Dystonia and Parkinsonism in COA7-related disorders: expanding the phenotypic spectrum.

BACKGROUND AND OBJECTIVE: Biallelic mutations in the COA7 gene have been associated with spinocerebellar ataxia with axonal neuropathy type 3 (SCAN3), and a notable clinical diversity has been observed. We aim to identify the genetic and phenotypic spectrum of COA7-related disorders. METHODS: We conducted comprehensive genetic analyses on the COA7 gene within a large group of Japanese patients clinically diagnosed with inherited peripheral neuropathy or cerebellar ataxia. RESULTS: In addition to our original report, which involved four patients until 2018, we identified biallelic variants of the COA7 gene in another three unrelated patients, and the variants were c.17A > G (p.D6G), c.115C > T (p.R39W), and c.449G > A (p.C150Y; novel). Patient 1 presented with an infantile-onset generalized dystonia without cerebellar ataxia. Despite experiencing an initial transient positive response to levodopa and deep brain stimulation, he became bedridden by the age of 19. Patient 2 presented with cerebellar ataxia, neuropathy, as well as parkinsonism, and showed a slight improvement upon levodopa administration. Dopamine transporter SPECT showed decreased uptake in the bilateral putamen in both patients. Patient 3 exhibited severe muscle weakness, respiratory failure, and feeding difficulties. A haplotype analysis of the mutation hotspot in Japan, c.17A > G (p.D6G), uncovered a common haplotype block. CONCLUSION: COA7-related disorders typically encompass a spectrum of conditions characterized by a variety of major (cerebellar ataxia and axonal polyneuropathy) and minor (leukoencephalopathy, dystonia, and parkinsonism) symptoms, but may also display a dystonia-predominant phenotype. We propose that COA7 should be considered as a new causative gene for infancy-onset generalized dystonia, and COA7 gene screening is recommended for patients with unexplained dysfunctions of the central and peripheral nervous systems.

Mimic of transient ischemic attack by anemia-induced asterixis: A novel differential diagnosis of stroke with critical pitfalls.

As most cases of asterixis with metabolic causes are asymptomatic, they have not been considered in the differential diagnosis of stroke. However, an asterixis occasionally resembles a transient ischemic attack (TIA). On the other hand, reports have indicated that anemia is an independent risk factor for brain ischemia. Therefore, both asterixis and anemia are important considerations for stroke diagnosis. A 79-year-old man with frequent leg palsy was initially diagnosed with recurrent TIA at the anterior cerebral artery (ACA) with a tiny callosal infarction and aspirin was prescribed immediately. However, subsequent careful physical examination revealed asterixis at both the wrist and knee joints. Laboratory testing and colonoscopy revealed severe anemia secondary to colon cancer. Blood transfusion immediately improved the asterixis and gait, thus confirming that anemia contributed to the patient's symptoms. This novel etiology of asterixis may be accompanied by misleading anemia-induced brain ischemic lesions detectable on magnetic resonance imaging (MRI). Anemia-induced asterixis should be considered as a novel differential diagnosis of a stroke to avoid pitfalls leading to unnecessary stroke treatment for patients with anemia.

Primary degeneration of oculomotor, motor, and somatosensory systems and auditory and visual pathways in spinocerebellar ataxia type 7: A clinicopathological study in a Japanese autopsy case.

