Intention Tremor Research Articles

S2755 Subclinical Liver Involvement in Wilson's Disease

Introduction: Wilson’s disease is an autosomal recessive disorder resulting in defective cellular copper transport. End-organ damage due to copper accumulation in the liver and brain disease (hepatolenticular degeneration) is the most common clinical manifestation. Case Description/Methods: A 29 year old woman was evaluated at the emergency department for a suicidal gesture. During the initial evaluation, she admitted she did not want to kill herself but was rather seeking immediate help for issues that she felt had been unattended to. Her complaints included bilateral leg pain associated with muscle cramps, stiffness, weakness, symmetric resting and intentional tremors, ataxia and depressed mood evolving over the previous six months. The patient had been diagnosed with a variety of psychiatric disorders. The patient stated she had moved to Indiana shortly after Hurricane Maria and returned to PR at the onset of the present illness. No family history of neurologic or liver disease. The physical exam revealed an unaltered mental status, flat affect, facial grimacing, cogwheel rigidity of the upper extremities with mild muscle weakness, bradykinesia, dystonia, fasciculations, muscle wasting, choreoathetosis and a Parkinsonian gait. Hepatomegaly or stigmata of cirrhosis were not found. Initial laboratories were negative for anemia, thrombocytopenia, coagulopathy or hyperbilirubinemia, as was serology for Lyme disease, syphilis, hepatitis and HIV. Moreover, transaminases, inflammatory markers, ANA, ASMA, ammonia and aldolase levels were also all normal. Brain MRI suggested encephalopathy. CSF revealed no pleocytosis. The working diagnosis was encephalitis, possibly infectious or autoimmune, and the patient was initially treated with antibiotics & intravenous glucocorticoids. An elevated AFP was reported which led to an abdominal CT scan that revealed hepatomegaly with heterogeneous enhancement throughout the liver parenchyma and surface nodularity. Ophthalmology evaluation showed Kaysher-Fleischer rings. Low ceruloplasmin levels, high urine copper levels and liver biopsy were all confirmatory of Wilson’s disease, and the patient was treated with penicillamine. Discussion: This case report emphasizes the importance of ruling out organic disease before diagnosing a psychiatric illness. A young patient with neurological symptoms in the absence of evident liver disease at presentation should prompt evaluation for uncommon disorders such as Wilson’s disease.

S1552 A Rare Care of Pancreatic Neuroendocrine Tumor and Hyperammonemic Encephalopathy

Introduction: Hyperammonemic encephalopathy infrequently occurs as the presenting manifestation of a pancreatic neuroendocrine tumor (PNET) without associated hepatic failure. We present a rare case of a patient with neurologic decline requiring hospitalization who was diagnosed with a PNET and hyperammonemic encephalopathy without liver failure. Case Description/Methods: A 59-year-old male attorney with hypertension presented to his primary care physician with a bilateral intention tremor and 2 weeks later developed progressively worsening cognition. His medical history was otherwise unremarkable. Upon hospitalization, vital signs were normal. A neurologic exam showed 1/4 recall and impaired attention. Labs revealed an elevated ammonia (219 mg/dL) and total bilirubin of 5.9 mg/dL (indirect 4.1 mg/dL). His CBC, CMP, AST/ALT/Alkaline phosphatase, coagulation panel, heavy metal screen, B1, B6, B12, folate, HIV, TSH, RPR, Lyme, infectious evaluation (including COVID), and lumbar puncture were normal. A brain MRI showed nonspecific bilateral basal ganglia changes. A RUQ ultrasound showed a pancreatic mass. His mental status improved after 2 days of lactulose titrated to 3-4 soft bowel movements daily. A chest / abdominal / pelvic CT scan revealed an 11.3 cm heterogeneous pancreatic mass encasing the splenic artery and abutting greater than 50% of the superior mesenteric vein, without evidence of pulmonary or hepatic metastases. CA 19-9 was 13 U/mL. Ultrasound-guided biopsy revealed a well-differentiated neuroendocrine tumor (WHO Grade 2) positive for synaptophysin, Cam 5.2, Chromogranin A, Ki67 5%, and mitotic count < 2/5 mm 2. The patient underwent an open distal pancreatectomy and splenectomy;a liver nodule, positive for well-differentiated neuroendocrine cells, was found. 5/65 lymph nodes were positive for metastatic disease. Pathologic stage was T3N1M1a. A PET scan, done approximately a month after surgery, showed mild metabolic activity in the pancreatic body and multiple liver metastases not seen on CT scan. Currently, the patient is being followed by oncology and is receiving Lanreotide. Discussion: This case is unusual because the patient presented with encephalopathy without evidence of hepatic failure. It is postulated that the encephalopathy was the result of microvascular portosystemic shunting due to unrecognized hepatic metastases. This case study emphasizes the potential need for advanced imaging in patients with PNET and encephalopathy when initial studies suggest no evidence of hepatic failure.

