3.17%). Four patients with ES were evaluated with polysomnography and test, multiple sleep latencies test, and actigraphic data. Two patients had a diagnosis of central hypersomnia, and one had narcolepsy. A history of steroid use was related to sleep complaints (insomnia and excessive sleepiness), whereas depression was related to excessive sleepiness. We observed a high prevalence of cognitive complaints in these patients. CONCLUSION: Complaints related to sleep, such as insomnia and excessive sleepiness, seem to be part of the clinical post-acute syndrome (long COVID syndrome), composing part of its clinical spectrum, relating to some clinical data.

Moyamoya associated with Turner syndrome in a patient with type 2 spinocerebellar ataxia-Occam's razor or Hickam's dictum: a case report.

BACKGROUND: Turner syndrome (TS) is a rare condition associated with a completely or partially missing X chromosome that affects 1 in 2500 girls. TS increases the risk of autoimmune diseases, including Graves' disease (GD). Moyamoya disease is a rare cerebral arteriopathy of unknown etiology characterized by progressive bilateral stenosis of the internal carotid artery and its branches. Both TS and GD have been associated with Moyamoya. Type 2 spinocerebellar ataxia (SCA2) is an autosomal dominant cerebellar ataxia caused by a CAG repeat expansion in ATXN2. We present the first case of Moyamoya syndrome in a patient with a previous diagnosis of TS and GD who tested positive for SCA2 and had imaging findings compatible with an overlap of SCA2 and Moyamoya. CASE PRESENTATION: A 43-year-old woman presented with mild gait imbalance for 2 years. Her family history was positive for type 2 spinocerebellar ataxia (SCA2). She had been diagnosed with Turner Syndrome (45,X) and Graves disease three years before. Brain MRI revealed bilateral frontal and parietal cystic encephalomalacia in watershed zones, atrophy of pons, middle cerebellar peduncles and cerebellum. MR angiography showed progressive stenosis of both internal carotid arteries with lenticulostriate collaterals, suggestive of Moya-Moya disease. Molecular analysis confirmed the diagnosis of SCA2. CONCLUSIONS: With increased availability of tools for genetic diagnosis, physicians need to be aware of the possibility of a single patient presenting two or more rare diseases. This report underscores the modern dilemmas created by increasingly accurate imaging techniques and available and extensive genetic testing.

Normal pressure hydrocephalus associated with COVID-19 infection: a case report.

BACKGROUND: COVID-19 is a pandemic disease responsible for many deaths worldwide. Many neurological manifestations have been described. We report a case of normal pressure hydrocephalus (NPH) 2 months after acute COVID19 infection, in a patient without other risk factors. CASE PRESENTATION: A 45-year-old male patient presented an 8-month history of progressive gait disorder and cognitive impairment after being hospitalized for SARS-CoV-2 infection. Magnetic resonance imaging (MRI) was compatible with NPH. A spinal tap test was positive and there was progressive improvement after shunting, with complete resolution of symptoms. CONCLUSION: Other infections such as syphilis, cryptococcosis and Lyme disease have been associated with NPH. Possible mechanisms for NPH after COVID include disruption of choroid plexus cells by direct viral invasion or as a result of neuroinflammation and cytokine release and hypercoagulability leading to venous congestion and abnormalities of CSF flow. Given the significance of NPH as a cause of reversible dementia, it is important to consider the possibility of a causal association with COVID19 and understand the mechanisms behind this association.

Myasthenia gravis exacerbation and myasthenic crisis associated with COVID-19: case series and literature review.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disorder of the neuromuscular junction that can be exacerbated by many viral infections, including COVID-19. The management of MG exacerbations is challenging in this scenario. We report 8 cases of MG exacerbation or myasthenic crisis associated with COVID-19 and discuss prognosis and treatment based on a literature review. RESULTS: Most patients were female (7/8), with an average age of 47.1 years. Treatment was immunoglobulin (IVIG) in 3 patients, plasma exchange (PLEX) in 2 patients, and adjustment of baseline drugs in 3. In-hospital mortality was 25% and 37.5% in 2-month follow-up. DISCUSSION: This is the largest case series of MG exacerbation or myasthenic crisis due to COVID-19 to this date. Mortality was considerably higher than in myasthenic crisis of other etiologies. Previous treatment for MG or acute exacerbation treatment did not seem to interfere with prognosis, although sample size was too small to draw definitive conclusions. Further studies are needed to understand the safety and effectiveness of interventions in this setting, particularly of PLEX, IVIG, rituximab, and tocilizumab.

Characteristics and management of Susac syndrome in an emergent country: a multi-center case series from Brazil.

