Cytomegalovirus-associated encephalomyelitis in an immunocompetent adult: a two-stage attack of direct viral and delayed immune-mediated invasions. case report.

BACKGROUND: It is clinically rare to find cytomegalovirus (CMV)-associated encephalomyelitis in immunocompetent adults. Here, we present the case of an adult patient who developed acute transverse myelitis that was followed by immune-mediated disseminated encephalomyelitis. CASE PRESENTATION: A 38-year-old man developed acute paraplegia with paresthesia below the level of the T7-8 dermatome. Both brain and spinal cord MRIs performed at admission appeared normal. Corticosteroid therapy was initiated, with the later addition of high-dose intravenous immunoglobulins. After polymerase chain reaction analysis indicated the presence of CMV DNA in his cerebrospinal fluid (CSF), anti-viral therapy was added. Forty days after symptom onset, despite an initial positive response to this therapy, he developed dysarthria and truncal ataxia. Repeated magnetic resonance imaging scans demonstrated progressively expanding lesions involving not only the spinal cord but also the cerebral white matter, suggestive of extensive immune-mediated demyelination involving the central nervous system (CNS), as is observed in acute disseminated encephalomyelitis (ADEM). CONCLUSION: This case report underscores the importance of careful patient observation following the initial diagnosis of a CMV-associated CNS infection, such as transverse myelitis, on the possibility that post-infectious ADEM may appear.

Cerebrospinal fluid dissemination of anaplastic intraventricular meningioma: report of a case presenting with progressive brainstem dysfunction and multiple cranial nerve palsies.

BACKGROUND: It is extremely rare to see cerebrospinal fluid dissemination of intraventricular meningioma, particularly with the development of acute, progressive brainstem/cerebellar dysfunction with an absence of mass formation in the corresponding anatomical sites. CASE PRESENTATION: An 81-year-old man was admitted because of double vision, right facial nerve palsy and truncal ataxia. Brain magnetic resonance imaging showed normal findings except for a tumor mass in the left lateral ventricle, which had been noted over 6 months previously. The patient developed hiccups, hyperventilation, and drowsiness, which worsened progressively, and did not respond to corticosteroid or intraventricular immunoglobulin therapy. Cerebrospinal fluid study revealed a mild elevation of protein, and cytology was negative. The patient died and an autopsy was performed. Postmortem investigation disclosed a malignant transformation of benign fibroid meningioma with cerebrospinal fluid dissemination of the malignant cells, diversely involving the surface of brainstem, cerebellum, and spinal cords, secondarily resulting in extensive ischemia in the brain parenchyma by vessel occlusion. CONCLUSION: If a patient with an intraventricular tumor develops acute, progressive neurological symptoms, the possibility that it is be caused by cerebrospinal fluid dissemination of tumor cells, after malignant transformation, should be considered.

A randomized double-blind multi-center trial of hydrogen water for Parkinson's disease: protocol and baseline characteristics.

BACKGROUND: Our previous randomized double-blind study showed that drinking hydrogen (H2) water for 48 weeks significantly improved the total Unified Parkinson's Disease Rating Scale (UPDRS) score of Parkinson's disease (PD) patients treated with levodopa. We aim to confirm this result using a randomized double-blind placebo-controlled multi-center trial. METHODS: Changes in the total UPDRS scores from baseline to the 8(th), 24(th), 48(th), and 72(nd) weeks, and after the 8(th) week, will be evaluated. The primary endpoint of the efficacy of this treatment in PD is the change in the total UPDRS score from baseline to the 72(nd) week. The changes in UPDRS part II, UPDRS part III, each UPDRS score, PD Questionnaire-39 (PDQ-39), and the modified Hoehn and Yahr stage at these same time-points, as well as the duration until the protocol is finished because additional levodopa is required or until the disease progresses, will also be analyzed. Adverse events and screening laboratory studies will also be examined. Participants in the hydrogen water group will drink 1000 mL/day of H2 water, and those in the placebo water group will drink normal water. One-hundred-and-seventy-eight participants with PD (88 women, 90 men; mean age: 64.2 [SD 9.2] years, total UPDRS: 23.7 [11.8], with levodopa medication: 154 participants, without levodopa medication: 24 participants; daily levodopa dose: 344.1 [202.8] mg, total levodopa equivalent dose: 592.0 [317.6] mg) were enrolled in 14 hospitals and were randomized. DISCUSSION: This study will confirm whether H2 water can improve PD symptoms. TRIAL REGISTRATION: UMIN000010014 (February, 13, 2013).