Safety and Outcomes of Dentate Nucleus Deep Brain Stimulation for Cerebellar Ataxia.

Cerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn-Tolosa-Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients' global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 ± 3.6 versus 10.1 ± 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 ± 17.2 versus 22.2 ± 19.5; p = 0.039) as did patients' global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement.

Features of “ET plus” correlate with age and tremor duration: “ET plus” may be a disease stage rather than a subtype of essential tremor

BackgroundEssential tremor (ET) is characterized by considerable clinical heterogeneity. In 2018, the term “ET plus” was introduced to mark a potential stratification point for dividing ET into subtypes – ET vs ET plus (i.e., ET cases with neurological features other than action tremor). However, as ET progresses, patients often develop increasingly severe tremor, spread of tremor, tremor under different activation conditions, and other features. Given this situation, ET plus may represent a disease stage rather than a disease classification or subtype. In theory, if the defining characteristics of a disease subtype fluctuate with age or disease duration, it raises the distinct possibility the “subtype” is a disease stage. MethodsA cohort of 241 prospectively enrolled ET cases underwent a detailed motor and cognitive assessment in which the features of ET plus including cerebellar signs (intention tremor, tandem gait difficulty), rest tremor, dystonia, and cognitive performance were evaluated. We determined whether these features of ET plus correlated with action tremor duration and age. ResultsWe demonstrated that numerous ET plus features were significantly correlated with both age and action tremor duration (numerous p values < 0.05). The same relationships were observed in a series of sensitivity analyses. ConclusionWe observed that the component parts of ET plus are highly age- and stage-dependent. These features are yearly-changing features conditional on a demographic and disease stage variable. These data support the notion that ET plus may represent a disease stage rather than a distinct disease subtype or disease classification.

Multidimensional Assessment of Tremors in Patient with Multiple Sclerosis

Background: Tremors can result in negative consequences on physical, emotional, and cognitive status in patients with multiple sclerosis, which may affect patient satisfaction, clinical recovery, and hospital length of stay. Aim: This study aimed to assess multidimensional of tremors in patients with multiple sclerosis. Design: A descriptive exploratory design was utilized. Setting: Multiple Sclerosis Outpatient Clinic at Ain Shams University Hospitals/Egypt. Study subject: A purposive sample of one hundred and fifty patients checked in the previous mentioned setting. Tools of data collection: Two tools were used for data collection: An interviewing questionnaire, multidimensional assessment of tremors in patients with multiple sclerosis. Results: 54.66%of the studied patients had tremors in right upper extremities while, 40% had intentional tremors. In addition, there was positive correlations between tremors severity scale and age. There was correlation between tremors and self-care. There were positive correlations between self-care productivity activities. There was positive correlation between productivity activities, leisure activities and also there was positive correlation between leisure activities and other activities among the studied patients suffering from multiple sclerosis. Conclusion: Patients with multiple sclerosis experienced tremors related to the patient's related factors such as psychological factors, physical factors and personal habits related factors. Recommendations: Health education should be given to MS patients with tremors on how to improve their quality of life with more efforts to improve awareness of patients regarding the techniques that can relieve pain or stress.