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disorder characterized by progressive cerebellar ataxia associated with retinal degeneration. The disease is rare in Japan, and this is the first full description of clinicopathological findings in a Japanese autopsy case of genetically confirmed SCA7 having 49 cytosine-adenine-guanine (CAG) trinucleotide repeats in the ataxin 7 gene. A 34-year-old Japanese man with no family history of clinically apparent neurodegenerative diseases presented with gait disturbance, gradually followed by truncal instability with progressive visual loss by the age of 42 years. He became wheelchair-dependent by 51 years old, neurologically exhibiting cerebellar ataxia, slow eye movement, slurred and scanning speech, lower limb spasticity, hyperreflexia, action-related slowly torsional dystonic movements in the trunk and limbs, diminished vibratory sensation in the lower limbs, auditory impairment, and macular degeneration. Brain magnetic resonance imaging revealed atrophy of the brainstem and cerebellum. He died of pneumonia at age 60 with a 26-year clinical duration of disease. Postmortem neuropathological examination revealed pronounced atrophy of the spinal cord, brainstem, cerebellum, external globus pallidus (GP), and subthalamic nucleus, microscopically showing neuronal cell loss and fibrillary astrogliosis with polyglutamine-immunoreactive neuronal nuclei and/or neuronal nuclear inclusions (NNIs). Degeneration was also accentuated in the oculomotor system, auditory and visual pathways, upper and lower motor neurons, and somatosensory system, including the spinal dorsal root ganglia. There was a weak negative correlation between the frequency of nuclear polyglutamine-positive neurons and the extent of neuronal cell loss. Clinicopathological features in the present case suggest that neurological symptoms, such as oculomotor, auditory, visual, and sensory impairments, are attributable to degeneration in their respective projection systems affected by SCA7 pathomechanisms and that dystonic movement is related to more significant degeneration in the external than internal GP.

Case Report: Anti-mGluR5 antibody-negative Ophelia syndrome with failed lymph node biopsy due to steroid therapy.

Ophelia syndrome is paraneoplastic limbic encephalitis (PLE) with Hodgkin lymphoma. Some Ophelia syndrome patients have been reported as testing positive for anti-metabotropic glutamate receptor 5 (mGluR5) antibodies. However, we experienced a case of anti-mGluR5 antibody-negative Ophelia syndrome. The type of onset, neurological symptoms, and imaging as well as electroencephalographic findings were like previous reports except for a normal cell count in cerebrospinal fluid (CSF). Unfortunately, a lymph node biopsy failed and could not diagnose the patient before death because steroid treatment for limbic encephalitis had shrunk lymph nodes. We believe it is essential to accumulate cases of this syndrome and clarify the association between PLE and Hodgkin lymphoma so chemotherapy can be initiated even if malignant lymphoma cannot be pathologically proven or when antibodies cannot be measured or are negative.

Focal brain lactate accumulation in metformin-induced encephalopathy without systemic lactic acidosis: A case report suggesting mitochondrial vulnerability in lentiform fork sign.

Metformin causes metabolic encephalopathy in some patients with end-stage chronic kidney disease, resulting in impaired consciousness and parkinsonism. This encephalopathy has a very characteristic magnetic resonance imaging feature in lentiform nuclei known as the "lentiform fork sign". However, the mechanism is unknown. Here, we report a case of metformin-induced encephalopathy with a novel observation of lactate accumulation in the lentiform nuclei on magnetic resonance spectroscopy without systemic lactic acidosis. Since metformin is an inhibitor of mitochondrial complex-I, this focal brain lactate accumulation implies that a part of the pathogenesis of metformin-induced encephalopathy is the focal vulnerability of mitochondria to metformin in the lentiform nuclei. When metformin causes encephalopathy, not only testing for serum lactic acidosis and performing routine magnetic resonance imaging but also evaluation of brain lactate accumulation by magnetic resonance spectroscopy should be required to elucidate the etiology.

Distressing Belching with Chorea Induced by Caudate Infarction.

Although belching is mostly associated with gastrointestinal disorders, it occasionally accompanies movement disorders such as Parkinsonism or dystonia. A woman in her 80s presented distressing belching and chorea of the right arm and leg from 3 years earlier. A brain MRI showed a left caudate infarction and atrophic change. Haloperidol significantly improved belching and chorea. Caudate infarction can cause distressing belching with chorea. It might be important to select the appropriate drug by referring to the accompanying involuntary movement to treat belching with movement disorders.

Tic Movement of Thyroid Cartilage as a Cause for Localized Cerebral Embolism: Mimics of Embolic Stroke of Undetermined Source with Non-Stenotic Carotid Plaque.