Good's syndrome with opportunistic infection of the central nervous system: a case report.

BACKGROUND: Immunodeficiency with a thymoma (Good's syndrome) is a rare condition occurring in patients with adult-onset hypogammaglobulinemia that is progressive after the removal of thymoma. Recently, we encountered a patient with Good's syndrome who suddenly developed opportunistic encephalitis 4 years after the resection of thymoma without a history of infectious complications. CASE PRESENTATION: A 58-year-old man, who underwent surgery to remove a thymoma at the age of 54, was admitted because of speech difficulties. A brain MRI showed multiple lesions involving the frontal lobes, but the CSF finding was normal. Acyclovir was empirically administered, and fever as well as his neurological symptoms fully recovered within a few days. However, 1 week after admission, motor aphasia and mild right hemiparesis reappeared. MRI showed that the lesion involving the left cingulate gyrus expanded in size, and revealed an abnormal signal intensity lesion in the left corona radiata. Laboratory examination found increased CMV pp65 antigen-positive lymphocytes in serum. Antiviral therapy using ganciclovir and immunoglobulin replacement therapy was started. The patient has since been free from any neurological symptoms for 1 year, and lesions demonstrated by MRI are gradually improving. CONCLUSION: Early recognition of this rare condition and prompt initiation of therapy are crucially important. Awareness of immunodeficiency in a patient after removal of thymoma may help neurologists to consider the possibility that opportunistic infection may be the cause of cerebral lesions.

Avoidance of swallowing saliva: a symptom related to aberrant basal ganglia functions?

We report two patients with avoidance of swallowing saliva despite intact swallowing functions. One, with mild, de novo Parkinson's disease, had a fear that his saliva was contaminated and would harm him. The other, with a history of CNS germinoma in remission for 3 years following chemotherapy, expectorated because his saliva was distasteful and disgusting. He had a lesion involving the left pallidum. Both appeared obsessed with the idea of saliva contamination and both expectorated compulsively, presenting obsessive-compulsive disorder (OCD) symptoms. OCD-like behavior may be induced in association with pathological conditions in which aberrant basal ganglia functions are present.

T-type calcium channel as a new therapeutic target for tremor.

Voltage-gated calcium channels play an important role in many physiological and pathological processes. Accumulating studies suggest that the T-type calcium channel is a potential target for the treatment of various neurological disorders, such as epilepsy, insomnia, and neuropathic pain. Here, we highlight recent advances in our understanding of T-type calcium channel regulation and their implications for tremor disorders. Several T-type calcium channel blockers effectively suppressed experimental tremors that have been suggested to originate from either the cerebellum or basal ganglia. Among T-type calcium channel blockers that have been used clinically, the anti-tremor efficacy of zonisamide garnered our attention. Based on both basic and clinical studies, the possibility is emerging that T-type calcium channel blockers that transit into the central nervous system may have therapeutic potentials for tremor disorders.

Herpes Zoster Radiculomyelitis With Aquaporin-4 Antibodies: A Case Report and Literature Review.

Background: The relationship between varicella-zoster virus (VZV)-associated myelitis and aquaporin-4 immunoglobulin-G (AQP4-IgG) remains unknown. Case Report: We report a case of acute radiculomyelitis with longitudinal extensive hyperintensity signals traversing the brainstem until the upper thoracic cord in a 55-year-old healthy woman following herpes zoster infection in the left C4-T3 dermatome. VZV-specific IgG in the cerebrospinal fluid (CSF) and AQP4-IgG positivity on enzyme-linked immunosorbent assay (ELISA) were undetectable. Thus, she was diagnosed with immune-competent VZV radiculomyelitis. Forty-two months later, she experienced a relapse, and AQP4-IgG positivity was detected on ELISA. A cell-based assay (CBA) showed AQP4-IgG positivity not only at the time of recurrence but also retrospectively at 1 month after the initial symptoms. We concluded that AQP4-IgG-positive neuromyelitis optica spectrum disorder (NMOSD) was concurrent with VZV myelitis. After the second attack, she was treated with azathioprine and has had no relapse since then. Conclusion: We reported a case of VZV radiculomyelitis with confirmed concurrent AQP4-IgG positivity. NMOSD induced by herpes zoster has been recently identified, but distinguishing it from VZV myelitis can be difficult and whether these two diseases aggravate each other is unknown. Awareness of the potentially varied presentation of VZV myelitis can enable earlier recognition and proper treatment.