A novel non-human primate model of Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a severe hypomyelinating disorder of the central nervous system (CNS) linked to mutations in the proteolipid protein-1 (PLP1) gene. Although there are multiple animal models of PMD, few of them fully mimic the human disease. Here, we report three spontaneous cases of male neonatal rhesus macaques with the clinical symptoms of hypomyelinating disease, including intention tremors, progressively worsening motor dysfunction, and nystagmus. These animals demonstrated a paucity of CNS myelination accompanied by reactive astrogliosis, and a lack of PLP1 expression throughout white matter. Genetic analysis revealed that these animals were related to one another and that their parents carried a rare, hemizygous missense variant in exon 5 of the PLP1 gene. These animals therefore represent the first reported non-human primate model of PMD, providing a novel and valuable opportunity for preclinical studies that aim to promote myelination in pediatric hypomyelinating diseases.

Cerebellar Oscillations in Familial and Sporadic Essential Tremor.

Enhanced cerebellar oscillations have recently been identified in essential tremor (ET) patients as a key pathophysiological change. Since ET is considered a heterogeneous group of diseases, we investigated whether cerebellar oscillations differ in ET subtypes (familial vs. sporadic). This study aims to determine cerebellar physiology in familial and sporadic ET. Using surface electroencephalogram, we studied cerebellar physiology in 40 ET cases (n = 22 familial and n = 18 sporadic) and 20 age-matched controls. Both familial and sporadic ET cases had an increase in the intensity of cerebellar oscillations when compared to controls. Interestingly, cerebellar oscillations correlated with tremor severity in familial ET but not in sporadic ET. Our study demonstrated that ET cases have enhanced cerebellar oscillations, and the different relationships between cerebellar oscillations and tremor severity in familial and sporadic ET suggest diverse cerebellar pathophysiology.

Deletion of the SELENOP gene leads to CNS atrophy with cerebellar ataxia in dogs.

We investigated a hereditary cerebellar ataxia in Belgian Shepherd dogs. Affected dogs developed uncoordinated movements and intention tremor at two weeks of age. The severity of clinical signs was highly variable. Histopathology demonstrated atrophy of the CNS, particularly in the cerebellum. Combined linkage and homozygosity mapping in a family with four affected puppies delineated a 52 Mb critical interval. The comparison of whole genome sequence data of one affected dog to 735 control genomes revealed a private homozygous structural variant in the critical interval, Chr4:66,946,539_66,963,863del17,325. This deletion includes the entire protein coding sequence of SELENOP and is predicted to result in complete absence of the encoded selenoprotein P required for selenium transport into the CNS. Genotypes at the deletion showed the expected co-segregation with the phenotype in the investigated family. Total selenium levels in the blood of homozygous mutant puppies of the investigated litter were reduced to about 30% of the value of a homozygous wildtype littermate. Genotyping >600 Belgian Shepherd dogs revealed an additional homozygous mutant dog. This dog also suffered from pronounced ataxia, but reached an age of 10 years. Selenop-/- knock-out mice were reported to develop ataxia, but their histopathological changes were less severe than in the investigated dogs. Our results demonstrate that deletion of the SELENOP gene in dogs cause a defect in selenium transport associated with CNS atrophy and cerebellar ataxia (CACA). The affected dogs represent a valuable spontaneous animal model to gain further insights into the pathophysiological consequences of CNS selenium deficiency.

Juvenile form of alexander disease caused by a previously undescribed mutation in the GFAP gene. a case report

Alexander disease is a form of leukoencephalopathy caused by mutations in the GFAP gene. There are three forms of the disease: infant, juvenile and adult. We present the clinical case of a patient born in 2004 (16 years old) with a debut of the disease at the age of 4 years with complex ticks. further neurological symptoms progressed and appeared atactic gait, intention tremor by performing coordination tests, muscle hypotension, decreased tendon reflexes, nasal voices, and behavior changes.Magnetic resonance imaging revealed changes in the white matter of both frontal lobes. An analysis was made of 59 genes of the panel “Leukodystrophy/leukoencephalopathy” by the method of mass parallel sequencing on the Ion S5. A mutation of the GFAP gene (Nm_002055), 4 exon c.758C&gt;A, p.ALA253Asp in a heterozygous state, not described in Human Gene mutation Database, was detected. The patient was confirmed to have a diagnosis of Alexander disease. According to tractography, a decrease in the number of fibers in the frontal lobes was found.The patient is currently receiving symptomatic treatment.

MRI findings in a young dog with gliomatosis cerebri.