Several studies have suggested that non-stenotic carotid plaque was a risk factor for embolic stroke of undetermined source in some patients. However, individual backgrounds of these patients is unclear. We encountered a 64-years-old female with cerebral emboli, from an apparently stable non-stenotic carotid plaque (only 1.42mm thick) at the distal left common carotid artery, caused by violent tic movement of thyroid cartilage under well controlled dyslipidemia. Even though the plaque appeared thin and stable, mechanical stimulation could cause multiple, unnaturally localized emboli by stimulation-induced atherogenesis and plaque rupture, resulting in a misdiagnose of embolic stroke of undetermined source with non-stenotic carotid plaque.

Hidden relationship between fingolimod and bleeding: Possible novel management of fingolimod-associated lymphopenia.

Fingolimod, a functional antagonist of sphingosine-1 phosphate receptor, is a disease modifying drug of multiple sclerosis and its remarkable adverse effect is peripheral lymphopenia because the drug retains lymphocyte in the secondary lymphoid tissues. Therefore, in theory, when severe bleedings occurred, the fingolimod-treated patients could not compensate for the loss of lymphocytes induced by bleedings because of the retention in the secondary lymphoid tissues. In addition, because most of the fingolimod is reported to be distributed in the erythrocytes, and the erythrocytes are the main regulator of serum sphingosine-1 phosphate concentration, bleeding may also affect metabolism of fingolimod and prognosis of multiple sclerosis. However, no study had focused the relationship between fingolimod and bleedings in multiple sclerosis. We encountered the first case in which fingolimod-associated lymphopenia worsened synchronously with gynecological bleeding, and was improved by the bleeding prophylaxis, uterine myomectomy. This case had statistically significant positive correlation between the serum hemoglobin level and peripheral lymphocyte count (P = 0.0000000507). We then had three similar cases. In these 4 correlative patients out of the 14 fingolimod-treated patients in our institution, the importance of the bleeding in fingolimod-treated patients was indicated by line graphs, point diagrams, and statistically significant correlation coefficients. Bleeding should be focused on by all of physicians treating multiple sclerosis with fingolimod.

Guillain-Barré Syndrome and Posterior Reversible Encephalopathy Syndrome following Spinal Surgery.

Guillain-Barré syndrome (GBS) typically occurs after gastroenteritis and respiratory tract infection, but surgery has also been considered one of the triggers. Posterior reversible encephalopathy syndrome (PRES) is a rare complication of GBS. A normotensive female in her 70s presented ascending paralysis and frontal-parieto-occipital subcortical lesions with intermittent hypertension after spinal surgery. Nerve conduction studies revealed demyelinating polyneuropathy. The patient's brain lesions disappeared with amelioration of hypertension. She was diagnosed with the demyelinating form of GBS and PRES caused by intermittent hypertension. Intravenous immunoglobulin G (IVIG) improved her symptoms without exacerbation of the PRES. Surgery can be a trigger of GBS, and GBS can cause PRES by hypertension and present as central nervous lesions. It is important to treat hypertension before using IVIG when PRES is suspected as a complication of GBS, since the encephalopathy can be exacerbated by IVIG. There may be more undiagnosed cases of the coexistence of GBS and PRES after surgery because surgery itself can also cause PRES. Proper control of blood pressure and confirmation of negative central nervous lesions are required to treat GBS patients with IVIG safely.

Guillain-Barré syndrome in a cancer patient treated with bevacizumab.

We describe a case of Guillain-Barré syndrome (GBS) in a patient treated with bevacizumab. Our case is a 60-year-old woman with Stewart-Treves syndrome (STS), and angiosarcoma of her left forearm, with onset 12 years after diagnosis with stage IIIA left breast cancer. She suffered from repeated distal metastases including skin, bone, and liver metastases. She underwent numerous treatments including left arm amputation, radiation, and chemotherapy, but her disease was resistant. Thereafter, she received bevacizumab. Two weeks following the first administration, she presented in poor physical condition. Although the cause was not specified at that time, bevacizumab was discontinued. At 1 month following first bevacizumab administration, she gradually developed dyspnea, and numbness in her tongue and hands. Soon after, she was emergently admitted to the hospital due to hyperventilation syndrome. On hospital day 4, she developed quadriparesis, and on hospital day 8, she was diagnosed with GBS following neurological testing. Treatment with intravenous immunoglobulins was started immediately upon diagnosis, and her neurological symptoms eventually resolved. A repeat challenge course of bevacizumab was avoided. Five months later, the patient perished from STS progression. GBS associated with malignancies and/or chemotherapies has been rarely described in patients with malignant lymphomas. Of note, there is only one reported case of GBS with bevacizumab. Furthermore, in some cases, GBS is lethal, and it should be considered in the differential diagnosis of patients treated with bevacizumab.

