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Carlo Alberto Pagni, born in La Spezia, Italy, on February 13, 1931, was an eminent and respected professor of neurosurgery and chairman of the neurosurgical clinic of the University of Turin from 1980 to 2003. He died on March 1, 2009. As a professor of neurology and neurological surgery he was renowned as an expert on vascular, tumor, and functional neurosurgery. Beyond the Italian Neurosurgical Society, he was the doyen of functional neurosurgery, specializing in motor cortex stimulation for the treatment of focal dystonia, Parkinson's disease, and postictal spasticity and pain. His home was his castle, and his family was fundamental to his life. He shared with his wife, Sandra, his passion for piano playing and for their remarkable library, and together with friends, he and his wife enjoyed dinners with fine food and Barolo wines. Listening to this Grand Seigneur talking about and explaining the music of, above all, Ludwig van Beethoven, and Richard Wagner, one felt he was emotionally just "music and mind". You can imagine this from his books on music, chess, and neuroscience. Indeed, he adored playing correspondence chess worldwide. A sportsman too, he loved hiking, mountaineering, skiing, swimming, and fishing. Nature was his source for slowing down, for regenerating, and for collecting his strength for new projects and new challenges. Friends will remember Dr. Pagni as a Grand Seigneur.
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PMID:Music and Mind: In Memoriam Professor Carlo Alberto Pagni, MD, PhD: February 13, 1931 -March 1, 2009. 2812 46

The intimate anatomical relationship of the facial nerve to the parotid parenchyma has a significant influence on the presenting signs and symptoms, diagnosis and treatment of parotid neoplasms. However, to our knowledge, hyperactivity of this nerve, presenting as facial spasm, has never been described as the presenting sign or symptom of a parotid malignancy. We report a case of carcinoma arising in a recurrent pleomorphic adenoma of the left parotid gland (i.e., carcinoma ex pleomorphic adenoma) that presented with hemifacial spasms. We outline the differential diagnosis of hemifacial spasm as well as a proposed pathophysiology. Facial paralysis, lymph node enlargement, skin involvement, and pain have all been associated with parotid malignancies. To date the development of facial spasm has not been reported with parotid malignancies. The most common etiologies for hemifacial spasm are vascular compression of the ipsilateral facial nerve at the cerebellopontine angle (termed primary or idiopathic) (62%), hereditary (2%), secondary to Bell's palsy or facial nerve injury (17%), and hemifacial spasm mimickers (psychogenic, tics, dystonia, myoclonus, myokymia, myorthythmia, and hemimasticatory spasm) (17%). Hemifacial spasm has not been reported in association with a malignant parotid tumor but must be considered in the differential diagnosis of this presenting symptom.
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PMID:Intermittent facial spasms as the presenting sign of a recurrent pleomorphic adenoma. 2824 88

Chorea-acanthocytosis (ChAc), a neurodegenerative disease, results from loss-of-function-mutations of the chorein-encoding gene VPS13A. Affected patients suffer from a progressive movement disorder including chorea, parkinsonism, dystonia, tongue protrusion, dysarthria, dysphagia, tongue and lip biting, gait impairment, progressive distal muscle wasting, weakness, epileptic seizures, cognitive impairment, and behavioral changes. Those pathologies may be paralleled by erythrocyte acanthocytosis. Chorein supports activation of phosphoinositide-3-kinase (PI3K)-p85-subunit with subsequent up-regulation of ras-related C3 botulinum toxin substrate 1 (Rac1) activity, p21 protein-activated kinase 1 (PAK1) phosphorylation, and activation of several tyrosine kinases. Chorein sensitive PI3K signaling further leads to stimulation of the serum and glucocorticoid inducible kinase SGK1, which in turn upregulates ORAI1, a Ca2+-channel accomplishing store operated Ca2+-entry (SOCE). The signaling participates in the regulation of cytoskeletal architecture on the one side and cell survival on the other. Compromised cytoskeletal architecture has been shown in chorein deficient erythrocytes, fibroblasts and endothelial cells. Impaired degranulation was observed in chorein deficient PC12 cells and in platelets from ChAc patients. Similarly, decreased ORAI1 expression and SOCE as well as compromised cell survival were seen in fibroblasts and neurons isolated from ChAc patients. ORAI1 expression, SOCE and cell survival can be restored by lithium treatment, an effect disrupted by pharmacological inhibition of SGK1 or ORAI1. Chorein, SGK1, ORAI1 and SOCE further confer survival of tumor cells. In conclusion, much has been learned about the function of chorein and the molecular pathophysiology of chorea-acanthocytosis. Most importantly, a treatment halting or delaying the clinical course of this devastating disease may become available. A controlled clinical study is warranted, in order to explore whether the in vitro observations indeed reflect the in vivo pathology of the disease.
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PMID:Neurons, Erythrocytes and Beyond -The Diverse Functions of Chorein. 2917 76