Effects of zonisamide on c-Fos expression under conditions of tacrine-induced tremulous jaw movements in rats: a potential mechanism underlying its anti-parkinsonian tremor effect.

OBJECTIVES: To examine the mechanisms underlying the anti-tremor effect of zonisamide in rats under conditions of tacrine-induced tremulous jaw movements (TJMs). METHODS: Male adult rats received systemic administration of either zonisamide (5 or 50mg/kg) or vehicle at 20min prior to the administration of tacrine hydrochloride (5mg/kg). Animals were sacrificed 2h later, and the brains collected and immunostained for quantitative assessment of c-Fos expression. RESULTS: There was no effect of zonisamide on tacrine-induced c-Fos expression in the ventrolateral striatum, a primary site of the pharmacological action of tacrine. Zonisamide suppressed the tacrine-induced c-Fos expression in the cortex, the dorsal striatum, and the nucleus accumbens, which are involved in the architecture of the cortico-basal ganglia-thalamocortical circuits. CONCLUSION: The anti-TJM effect of zonisamide may not relate to suppression of neural activity specifically in primary tremor-generating sites, but may be due to a more broad inhibitory effect on tremor-related structures such as the cortex or the striatum. This effect of zonisamide may be a contributing mechanism underlying its therapeutic efficacy on parkinsonian tremor.

Survival rate of patients with amyotrophic lateral sclerosis in Wakayama Prefecture, Japan, 1966 to 2005.

To investigate longitudinal changes in the survival rate of patients with amyotrophic lateral sclerosis in Wakayama Prefecture, Japan, we made a retrospective hospital-based study of 454 patients diagnosed with motor neuron disease (MND) at Wakayama Medical University (WMU) Hospital between 1966 and 2005. Of the 454 patients, 240 who were born and who lived in Wakayama Prefecture were diagnosed with definite or probable ALS during this period, according to the El Escorial criteria. The clinical data of the 240 patients, including sex, birth date, birthplace, address, age at onset, initial symptoms, date when respiratory support was applied (tracheostomy, noninvasive positive pressure ventilation, or mandatory artificial ventilation), and date of death were reviewed retrospectively. The age at onset of patients who developed initial symptoms before 1990 was 53.4+/-10.6 (mean+/-S.D.) and that in 1990 or thereafter was 64.8+/-10.3, respectively, showing a significant difference (p<0.0001). Clinical duration was determined from onset to either date of death or initiation of respiratory support in this study. Survival rate was compared using the Kaplan-Meier method according to age at onset, sex, initial symptoms and year of onset. Mean age at onset shifted towards older age according to a later year of onset, due to the overwhelming senility rate in Wakayama Prefecture. Older onset patients had a significantly poorer survival rate than younger onset patients when it was compared based on 10-year age groups (log rank, p<0.0001). Male patients had a poorer survival rate than female patients (p<0.0001). ALS patients with bulbar palsy onset showed shorter clinical durations than those with lower leg onset (p<0.0071, Breslow-Gehan-Wilcoxon test). Patients over 70 years old more frequently showed bulbar palsy onset compared to those younger than 69 (p=0.003). In a comparison of year of onset before and after 1990, ALS patients after 1990 had characteristics of older age onset and shorter clinical duration, and more frequently showed bulbar palsy onset compared with those before 1990. These findings indicated that younger onset patients with ALS decreased after 1990 in Wakayama Prefecture and this might partly explain the recent decline of ALS incidence in Wakayama Prefecture. The shift of the mean age at onset to older age might be due to exogenous factors, including changes in lifestyle, food, and drinking water in this area. Bulbar palsy onset and age at onset were expected as predictors of the survival rate.

