Hirokatsu Takahashi

Two different clinical phenotypes of Creutzfeldt-Jakob disease with a M232R substitution.

ObjectiveTo describe the clinical features of Creutzfeldt-Jakob disease with a substitution of arginine for methionine (M232R substitution) at codon 232 (CJD232) of the prion protein gene (PRNP).Patients and methodsWe evaluated the clinical and laboratory features of 20 CJD232 patients: age of onset, initial symptoms, duration until becoming akinetic and mute, duration until occurrence of periodic sharp and wave complexes on EEG (PSWC), MRI findings, and the presence of CSF 14-3-3 protein. Immunohistochemically, prion protein (PrP) deposition was studied.ResultsNone of the patients had a family history of CJD. We recognized two clinical phenotypes: a rapidly progressive type (rapidtype) and a slowly progressive type (slow-type). Out of 20 patients, 15 became akinetic and mute, demonstrated myoclonus, and showed PSWC within a mean duration of 3.1, 2.4, and 2.8 months, respectively (rapid-type). Five showed slowly progressive clinical courses (slow-type). Five became akinetic and mute and four demonstrated myoclonus within a mean duration of 20.6 and 15.3 months, respectively, which were significantly longer than those in the rapid-type. Only one demonstrated PSWC 13 months after the onset. Diffuse synaptic-type deposition was demonstrated in four rapidtype patients, and perivacuolar and diffuse synaptic-type deposition in two, and diffuse synaptic-type deposition in one slow-type patient. Three of 50 suspected but non-CJD patients had the M232R substitution.ConclusionsPatients with CJD232 had no family history like patients with sCJD, and showed two different clinical phenotypes in spite of having the same PRNP genotype. More studies are needed to determine whether M232R substitution causes the disease and influences the disease progression.

Anti-GQ1b antibody does not affect neuromuscular transmission in human limb muscle

Anti-ganglioside GQ1b antibody induces neuromuscular blocking on mouse phrenic nerve-diaphragm preparations. Several reports suggest that patients with this antibody show abnormal neuromuscular transmission in the facial or limb muscles, but limb muscle weakness is unusual in Miller Fisher syndrome that is often associated with anti-GQ1b antibody. To determine whether anti-GQ1b sera affect neuromuscular transmission in human limb muscles, axonal-stimulating single fiber electromyography was performed in the forearm muscle of seven patients with anti-GQ1b antibody. All showed normal jitter and no blocking. Anti-GQ1b antibody does not affect neuromuscular transmission in human limb muscles. The different findings in mouse and human may be explained by the extent of expression of GQ1b on the motor nerve terminals in the muscle examined.

High-dose intravenous immunoglobulin for the treatment of MuSK antibody-positive seronegative myasthenia gravis.

We treated two patients with anti-muscle specific tyrosine kinase (MuSK)-antibody positive seronegative myasthenia gravis (MG) with high-dose intravenous gammaglobulin (IVIg) and evaluated their clinical courses. Both patients were Japanese women, MuSK-positive seronegative MG, and were unresponsive to conventional treatments, including thymectomy, steroids, and tacrolimus. The patients required frequent hospitalization for plasmapheresis. In case 1, a 45-year-old woman, it was difficult to obtain blood access for plasmapheresis. High-dose IVIg, 400 mg/kg per day for 5 days, was administered in cases 1 and 2. In both cases, clinical improvement was observed 3 days after the start of IVIg therapy and lasted for 2 to 3 months. We propose that IVIg therapy is an effective treatment for MuSK-positive seronegative MG, when conventional treatments have failed.

Anti-MuSK-positive myasthenia gravis: neuromuscular transmission failure in facial and limb muscles

The presence of antibodies against muscle‐specific receptor tyrosine kinase (MuSK) appears to define a subgroup of patients with myasthenia gravis (MG) characterized by weakness predominant in bulbar, facial and neck muscles compared with anti‐acetylcholine receptor (AChR) antibody‐positive MG. To investigate the patterns and severity of neuromuscular transmission failure in different muscles in MuSK‐positive MG, we performed single fiber electromyography (SFEMG) in the facial (frontalis) and limb (extensor digitorum communis, EDC) muscles in three anti‐Musk‐positive patients, and compared results with those of 11 anti‐AChR‐positive patients. Only one of the three MuSK‐positive patients had abnormal jitter in EDC, but all the three showed clearly increased jitter in the frontalis. By contrast, the AChR‐positive patients showed similarly abnormal jitter for the two muscles. These results suggest that when the diagnosis of anti‐MuSK‐positive MG is suspected, SFEMG should be performed in most prominently affected muscles.