Movement disorders (MDs) are common in patients with autoimmune disorders affecting the central and peripheral nervous system. They may be observed in autoimmune disorders triggered by an infectious agent, such as streptococcus in Sydenham's chorea, or in basal ganglia encephalitis with antibodies against the dopamine-D2 receptors. In these patients chorea or dystonia are usually the most prominent hyperkinetic MDs. MDs are also observed in patients with diffuse or limbic encephalitis with antibodies directed against neuronal cell-surface antigens. Anti-NMDA receptor encephalitis is one of the most common and may present with a variety of MDs, including: chorea, stereotypies, dystonia and myorhythmia. The recognition of other abnormal motor phenomena such as "faciobrachial dystonic seizures" and neuromyotonia, observed in patients with LGI1 and Caspr-2 antibodies, is important because they may herald the onset of overt limbic encephalitis. Autoimmunity directed against the intracellular enzyme glutamic acid decarboxylase usually presents with MDs, most commonly stiff-person syndrome or cerebellar ataxia. Chorea may be observed in rheumatologic disorders such as systemic lupus erythematosus or antiphospholipid syndrome. Disorders with uncertain autoimmune mechanisms such as Hashimoto's encephalitis and idiopathic opsoclonus-myoclonus syndrome commonly present with tremor, myoclonus and ataxia. A rapid diagnosis of an autoimmune disorder, which typically presents with subacute onset, is critical as early therapeutic intervention improves long-term prognosis and may be life-saving. Treatment usually involves some form of immunotherapy and symptomatic therapy of the abnormal movements with dopamine depleters, dopamine receptor antagonists, or GABAergic drugs. Detection and removal of an underlying tumor is essential for optimal outcome.
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PMID:Autoimmune and paraneoplastic movement disorders: An update. 2940 2

Ataxia-oculomotor apraxia type 4 (AOA4) is a rare autosomal recessive neurologic disorder. The phenotype is characterized by ataxia, oculomotor apraxia, peripheral neuropathy and dystonia. AOA4 is caused by biallelic pathogenic variants in the PNKP gene encoding a polynucleotide kinase 3'-phosphatase with an important function in DNA-damage repair. By whole exome sequencing, we identified 2 variants within the PNKP gene in a 27-year-old German woman with a clinical AOA phenotype combined with a cerebellar pilocytic astrocytoma diagnosed at 23 years of age. One variant, a duplication in exon 14 resulting in the frameshift c.1253_1269dup p.(Thr424fs*49), has previously been described as pathogenic, for example, in cases of AOA4. The second variant, representing a nonsense mutation in exon 17, c.1545C>G p.(Tyr515*), has not yet been described and is predicted to cause a loss of the 7 C-terminal amino acids. This is the first description of AOA4 in a patient with central European descent. Furthermore, the occurrence of a pilocytic astrocytoma has not been described before in an AOA4 patient. Our data demonstrate compound heterozygous PNKP germline variants in a German patient with AOA4 and provide evidence for a possible link with tumor predisposition. Localization of the 2 variants in human PNKP NP_009185.2. NM_007254.3:c.1253_1269dup p.(Thr424fs*49) is predicted to cause a frameshift within the kinase domain, NM_007254.3:c.1545C>G p.(Tyr515*) is predicted to cause loss of 2 C-terminal amino acids of the kinase domain and 5 additional C-terminal amino acids.
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PMID:Rare compound heterozygous variants in PNKP identified by whole exome sequencing in a German patient with ataxia-oculomotor apraxia 4 and pilocytic astrocytoma. 2949 15