A 3-year-old male entire boxer presented with a 3-week history of lethargy, hyporexia, hypersalivation, low-head carriage, pelvic limb tremors and intermittent vestibular ataxia. Neurological examination revealed kyphosis, wide-based stance, an alternating head tilt, left leaning, bilateral positional ventral strabismus and intermittent vertical nystagmus. Exacerbation of neurological signs and increased extensor tone in all limbs were noticed after dorsal extension of the neck. Neuroanatomical localisation was cerebellum and/or brainstem. Haematology, biochemistry and blood pressure were within normal limits. Serology for common infectious diseases was negative. MRI demonstrated non-enhancing mild T2W and FLAIR hyperintensity and swelling of the whole cerebellum with more marked hyperintensity on the ventrolateral left hemisphere/flocculus (Fig. 1A,B,C). Increased intracranial pressure was suspected based on rostral transtentorial and foramen magnum herniation, cervical syringomyelia and lateral ventricular dilation, and therefore cerebrospinal fluid was not collected. Thoracic and abdominal CT was unremarkable. Differential diagnoses included inflammation (meningoencephalitis of unknown origin [MUO]), protozoal cerebellitis) or neoplasia (glioma/gliomatosis cerebri, lymphoma). MUO was considered likely; immunosuppressive prednisolone and mycophenolate and prophylactic clindamycin were started. After mild improvement, signs were static for 5 months. Mycophenolate was discontinued at 3 months due to gastrointestinal signs; owner declined another chemotherapeutic and prednisolone was continued. Two months later, the dog deteriorated (intention tremors, ataxia, intermittent collapses), with cerebellar changes being static on repeat MRI (Fig. 1D,E,F). Intravenous cytarabine was tried without response. Owners elected euthanasia. Histopathology revealed a disseminated proliferation of presumed glial origin infiltrating the subpial region, molecular layer, nuclei and white matter of the cerebellum bilaterally, the cerebrum, medulla, midbrain, hippocampus and medial geniculate bodies, consistent with gliomatosis cerebri (type 1). This case demonstrates a rare pattern of gliomatosis cerebri predominantly affecting the cerebellum. There was little progression in the imaging changes over a 5-month period, with clinical stability upon treatment.

Symposium 2: Movement Disorders SY2.1. Evaluation of Tremor

Tremor is defined as an involuntary, rhythmic (regularly recurrent) and oscillatory (rotating around a central plane) movement of the body part. The evaluation of tremor should begin with careful history taking and a focused clinical examination on tremor phenomenology and associated neurological signs. The first step of the approach is to exclude tremor mimics such as myoclonus, clonus or other hyperkinetic movements. The second step is to carefully evaluate clinical features and establish whether the tremor is isolated or combined with other neurological problems and the predominant tremor is at rest or action. Tremor can be classified into syndromes depending on the characteristics (e.g. activation of tremor, distribution of tremor) and prominent additional signs. The common tremor syndromes during action are essential tremor, enhanced physiologic tremor, dystonic tremor, drug-induced tremor, cerebellar tremor, rubral tremor, and orthostatic tremor while the common tremor syndromes at rest are parkinsonian tremor. A detailed tremor history and neurological examination are usually enough for the clinical evaluation of tremor syndromes. However, the clinical presentations are sometimes complex and electrophysiologic investigations can be helpful in making the diagnosis of tremor subtypes. The basic neurophysiologic test is a multi-channel surface EMG combined with accelerometry to assess the distribution of tremor, tremor frequency, and amplitude during various types of activation of tremor, the effect of loading and distraction on tremor frequency and amplitude. The characteristics of central tremor syndromes are more stable tremor frequency and less influenced by loading compared to peripheral tremor syndromes. The peak tremor frequency can be overlapped among tremor subtypes but a unique tremor frequency can be found in some syndrome such as orthostatic tremor, cerebellar tremor and rubral tremor. The specific neurophysiologic procedures including distractibility and entrainment are sensitive and specific for functional tremors. Recently, more advanced neurophysiologic tests have emerged. There is a promising role of intermuscular coherence analysis in the differential diagnosis of tremor subtypes. Evaluation of tremor based on clinical and neurophysiological features are important, leading to the appropriate diagnosis and treatment.