Parkinsonism Improved With Levodopa After Endoscopic Third Ventriculostomy in Shunted Hydrocephalus Due to Aqueductal Stenosis.

INTRODUCTION: Levodopa-responsive parkinsonism has been reported following ventriculoperitoneal (VP) shunt in patients with obstructive hydrocephalus due to aqueductal stenosis. It has been thought to arise from injury to the global rostral midbrain including the nigrostriatal pathway by a transtentorial pressure gradient. We present a similar patient, but his parkinsonism resisted levodopa administration during the initial therapy. CASE REPORT: A 51-year-old man suffered from hydrocephalus due to secondary aqueductal stenosis presumably attributed to massive bleeding during surgery for a fourth ventricle hemangioblastoma. After resolution of the hydrocephalus with VP shunt, he developed severe parkinsonism, Parinaud syndrome, and hyperreflexia, suggesting global rostral midbrain dysfunction, but high-dosage levodopa therapy was not effective. An inverted transtentorial pressure gradient suggested by his unilateral slit-like ventricle was assumed to be the cause of the levodopa resistance. Also based on an assumption that the absorption of cerebrospinal fluid was impaired due to the intraoperative bleeding, a lumbar peritoneal shunt was added to the preexisting VP shunt, but it failed to control the ventricular size. Instead, endoscopic third ventriculostomy stabilized it, characteristically inducing levodopa responsiveness in our patient. An increase of the levodopa dosage led to clinical improvement, which needed a maintenance dosage because of dependency. CONCLUSION: The details of this patient suggest that a transtentorial pressure gradient may have impaired more distal basal ganglia connections over a global rostral midbrain including the nigrostriatal pathway, and that aggressive levodopa therapy after endoscopic third ventriculostomy can be effective for refractory parkinsonism.

Clinicopathological features of neuropathy associated with lymphoma.

Lymphoma causes various neurological manifestations that might affect any part of the nervous system and occur at any stage of the disease. The peripheral nervous system is one of the major constituents of the neurological involvement of lymphoma. In this study we characterized the clinical, electrophysiological and histopathological features of 32 patients with neuropathy associated with non-Hodgkin's lymphoma that were unrelated to complications resulting from treatment for lymphoma. Nine patients had pathologically-proven neurolymphomatosis with direct invasion of lymphoma cells into the peripheral nervous system. These patients showed lymphomatous cell invasion that was more prominent in the proximal portions of the nerve trunk and that induced demyelination without macrophage invasion and subsequent axonal degeneration in the portion distal from the demyelination site. Six other patients were also considered to have neurolymphomatosis because these patients showed positive signals along the peripheral nerve on fluorodeoxyglucose positron emission tomography imaging. Spontaneous pain can significantly disrupt daily activities, as frequently reported in patients diagnosed with neurolymphomatosis. In contrast, five patients were considered to have paraneoplastic neuropathy because primary peripheral nerve lesions were observed without the invasion of lymphomatous cells, with three patients showing features compatible with chronic inflammatory demyelinating polyneuropathy, one patient showing sensory ganglionopathy, and one patient showing vasculitic neuropathy. Of the other 12 patients, 10 presented with multiple mononeuropathies. These patients showed clinical and electrophysiological features similar to those of neurolymphomatosis rather than paraneoplastic neuropathy. Electrophysiological findings suggestive of demyelination were frequently observed, even in patients with neurolymphomatosis. Eleven of the 32 patients, including five patients with neurolymphomatosis, fulfilled the European Federation of Neurological Societies/Peripheral Nerve Society electrodiagnostic criteria of definite chronic inflammatory demyelinating polyneuropathy. Some of these patients, even those with neurolymphomatosis, responded initially to immunomodulatory treatments, including the administration of intravenous immunoglobulin and steroids. Patients with lymphoma exhibit various neuropathic patterns, but neurolymphomatosis is the major cause of neuropathy. Misdiagnoses of neurolymphomatosis as chronic inflammatory demyelinating polyneuropathy are frequent due to a presence of a demyelinating pattern and the initial response to immunomodulatory treatments. The possibility of the concomitance of lymphoma should be considered in various types of neuropathy, even if the diagnostic criteria of chronic inflammatory demyelinating polyneuropathy are met, particularly in patients complaining of pain.