Paraneoplastic movement disorders are rare, autoimmune-mediated, nonmetastatic complications of malignant neoplasms. Common paraneoplastic movement disorders include paraneoplastic chorea, dystonia, cerebellar degeneration, different types of encephalitis, opsoclonus-myoclonus syndrome, stiff person syndrome, and neuromyotonia. Syndromes usually develop before tumor diagnosis, have subacute onset, and are associated with serum or cerebrospinal fluid antibodies. Two types of antibodies can be distinguished: antibodies against nuclear and cytoplasmic neuronal antigens (anti-Hu, anti-Ri, anti-Yo, anti-Ma, anti-CV2/CRMP5, anti-Gephrin, and anti-GABATRAP) and antibodies recently identified against cell surface and synaptic proteins (anti-NMDAR, anti-LGI1, and anti-Caspr2). These two types differ from each other in a few important aspects. Antibodies against cell surface and synaptic protein disrupt cell-surface antigens. Clinical symptoms are related to the disruption of antigens and potentially can be reversed by immunotherapy. The association between these antibodies and malignancy is much less consistent. On the other hand, antibodies against nuclear and cytoplasmic neuronal antigens seem to be not pathogenic; however, they most likely indicate a T-cell-mediated immune response against neurons. Due to T-cell-mediated neuronal loss, response to immunotherapy is generally disappointing. Early recognition of all these diseases is crucial because it may lead to the disclosure of occult cancer. This review is focused on paraneoplastic movement disorders with emphasis on clinical presentations, investigational findings, and therapeutic results.
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PMID:Paraneoplastic movement disorders. 2956 31

Autoimmune encephalitides, with an estimated incidence of 1.5 per million population per year, although described only 15 years ago, have already had a remarkable impact in neurology and paved the field to autoimmune neuropsychiatry. Many patients traditionally presented with aberrant behavior, especially of acute or subacute onset, and treated with anti-psychotic therapies, turn out to have a CNS autoimmune disease with pathogenic autoantibodies against synaptic antigens responding to immunotherapies. The review describes the clinical spectrum of these disorders, and the pathogenetic role of key autoantibodies directed against: a) cell surface synaptic antigens and receptors, including NMDAR, GABAa, GABAb, AMPA and glycine receptors; b) channels such as AQP4 water-permeable channel or voltage-gated potassium channels; c) proteins that stabilize voltage-gated potassium channel complex into the membrane, like the LGI1 and CASPR2; and d) enzymes that catalyze the formation of neurotransmitters such as Glutamic Acid Decarboxylase (GAD). These antibodies, effectively target excitatory or inhibitory synapses in the limbic system, basal ganglia or brainstem altering synaptic function and resulting in uncontrolled neurological excitability disorder clinically manifested with psychosis, agitation, behavioral alterations, depression, sleep disturbances, seizure-like phenomena, movement disorders such as ataxia, chorea and dystonia, memory changes or coma. Some of the identified triggering factors include: viruses, especially herpes simplex, accounting for the majority of relapses occurring after viral encephalitis, which respond to immunotherapy rather than antiviral agents; tumors especially teratoma, SCLC and thymomas; and biological cancer therapies (immune-check-point inhibitors). As anti-synaptic antibodies persist after viral infections or tumor removal, augmentation of autoreactive B cells which release autoantigens to draining lymph nodes, molecular mimicry and infection-induced bystander immune activation products play a role in autoimmunization process or perpetuating autoimmune neuroinflammation. The review stresses the importance of early detection, clinical recognition, proper antibody testing and early therapy initiation as these disorders, regardless of a known or not trigger, are potentially treatable responding to systemic immunotherapy with intravenous steroids, IVIg, rituximab or even bortezomid.
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PMID:The immunobiology of autoimmune encephalitides. 3161 Nov 42