P-MD011. Persistent cerebellar dysfunction post toluene sniffing

Introduction . Toluene toxicity from glue, paint thinners and petrol (gasoline) sniffing is being recognized globally for its neurotoxic effect. We describe 2 patients (siblings) with toluene induced encephalopathy at our centre. Both of them presented with cerebellar signs and had glue sniffing activities. Methods . A 24 years old gentleman presented with progressive hand tremor, unsteadiness with abnormal eye movement for 3 years duration. Patient was an active substance abuser and glue sniffer. On examination, he had an ataxic gait. He was dysarthric and had rotatory nystagmus in both eyes. He demonstrated past pointing, intention tremor with dysdiadochokinesia. The Romberg test was normal. He had normal tone, power, reflexes and sensory over all limbs. He had normal full blood count, renal function, liver function test, serum B12, red cell folate, T4, TSH, urine microscopy, HIV- 1 and 2, ANA, C-reactive protein, ESR, creatinine kinase and serum magnesium. MRI of the brain revealed symmetrical T2W/FLAIR hyperintense signals in substantia nigra of midbrain and surrounding the third ventricles. No enhancing brain parenchymal lesion. There was presence of cerebral and cerebellar atrophy. His sibling is a 22 years old gentleman with underlying bronchial asthma, active heroin chaser and glue sniffer presented with complex partial seizure with post-ictal drowsiness. He had ataxic gait, staccato speech, right upper limb past pointing, dysdiadochokinesia and bilateral eyes nystagmus. Romberg test is normal. Neurological examination revealed normal tone and reflexes, and full power of all extremities. His CT brain, cerebrospinal fluid analysis and other blood investigations were normal. He remained ataxic upon discharge but subsequently defaulted follow up. Conclusion . Chronic toluene exposures can affect central nervous system by causing demyelination and gliosis in cerebral and cerebellar white matter. This case series highlight the presence of persistent cerebellar signs post toluene abuse.

Relationships between motor scores and cognitive functioning in FMR1 female premutation X carriers indicate early involvement of cerebello-cerebral pathways

BackgroundSmaller expansions of CGG trinucleotide repeats in the FMR1 X-linked gene termed ‘premutation’ lead to a neurodegenerative disorder: Fragile X Associated Tremor/Ataxia Syndrome (FXTAS) in nearly half of aged carrier males, and 8–16% females. Core features include intention tremor, ataxia, and cognitive decline, and white matter lesions especially in cerebellar and periventricular locations. A ‘toxic’ role of elevated and expanded FMR1 mRNA has been linked to the pathogenesis of this disorder. The emerging issue concerns the trajectory of the neurodegenerative changes: is the pathogenetic effect confined to overt clinical manifestations? Here we explore the relationships between motor and cognitive scale scores in a sample of 57 asymptomatic adult female premutation carriers of broad age range.MethodsThree motor scale scores (ICARS-for tremor/ataxia, UPDRS-for parkinsonism, and Clinical Tremor) were related to 11 cognitive tests using Spearman’s rank correlations. Robust regression, applied in relationships between all phenotypic measures, and genetic molecular and demographic data, identified age and educational levels as common correlates of these measures, which were then incorporated as confounders in correlation analysis.ResultsCognitive tests demonstrating significant correlations with motor scores were those assessing non-verbal reasoning on Matrix Reasoning (p-values from 0.006 to 0.011), and sequencing and alteration on Trails-B (p-values from 0.008 to 0.001). Those showing significant correlations with two motor scores-ICARS and Clinical Tremor- were psychomotor speed on Symbol Digit Modalities (p-values from 0.014 to 0.02) and working memory on Digit Span Backwards (p-values from 0.024 to 0.011).ConclusionsSubtle motor impairments correlating with cognitive, particularly executive, deficits may occur in female premutation carriers not meeting diagnostic criteria for FXTAS. This pattern of cognitive deficits is consistent with those seen in other cerebellar disorders. Our results provide evidence that more than one category of clinical manifestation reflecting cerebellar changes – motor and cognitive - may be simultaneously affected by premutation carriage across a broad age range in asymptomatic carriers.