Alteration of eating behaviors in patients with Parkinson's disease: possibly overlooked?

Patients with Parkinson's disease (PD) occasionally show food cravings and/or compulsive eating that result in significant, undesired weight gain. Dopamine replacement therapy may be the cause of this type of eating disorder. We evaluated 60 consecutive patients to see if they had any alteration of eating patterns after starting levodopa. Among them, five (8.3%) patients exhibited characteristic alterations of food preference following the start of dopamine replacement therapy. One patient showed an undesirable weight gain. Of the five patients exhibiting food preference alterations, all showed increased preference to consume sweet snacks, although this alteration was not always associated with hyperphagia (eating too much). This type of dietary alteration was not related to a specific antiparkinsonian drug, and could be observed in patients undergoing dopamine agonist monotherapy. Alteration of eating behavior may not be uncommon in PD patients, and is possibly overlooked. Since dopamine is closely involved in acquisition of food preferences, dietary changes with/without compulsive eating may be a manifestation of an alteration of appetitive behaviors due to excessive dopaminergic neurotransmission.

Effects of zonisamide on experimental tremors in rats.

OBJECTS: To study the effect of zonisamide on experimental tremors in rats. METHODS: Effect of zonisamide on harmaline- or oxotreorine-induced tremors, and tacrine-induced tremulous jaw movements (TJMs) was studied. RESULTS: Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors dose-dependently. Zonisamide also significantly suppressed tacrine-induced TJMs, and this effect was not lost under conditions of monoamine-depletion or dopaminergic blockade. CONCLUSION: The anti-tremor effects of zonisamide may be achieved by a non-dopaminergic mechanism. Since it effectively suppressed tremors that are based on different kinds of tremors, we propose a novel perspective of clinical potential of zonisamide as a non-specific, anti-tremor drug.

Cervico-shoulder dystonia following lateral medullary infarction: a case report and review of the literature.

BACKGROUND: Secondary cervical dystonia is induced by organic brain lesions involving the basal ganglia, thalamus, cerebellum, and brain stem. It is extremely rare to see cervical dystonia induced by a medullary lesion. CASE PRESENTATION: We report a case of an 86-year-old Japanese woman who developed cervical dystonia following lateral medullary infarction. She developed sudden-onset left upper and lower extremity weakness, right-side numbness, and dysarthria. Brain magnetic resonance imaging revealed an acute ischemic lesion involving the left lateral and dorsal medullae. A few days after her stroke, she complained of a taut sensation in her left neck and body, and cervico-shoulder dystonia toward the contralateral side subsequently appeared. Within a few weeks, it disappeared spontaneously, but her hemiplegia remained residual. CONCLUSIONS: To date, to the best of our knowledge, there has been only one reported case of cervical dystonia associated with a single medullary lesion. It is interesting to note the similarities in the clinical characteristics of the previously reported case and our patient: the involvement of the dorsal and caudal parts of the medullary and associated ipsilateral hemiplegia. The present case may support the speculation that the lateral and caudal regions of the medulla may be the anatomical sites responsible for inducing cervical dystonia.

[Placebo effect in Parkinson's disease].