Blepharospasm is a type of focal dystonia depicted by periodic and spontaneous closure of the orbicularis oculi and surrounding muscles. Typical secondary etiologies of blepharospasm may include ophthalmologic and structural brain lesions. In this article, we report a novel case of a patient with a biopsy-proven concurrent papillary carcinoma of the thyroid gland and adenoma of the parathyroid gland with blepharospasm as an exceptionally unique initial manifestation. This report showed that a diagnostic work-up for causes of blepharospasm may include a search for these neoplasm and surgical removal of these masses may offer significant symptomatic control of the focal dystonia.
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PMID:Blepharospasm as the presenting feature of papillary thyroid cancer and parathyroid adenoma. 3188 44

Background: This study's aim was to investigate a large cohort of dystonia patients for pathogenic and rare variants in the ATM gene, making use of a new, cost-efficient enrichment technology for NGS-based screening. Methods: Single molecule Molecular Inversion Probes (smMIPs) were used for targeted enrichment and sequencing of all protein coding exons and exon-intron boundaries of the ATM gene in 373 dystonia patients and six positive controls with known ATM variants. Additionally, a rare-variant association study was performed. Results: One patient (0.3%) was compound heterozygous and 21 others were carriers of variants of unknown significance (VUS) in the ATM gene. Although mutations in sporadic dystonia patients are not common, exclusion of pathogenic variants is crucial to recognize a potential tumor predisposition syndrome. SmMIPs produced similar results as routinely used NGS-based approaches. Conclusion: Our results underline the importance of implementing ATM in the routine genetic testing of dystonia patients and confirm the reliability of smMIPs and their usability for germline screenings in rare neurodegenerative conditions.
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PMID:Single Molecule Molecular Inversion Probes for High Throughput Germline Screenings in Dystonia. 3192 Sep 50

To investigate clinical features of leucine-rich glioma inactivated 1 protein (LGI1) antibody-associated autoimmune encephalitis (AE). The clinical data were collected and analyzed in nine patients with LGI1 AE. All nine patients (100%) presented acute/subacute onset, had seizures, cognitive impairment, mental/behavioral abnormalities, six had sleep disorders and seven showed hyponatremia. Seizures manifested in three types: faciobranchial dystonia seizure (FBDS) (44%), mesial temporal lobe epilepsy (MTLE)-like seizure (66%), and focal to bilateral tonic-clonic seizure (FBTCS) (77%). Six of nine cases (66%) showed abnormalities in brain MRI, among them four showed high T2/flair signal on unilateral/bilateral hippocampus, two showed high T1/T2 signal on unilateral basal ganglia. All nine patients (100%) showed abnormalities in EEG, among them 1 (11%) showed diffuse slow waves, 8 (88%) showed focal slow waves; 6 (66%) revealed interictal epileptic discharges; ictal EEG was recorded in five patients, two were FBDS, three were MTLE-like seizure.LGI1 antibodies in serum and cerebrospinal fluid were both positive. No signs of tumor were found in all patients. Eight of nine patients received immunotherapy and antiepileptic drug (AED) treatment, one only treated with AED without immunotherapy. Eight patients improved significantly with seizure-free after immunotherapy, only one still had FBDS after immunotherapy and AED treatment. In LGI1 AE hippocampus and basal ganglia were two main targets, the corresponding seizure type was MTLE-like seizure and FBDS respectively. Diagnosis depended on detection of LGI1 antibodies in CSF. The incidence of tumor was low. The effect of immunotherapy was good and AEDs should be considered as add-on symptomatic treatment.
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PMID:Clinical features of nine cases of leucine-rich glioma inactivated 1 protein antibody-associated encephalitis. 3223 1


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