A state hospital survey of movement disorders including intention tremor

AimsIn a survey of movement disorders in patients in a State Hospital the finger-nose test was included because of increasing interest in the cerebellum in schizophrenia. It was expected that this would reflect the pathobiology of schizophrenia and be unrelated to the type of medication.BackgroundAbnormalities of movement and involuntary movements have gone from being considered part of schizophrenia to side-effects of medication to now demonstrably present in those who have never taken anti-psychotic medication. Soft neurological signs (SNS) are increased in schizophrenia, unrelated to medication, considered not to indicate brain localization, yet often include the finger-nose test which localizes to the cerebellum.MethodAll available patients in a State Hospital were examined for movement disorders. They were rated on the following scales: Abnormal Involuntary Movement Scale (AIMS) for Tardive Dyskinesia (TD), Simpson-Angus Neurological Rating Scale for Parkinsonism (SANRS), Barnes Akathisia Scale (BAS), a Dystonia scale and the finger-nose test.Result250 patients were included, 174 were examined or observed for movement disorder: 120 had no missing data, 54 refused part of the exam. Their mean age was 47, 62% male, 53% black, 26% Hispanic, 17% white.Medication: First Generation Antipsychotic (FGA) 35 (mean CPZ equivalent dose:1177mg), Second Generation Antipsychotic (SGA) 159 (734mg), both FGA and SGA 56 (1907mg), no antipsychotic 3; anticholinergic or amantidine: FGA 57%, SGA 16%, both FGA and SGA: 50%.Tardive Dyskinesia: all 23%, FGA 36%, SGA 25%, both 7%Parkinsonism: all 38%, FGA 43%, SGA 33%, both 34%Akathisia: all 3%, FGA 0%, SGA 4%, both 3%Pseudo-akathisia: FGA 11%, SGA 4%, both13%Dystonia: all 10%, FGA 13%, SGA 11%, both 8%Intention Tremor: all 16%, FGA 0%, SGA 21%, both 16%Half of those with Intention Tremor had Parkinsonism, a third had TD and a half were on anti-Parkinson medication.None of these differences were statistically significant at p = 0.05 though intention tremor did show a trend (p = 0.08). The difference between FGA and SGA only became significant when all movement disorders were added together with those on anticholinergics with no movement disorder.When compared with rates in similar State Hospitals in the 1970s tardive dyskinesia was now half the rate and Parkinsonism about the same.ConclusionOverall rates of movement disorder are not very different between FGA and SGA. The surprise was that intention tremor only occurred with SGAs. Why?

An Atypical Case of TSH-Secreting Pituitary Adenoma in a Patient Presenting With Low Libido and Insomnia

Background: TSH-secreting pituitary adenoma is an incredibly rare cause of hyperthyroidism. Most patients with TSHomas present with clinical hyperthyroidism, but some patients may have atypical signs. Here we present the case of a patient who had been suffering from low libido and insomnia who was found to have secondary hyperthyroidism from a TSH-secreting pituitary adenoma. Clinical Case: A 47-year-old man presented with complaints of progressive headache, fatigue, depression, insomnia, low libido and erectile dysfunction. After questioning, he noted the presence of intentional tremor for more than 5 years. He denied anxiety, palpitations, heat intolerance, hyper defecation, proximal muscle weakness, local compressive symptoms of the neck and ocular symptoms. Physical exam was notable for fine tremor and mild thyromegaly, but otherwise patient had no evidence of anxiety, exophthalmos, hyperreflexia or diaphoresis. The patient was found to have a normal free testosterone (46 pg/mL, n 30-140 pg/mL) but had an elevated TSH (6.302 IU/mL, n 0.4-5 IU/mL), elevated Free T4 (3.6 ng/dL, n 0.6-1.2 ng/dL) and an elevated T3 (422 ng/dL, n 73-178 ng/dL). Further lab work revealed elevated alpha-subunit (4.4 ng/mL, n <0.5 ng/mL) suggestive of TSH-secreting pituitary adenoma. Prolactin and IGF-1 levels were normal. Patient had an MRI pituitary which showed a 2.3 cm sellar mass abutting the optic chiasm without involvement of the cavernous sinus. Patient proceeded to trans-sphenoidal resection. Post-operatively, TSH had dropped from 6.534 to 0.002 IU/mL (n 0.4-5 IU/mL) and Free T4 had dropped from 3.1 to 0.5 ng/dL (n 0.6-1.2 ng/dL). Interestingly, immunohistochemical staining was negative for TSH but the specimen did show histologic features characteristic of TSH-producing adenoma including extensive stromal fibrosis and nuclear pleomorphism. Patient was seen in clinic post-operatively where he noted a dramatic improvement in his headache and insomnia. He did show signs of hypothyroidism including constipation and weight gain. Patient was started on levothyroxine 75 mcg PO daily. Conclusion: This demonstrates the case of a patient with a TSH-secreting pituitary adenoma who presented with minimal thyrotoxic symptoms despite elevated thyroid hormones. Patients with this condition may present with atypical symptoms, thus requiring clinicians to have a high index of suspicion for this rare tumor.