Tolosa-hunt syndrome associated with cytomegalovirus infection.

We herein present the case of a 38-year-old woman with left-sided oculomotor paralysis with ocular pain that developed after a respiratory infection. Her serum was positive for IgM against GM2 and GalNAc-GD1a gangliosides and cytomegalovirus. Thin-slice magnetic resonance imaging revealed enhanced abnormal tissue located primarily in the superolateral part of the left-sided cavernous sinus, which corticosteroids subsequently obscured with immediate resolution of the patient's ocular symptoms. These clinical features were consistent with those of Tolosa-Hunt syndrome (THS). Our findings in the present patient suggest that cytomegalovirus may provoke granuloma formation in the cavernous sinus, as reported in other various organs, thereby leading to the development of THS.

Long-term follow up of thymus in patients with myasthenia gravis.

We examined transversely the thymus of 33 myasthenia gravis (MG) patients followed up for more than 5 years and found three thymomas. One was found 21 years after thymoma resection (Masaoka I, WHO Type B2 thymoma) and extended thymectomy. The other two were non-thymomatous at onset, and they were not treated with extended thymectomy. Therapeutic guidelines should mention the importance of follow-up in MG thymus.

Expression of caveolar components in primary desminopathy.

Myofibrillar myopathies (MFM) involve accumulation of various proteins in the muscle cytoplasm. In myopathy with a heterozygous A337P mutation of the desmin gene, electron-micrographs showed aggregates of vesicular and tubular structures. Positive cytoplasmic reaction for caveolin-3 immunohistochemistry and cholera toxin B binding suggested that caveolae comprised some of the aggregates. As caveolae occur in the Golgi complex and are transported to the cell surface, the results suggest inhibition of their trafficking to the sarcolemma. Alternatively, they could be trapped during internalization. We hypothesize that the accumulation of multiple proteins in MFM could be partially due to inhibited intracellular trafficking.

Purkinje cell loss in the cerebellar flocculus in patients with ataxia with ocular motor apraxia type 1/early-onset ataxia with ocular motor apraxia and hypoalbuminemia.

We genetically screened patients with ataxia with ocular motor apraxia type 1 (AOA1)/early-onset ataxia with ocular motor apraxia and hypoalbuminemia (EAOH), with a Japanese variant form of Friedreich's ataxia. Three patients were found to have a homozygous insertion mutation of the aprataxin gene (689insT). An elder sister of a patient in this series died of cerebral hemorrhage at the age of 45, and underwent autopsy. In her cerebellar cortex, the mean density of Purkinje cells in the flocculus had predominantly decreased to 6.7% of normal controls, whereas the Purkinje cells in the other areas of the cerebellar hemisphere had decreased to 78.2%. This suggests that the cerebellar flocculus is the primary affected lesion in AOA1/EAOH, which should be associated with ocular motor apraxia.

Identification of ER membrane targeting signal of kinectin.

Kinectin has been identified as a kinesin receptor on endoplasmic reticulum (ER). The ER membrane binding domain of kinectin is still obscure and is thought to require a half of the molecule. To determine the ER insertion site, we produced several constructs around N-terminus of kinectin connected with green fluorescent protein (GFP) and visualized the distribution in Cos-7 cells. The fragment of residues 7-29 appeared in the reticular pattern exactly colocalized with the ER marker but did not remain for a long time. On the other hand, residues 1-106 maintained a reticular pattern for more than seven days. These results indicate that residues 7-29 of kinectin are sufficient for targeting to the ER membrane but insufficient for remaining on the ER.