Is tongue atrophy reversible in anti-MuSK myasthenia gravis? Six-year observation

Approximately 15% of myasthenia gravis (MG) patients do not have any detectable antiacetylcholine receptor (AChR) antibodies and are referred to as ‘seronegative.’ Of these, antibodies against muscle-specific tyrosine kinase (MuSK) are positive in 30–50%.1 2 Tongue muscle atrophy is frequent in MuSK-positive MG.3 The pathophysiology of muscle atrophy is unclear, and it has not yet been reported whether tongue muscle atrophy in MuSK-MG is reversible or not. We herein report a 6-year observation of tongue muscle atrophy with its MRI evaluation in a MuSK-MG patient. In 2002, a 46-year-old woman was admitted with an 8-month history of progressive neck weakness, hoarseness and dysphagia. These symptoms did not fluctuate throughout the day. The patient had lost her body weight by 14 kg over 8 months. Neurological examination showed equivocal blepharoptosis on the right, prominent nasal voice and dysphagia, and mild atrophy of the tongue. There was moderate weakness in the neck muscles and mild weakness in the limbs. No fasciculations were observed. Tendon reflexes were active in all four limbs. Serum anti-AChR antibodies were negative. The patients percentage vital capacity (%VC) was decreased to 62%. An edrophonium test was negative. A repetitive nerve stimulation test showed no significant decremental responses in …

Bickerstaff brainstem encephalitis after heat stroke

Sirs: Bickerstaff brainstem encephalitis (BBE) is characterized by acute onset of ophthalmoplegia and ataxia with symptoms and signs indicative of involvement of the central nervous system such as consciousness disturbance [1]. It has been proposed that BBE, Miller Fisher syndrome, and Guillain-Barre syndrome (GBS) are related disorders [8–10]. In fact, a considerable number of patients with BBE have overlapping GBS [8, 15]. A number of factors have been described as triggers of GBS [13]. Heat stroke produces a wide variety of neurological complications [6], but only one case of GBS after heat stroke has been reported [11]. We present a patient with overlapping BBE and GBS after heat stroke. To our knowledge, this is the first report of such a patient. A previously healthy 43-year-old man experienced generalized tonic seizure with loss of consciousness during hard physical work on a hot summer day. He was transferred to our intensive care unit. The core temperature was 42.8°C, heart rate 173 bpm, and blood pressure 66/36 mmHg. Deep coma and bilateral miotic pupils were observed. Laboratory tests showed a platelet count of 113.000/mm3, creatinine 2.73 mg/dL, creatine kinase 2833 U/L, and serum interleukin-6 8594 pg/ml (normal < 4). He was treated with surface cooling (35 °C), mechanical ventilation, intravenous dopamine, and continuous hemodiafiltration. His general status gradually improved. On day 8, he was weaned from mechanical ventilation. On day 9, he was fully conscious with no weakness in the limbs, normal external ocular movements, and normal tendon reflexes. The next day, he again showed consciousness disturbance and weakness in all four limbs. On day 11, he was drowsy, but he was able to respond to commands. His pupils were equal (3.0 mm) and pupillary light reflexes absent. There were complete external ophthalmoplegia, bilateral facial palsy, aphonia, tetraparesis (MRC grade 3 for the upper extremities, grade 2 for the lower ones), limb ataxia, and areflexia. Laboratory examinations on day 12 revealed near-normal blood cell count (white blood cell, 9.900/mm3), and normal serum electrolytes and vitamin B1 levels. Brain MRI found no obvious abnormalities responsible for his consciousness disturbance and muscle weakness. Serum antibodies against ganglioside GM1, GD1a, GT1a, or GQ1b were negative. Cerebrospinal fluid (CSF) contents on day 12 were normal (cell count, 0/mm3; protein level, 21 mg/dl), and a follow-up CSF examination on day 30 revealed the slightly increased protein level (43 mg/dl; normal < 40 mg/dl). Nerve conduction studies (NCS) showed slightly decreased compound muscle action potential (CMAP) amplitudes, normal nerve conduction velocities and distal latencies, and absent F-waves in all the nerves tested (the median, ulnar, peroneal, and tibial nerves). He underwent plasmapheresis 4 times, every other day from day 15. After this treatment, his neurological symptoms were gradually improved. On day 24, he could talk, but his speech was slurred and ataxic. On day 35, when his muscle strength was near-normal, NCS revealed restored F-waves and increased CMAP amplitudes. On day 60, he was discharged to a rehabilitation facility because he was still unable to stand independently due to ataxia. This patient was characterized by acute consciousness disturbance, ophthalmoplegia, facial palsy, tetraparesis, and ataxia, 7 days after heat stroke. After treatment with plasmapheresis, the signs gradually lessened, resulting in a monophasic course. Although several diseases including Wernicke’s encephalopathy, infectious brainstem encephalitis, and GBSlike syndrome by severe exertion [16] should be considered in the differential diagnosis, his clinical features met the criteria for BBE and overlapping GBS [8, 15], suggesting that the disorders may have been triggered by heat stroke. The absence of F-waves during tetraparesis and their restitution in the recovery phase are consistent with proximal conduction block [7]. Pfeiffer reported the only case of GBS after heat stroke, and speculated that heat stroke activates the immune system by cytokine release which opens the blood-nerve barrier and exposes peripheral nerve antigens, thereby inducing GBS [11]. In fact, various cytokines including tumor necrosis factoralpha and interleukin (IL)–6 are conjectured to function in the pathogenesis of heat stroke [2, 4], and also of GBS and related diseases [3, 5, 12, 14]. Elevated serum IL-6 was detected in our patient. Hypercytokinemia may be the key to the association of GBS and related diseases with heat stroke. LETTER TO THE EDITORS