Haploinsufficiency of POU4F1 causes an ataxia syndrome with hypotonia and intention tremor

De novo, heterozygous, loss-of-function variants were identified in Pou domain, class 4, transcription factor 1 (POU4F1) via whole-exome sequencing in four independent probands presenting with ataxia, intention tremor, and hypotonia. POU4F1 is expressed in the developing nervous system, and mice homozygous for null alleles of Pou4f1 exhibit uncoordinated movements with newborns being unable to successfully right themselves to feed. Head magnetic resonance imaging of the four probands was reviewed and multiple abnormalities were noted, including significant cerebellar vermian atrophy and hypertrophic olivary degeneration in one proband. Transcriptional activation of the POU4F1 p.Gln306Arg protein was noted to be decreased when compared with wild type. These findings suggest that heterozygous, loss-of-function variants in POU4F1 are causative of a novel ataxia syndrome.

Toxic accumulation of copper and neuropsychiatric symptoms due to a familial tunisian compound heterozygous ATP7B missense mutation

IntroductionWilson disease (WD) is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B (ATPase copper-transporting beta), which transports copper out of cells. It is characterized by toxic accumulation of copper primarily in the liver and brain, leading to liver disorders and/or neuropsychiatric symptoms.ObjectivesHere, we report a Tunisian pedigree associated to familial ATP7B gene mutation.MethodsMedical genetic investigations, and molecular screening of ATP7B gene mutations were performed to a Tunisian three-generation pedigree with eight members having neuropsychiatric symptoms. Molecular genetic testing of the ATP7B 21 exons was carried out by direct sequencing.ResultsA compound heterozygote mutational status of ATP7B with 2 substitutions: p.H1069Q and p.D642H was found. The family originated from the city of Sfax (Tunisia) showed a pronounced amount of consanguinity and eight members affected by WD. All cases derived from consanguineous couples and harbored psychiatric disorders associated or not to neurologic symptoms. Diagnosis of WD was piloted first through the cases harbouring intention tremor in the upper limbs and ataxia associated with psychiatric symptoms.ConclusionsThe first missense mutation p.H1069Q - c.3207C&gt;A (CAC-CAA) (exon 14) is the most commonest mutation in WD associated with late onset neurological conditions in Europe (Natural variantiVAR_000758 dbSNP:rs76151636). The second missense mutation in exon 6 : p.D642H - c.1924G&gt;C (GAC-CAC) (Natural variantiVAR_000713 dbSNP:rs72552285) affects the domain affinity to copper or the folding structure in the cytoplasmic region and decreases the stability, leading to abnormal localization of the protein within cytoplasm and an impairment of protein function.DisclosureNo significant relationships.

Tremors

Tremor is the most common movement disorder and denotes a rhythmic and involuntary movement of one or several regions of the body. This review covers disease definition, essential tremor, enhanced physiologic tremor, parkinsonian tremor, dystonic tremor, orthostatic tremor, cerebellar tremor, Holmes tremor, neuropathic tremor, palatal tremor, drug-induced and toxic tremors, functional tremor, rare tremor syndromes, tremorlike conditions, and treatment of tremor. Figures show action tremor assessment, the central nervous system circuits of tremor, magnetic resonance imaging findings in specific tremor conditions, general management of tremor patients, an algorithm for the treatment of parkinsonian tremor, and an algorithm for the treatment of dystonic tremor and primary writing tremor. Tables list types of tremor according to the condition of activation, tremor conditions in newborns and during childhood, clinical features of the most common tremor syndromes, motor signs other than tremor and nonmotor features of essential tremor patients, Movement Disorder Society consensus criteria for the diagnosis of essential tremor, genetic and environmental causes of essential tremor, causes of enhanced physiologic tremor, drugs and toxins known to cause tremor, paroxysmal tremors, pseudorhythmic myoclonus in the differential diagnosis of tremor, and pharmacologic management of essential tremor. Key words: essential tremor, movement disorder, pathologic tremor, physiologic tremor, tremor This review contains 6 highly rendered figures, 7 videos, 11 tables, and 163 references.