"Placebo" is Latin for "I shall please". The placebo effect has been widely documented by randomized placebo-controlled drug studies. One of the best examples of placebo effectiveness is that have been shown in clinical trials of anti-parkinsonian drugs. The placebo effect is observable not only in drug trials but also with deep brain stimulation. Recent advances in research on the placebo effect in Parkinson's disease (PD) have suggested that motor symptoms of PD can be essentially improved by placebo. A recent study using positron emission tomography (PET) with raclopride demonstrated that release of endogeneous dopamine in the dorsal striatum occurs in placebo-responsive patients with PD. This suggests that placebo-induced expectation of clinical improvement may activate endogenous dopamine in the striatum, and that placebo effectiveness is thus achieved by endogenous dopamine supplementation. Indeed, decreased neuronal activities in the subthalamic nucleus (STN), that were recorded during surgery to implant deep brain stimulation electrodes, correlated well with placebo-induced clinical improvement in patients with PD. Although the detailed pathophysiological mechanism underlying the placebo effects remains uncertain, theoretically, the placebo effect has generally been explained by two different mechanisms: one is conditioning theory (pavlovian conditioning), and the other is cognitive theory (expectation of clinical improvement). Although both mechanisms may contribute to placebo effects, the placebo effect in PD may be attributed more to cognitive mechanisms such as expectation of improvement, because the placebo effect can be obtained in de novo PD patients. There have been accumulating findings that suggest a functional relationship between dopamine and the expectation of clinical improvement (reward). Further basic studies are required to clarify the complex link between dopamine and the reward system, but such findings will contribute to a better understanding of the pathophysiological mechanism underlying the placebo effect in PD.

Deep cerebral venous thrombosis mimicking influenza-associated acute necrotizing encephalopathy: a case report.

BACKGROUND: Acute necrotizing encephalopathy is one of the most devastating neurological complications of influenza virus infection. Acute necrotizing encephalopathy preferentially affects the thalamus bilaterally, as does deep cerebral venous thrombosis, which can lead to misdiagnosis. CASE PRESENTATION: A 52-year-old Japanese woman infected with seasonal influenza B virus presented to the emergency care unit in our hospital with progressive alteration of her level of consciousness. Bilateral thalamic lesions were demonstrated by magnetic resonance imaging, leading to a tentative diagnosis of acute necrotizing encephalopathy. However, she had deep cerebral venous thrombosis, and the presence of diminished signal and enlargement of deep cerebral veins on T2*-weighted imaging contributed to a revised diagnosis of deep cerebral venous thrombosis. Anticoagulant therapy was initiated, leading to her gradual recovery, with recanalization of the deep venous system and straight sinus. CONCLUSIONS: To the best of our knowledge, these results represent the first report of deep cerebral venous thrombosis associated with influenza infection. It is clinically important to recognize that deep cerebral venous thrombosis, although rare, might be one of the neurological complications of influenza infection. In the presence of bilateral thalamic lesions in patients with influenza infection, deep cerebral venous thrombosis should be considered in addition to acute necrotizing encephalopathy. Delays in diagnosis and commencement of anticoagulant therapy can lead to unfavorable outcomes.

A species-specific difference in the effects of harmaline on the rodent olivocerebellar system.

The rodent model of harmaline-induced tremor has been widely used for experimental analysis of tremor. Activation of the olivocerebellar system plays a key role in tremor-generating mechanisms. One undetermined problem is whether there are species-specific differences in effects of harmaline. The present study investigated effects of harmaline on olivocerebellar systems of mice and rats. Systemic administration of harmaline, but not vehicle, produced generalized, high-frequency tremors in both types of rodents. Immunohistochemical studies revealed significant degeneration of Purkinje cells that was associated with activated microgliosis in the cerebellar cortex, following administration of harmaline in rats but not in mice. However, in mice but not rats, microgliosis was induced following administration of harmaline in the inferior olivary nucleus (ION), particularly in its caudal and medial subdivisions. Numbers of neurons in the mouse ION did not decrease, suggesting the possibility that microgliosis in ION might not be a simple neurotoxic effect. Presumably, differences in sensitivity of Purkinje cells between rats and mice may be related to differences in functional alterations in their respective olivocerebellar systems induced by harmaline. Recognition of these species-specific differences in the response of the olivocerebellar system to harmaline is an important consideration for experimental analysis of the rodent model of tremors.

Intragastric proteasome inhibition induces alpha-synuclein-immunopositive aggregations in neurons in the dorsal motor nucleus of the vagus in rats.