BACKGROUND: Susac syndrome (SS) is a rare endotheliopathy with an estimated prevalence of 0.14-0.024 per 100,000. It is an important differential diagnosis in demyelinating disorders. There are few case series and no large randomized controlled trials, and most reports come from developed countries. We report six cases of SS in three centers in Brazil and discuss management challenges in emergent countries. METHODS: This is a retrospective case series of patients diagnosed with SS in three medical centers in Brazil between April 2018 and July 2021. The European Susac consortium (EuSaC) criteria were used for diagnosis of SS. Demographic data and clinical interventions were described and outcomes were assessed subjectively and by applying the modified Rankin Scale (mRS) on last follow-up. RESULTS: Six patients were diagnosed with SS (3 males, 3 females). Mean age at presentation was 36 years (range 17 to 54). The most common initial symptom was confusion, followed by visual impairment and hearing loss. Characteristic snowball lesions on magnetic resonance imaging (MRI) were present in four patients (66%). Retinal artery abnormalities were present in half (3/6) of patients, and sensorineural hearing loss was present in four patients (66%). Outcome was favorable (mRS ≤ 2) in five patients (86%). Patients treated early had a more favorable outcome. CONCLUSION: Emergent countries face challenges in the diagnosis and management of patients with SS, such as access to advanced tests (fluorescein angiography, serial MRI) and treatment drugs (rituximab, mycophenolate). Further research should consider particularities of patients with SS in emergent countries.

Myelopathy associated with intrathecal methotrexate.

A 21-year-old man developed progressive and bilateral lower limb numbness, gait impairment and urinary incontinence over 10 days. He had received intrathecal methotrexate 20 days previously for acute lymphoblastic B-cell leukaemia, following 7 months of systemic chemotherapy. MR scan of the spinal cord showed bilateral symmetric and extensive T2/fluid attenuated inversion recovery (FLAIR) increased signal involving the dorsal columns in the thoracic cord. His serum folate concentration was at the lower end of the normal range. We stopped the intrathecal chemotherapy and gave folate; after a few days, he progressively improved. Myelopathy is an important adverse effect of intrathecal methotrexate, which may cause clinical and imaging features resembling subacute combined degeneration of the spinal cord. CNS infiltration must be excluded, intrathecal chemotherapy stopped and deficiency of folate or vitamin B12 treated as appropriate.

Intracranial mass lesions and skin discoloration in the armpits as unusual clues to Erdheim-Chester disease: a case report.

BACKGROUND: Erdheim-Chester disease (ECD) is a non-Langerhans histiocytosis that results in multi-organ disease involving the skin, bones, lungs and kidneys. Central nervous system (CNS) involvement occurs in about 50 % of patients, and diabetes insipidus, visual disturbances, and cerebellar ataxia are the most frequent neurological signs. We report a case of Erdheim-Chester disease with central nervous system involvement in the form of enhancing intracranial mass lesions with massive edema. CASE PRESENTATION: The patient presented with vertigo, ataxia, encephalopathy and pyramidal signs. Diagnosis was suggested by xanthomatous skin lesions and a biopsy was compatible with Erdheim-Chester disease demonstrating xanthogranulomas CD68 positive (clone KP1) and CD1a and S100 negative. Testing for BRAF mutation was negative, which precluded treatment with Vemurafenib. Treatment with steroids and interferon resulted in improvement of neurological signs and regression of edema on MRI. CONCLUSIONS: The diagnosis of Erdheim-Chester disease should be considered in intracranial mass lesions. Xanthomatous skin lesions are a clue to the diagnosis.

Steroid responsive cavernous sinus syndrome due to Rosai-Dorfman disease: beyond Tolosa-Hunt syndrome - a case report.

BACKGROUND: The term "Tolosa-Hunt syndrome" (THS) has been used to refer to painful ophthalmoplegia associated with nonspecific inflammation of the cavernous sinus and many processes can result in a similar clinical picture, including infectious, inflammatory and neoplastic diseases. Rosai-Dorfman disease (RDD) is a lymphoproliferative disorder that rarely affects the central nervous system. We report a case of isolated CNS Rosai-Dorfman disease involving the cavernous sinus and presenting as "Tolosa-Hunt syndrome". CASE PRESENTATION: Our patient presented with horizontal diplopia due to impairment of cranial nerves III, IV and VI and a stabbing/throbbing headache predominantly in the left temporal and periorbitary regions. There was a nonspecific enlargement of the left cavernous sinus on MRI and the patient had a dramatic response to steroids. Biopsy of a frontal meningeal lesion was compatible with RDD. CONCLUSIONS: We highlight the importance of including Rosai-Dorfman disease as a differential diagnosis in cavernous sinus syndrome and demonstrate a satisfactory long-term response to steroid treatment in this disease.