Abnormal cerebellar function and tremor in a mouse model for non-manifesting partially penetrant dystonia type 6.

Loss-of-function mutations in the Thap1 gene cause partially penetrant dystonia type 6 (DYT6). Some non-manifesting DYT6 mutation carriers have tremor andabnormal cerebello-thalamo-cortical signalling. We show that Thap1 heterozygote mice have action tremor, a reduction in cerebellar neuron number, andabnormal electrophysiological signals in the remaining neurons. These results underscore the importance of Thap1 levels for cerebellar function. These results uncover how cerebellar abnormalities contribute to different dystonia-associated motor symptoms. Loss-of-function mutations in the Thanatos-associated domain-containing apoptosis-associated protein 1 (THAP1) gene cause partially penetrant autosomal dominant dystonia type 6 (DYT6). However, the neural abnormalities that promote the resultant motor dysfunctions remain elusive. Studies in humans show that some non-manifesting DYT6 carriers have altered cerebello-thalamo-cortical function with subtle but reproducible tremor. Here, we uncover that Thap1 heterozygote mice have action tremor that rises above normal baseline values even though they do not exhibit overt dystonia-like twisting behaviour. At the neural circuit level, we show using in vivo recordings in awake Thap1+/- mice that Purkinje cells have abnormal firing patterns and that cerebellar nuclei neurons, which connect the cerebellum to the thalamus, fire at a lower frequency. Although the Thap1+/- mice have fewer Purkinje cells and cerebellar nuclei neurons, the number of long-range excitatory outflow projection neurons is unaltered. The preservation of interregional connectivity suggests that abnormal neural function rather than neuron loss instigates the network dysfunction and the tremor in Thap1+/- mice. Accordingly, we report an inverse correlation between the average firing rate of cerebellar nuclei neurons and tremor power. Our data show that cerebellar circuitry is vulnerable to Thap1 mutations and that cerebellar dysfunction may be a primary cause of tremor in non-manifesting DYT6 carriers and a trigger for the abnormal postures in manifesting patients.

Expanding the Spectrum of EEG Periodic Discharges in Subacute Sclerosing Panencephalitis: A Case Report

Abstract Background Atypical electroencephalogram (EEG) abnormalities emerge in patients with subacute sclerosing panencephalitis (SSPE), especially in cases with an atypical clinical presentation that can lead to diagnostic difficulties. Case Report In this article, we presented a case of SSPE with an atypical onset with epileptic seizures and Parkinson's features. The neurological examination during the initial evaluation of the patient showed extrapyramidal syndrome, hyperreflexia, intention tremor, and dysmetria. Cranial magnetic resonance imaging was normal. Video EEGs were performed in wakefulness and sleep. In wakefulness, multiple brief seizures (1–1.5 seconds were recorded, consisting of gradual bending of the body forward and to the right that lacked the sudden characteristic of myoclonia. During those episodes, we recorded generalized epileptiform activity of 4 or 5 sharp waves, with higher amplitude in the anterior regions, in some of the paroxysms superimposed on a slow wave or followed by a high amplitude slow wave. The paroxysms appeared periodically every 15 to 30 seconds. However, 2 months later, the EEG showed typical periodic generalized activity of biphasic/triphasic slow waves (Radermecker complexes), accompanied by myoclonias. Conclusion We reported a peculiar EEG pattern in a patient with SSPE that consists of periodic generalized activity of sharp waves. Atypical EEG patterns can appear when the disease progresses, but initially too, before typical periodic complexes and can complicate the diagnostic process.