The neuropathological hallmark of idiopathic Parkinson's disease (PD) is dopaminergic neuron degeneration in the substantia nigra. However, it has been suggested that the neurodegenerative process initially may occur in the dorsal motor nucleus of the vagus (DMV). This implies that unidentified environmental toxins or neurotropic pathogens that is capable of passing the mucosal barrier of the gastrointestinal tract might affect the enteric nerve endings of the vagal neurons, possibly resulting in retrograde degeneration of the DMV. The present study aimed to evaluate the effects of proteasome inhibition of the intragastric nerve terminals of the DMV in rats. Following multiple injections of PSI, a selective proteasome inhibitor, or vehicle into the ventral wall of the stomach, the medulla oblongata was studied immunohistologically. In the DMV neurons of rats treated with PSI but not vehicle, alpha-synuclein-immunopositive intracytoplasmic inclusions and activated microglia were observed, predominantly in the left DMV. However, there was no significant loss of neurons. These results suggest that intragastric proteasome inhibition has a retrograde effect on DMV neurons but is insufficient to induce cell death, suggesting no causal linkage between inclusion body formation with proteasome inhibition and neuron death in the DMV. This might also implicate that Lewy body formation in the DMV in PD is possibly related to peroral invasion of environmental toxins that inhibit ubiquitin-proteasome system function.

[Chronic inflammatory demyelinating polyneuropathy followed by systemic lupus erythematosus and Sjögren syndrome: a case report].

We report a 60-year-old man with chronic inflammatory demyelinating polyneuropathy (CIDP) accompanying systemic lupus erythematosus (SLE) and Sjögren syndrome (SS). He was admitted to our hospital because of progressive weakness and dysesthesia in the distal parts of the bilateral upper and lower extremities. We diagnosed the illness as CIDP and treated him with steroids, plasma filtration and high-dose intravenous immunoglobulin therapy (IvIg). Consequently, his symptoms improved gradually and he was discharged. However, 2 years after the first admission, he experienced dyspnea on effort and chest X-ray demonstrated right pleural effusion. Consequently, he gradually developed gait disturbance, loss of taste, and severe dysesthesia in his lower limbs. Therefore, he was admitted again. On neurological examination, mild weakness was detected in all limbs distally. Deep tendon reflexes were absent. The sensation of position and vibration was diminished in the fingers and toes. He could not walk by himself and demonstrated an ataxic gait with a wide base. Examination of cranial nerves demonstrated no abnormalities, except for loss of taste. Serological examination demonstrated positive auto-antibodies including antinuclear, anti-DNA, and anti-SS-A antibodies. Urinalyses showed albuminuria and microscopic hematuria. Cerebrospinal fluid (CSF) was clear and colorless, containing 3 mononuclear cells per cubic mm, with a protein of 275 mg/dl. Magnetic resonance images (MRIs) of the brain and entire spine were normal. Neurophysiological studies demonstrated an absence of sensory nerve action potentials in the right arm and markedly slow conduction velocities, conduction block in the ulnar forearm segment and absence of F waves in all limbs. The renal biopsy revealed lupus nephritis. The lip biopsy demonstrated chronic sialoadenitis consistent with SS, altough patient did not show symptoms of arthritis or vasculitis. It is well known that mononeuritis multiplex and acute demyelinating polyneuropathy accompany SLE. However there are few reports that describe the occurrence of CIDP in patients with SLE, and the association of "CIDP-like" neuropathy in patients with SS. Our case suggests that the autoimmune disease associated with SLE and SS may induce "CIDP-like" inflammatory demyelinating polyneuropathy.

[Amyotrophic lateral sclerosis associated with extrapyramidal symptoms or signs].

This investigation was conducted to clarify the frequency and characteristics of ALS associated with extrapyramidal symptoms or signs in Wakayama prefecture. The questionnaires to survey ALS cases were mailed to all medical centers in Wakayama prefecture. A total of 252 cases were found to have motor neuron diseases. Among them, 204 cases fulfilled probable or definite according to El Escorial Criteria. In 10 of them, extrapyramidal signs were identified as follows: rigidity 50%, tremor 40% and akinesia 10%. Family history of ALS in these cases (20%) is higher than expected in usual ALS, and all of them are negative for SOD-1 mutation. Dementia and autonomic nervous symptoms were observed in several cases. Incidence of extrapyramidal signs in ALS resulted in 4.8%. The incidence of extrapyramidal signs is more frequent than expected by chance, suggesting that the degeneration of basal ganglia and/or substantia nigra may not be so rare in ALS.