Anti-GAD Antibody-associated Syndrome Presenting with Limb Myoclonus.

Background: The clinical spectrum of anti-glutamic acid decarboxylase (GAD) antibody-associated neurologic syndromes is expanding, with focal, generalized, and atypical forms. Case Report: We describe a 59-year-old female showing continuous right lower limb myoclonus and mild encephalopathy. These symptoms started 2 weeks prior to evaluation. The patient had great improvement with intravenous steroids. An autoantibody panel was positive for anti-GAD. Discussion: Various clinical manifestations, including myoclonus, may relate to anti-GAD antibodies. The treatment options available include symptomatic drugs, intravenous immunoglobulin, steroids, and other immunosuppressant agents.

Severe chronic lithium intoxication in patient treated for bipolar disorder.

OBJECTIVE: Lithium has been long used in psychiatry as an adjuvant treatment for bipolar disorder. Chronic lithium intoxication is very rare. DESIGN: We present the case of a 72-year-old female, treated with lithium for more than 10 years for bipolar disorder, who was admitted for gait impairment with weakness of limbs, myoclonus, speech impairment and memory disturbances. RESULTS: Diagnosis of lithium intoxication was based on clinical picture and determination of serum lithium levels. EEG showed severe encephalopathy with triphasic wave complexes. Sensory and motor axonal neuropathy was observed by EMG. Discontinuation of the drug leads to clinical improvement, although not to a fully neurological recovery. CONCLUSION: Lithium is still very effective drug, but requires regular monitoring of serum levels to prevent overdose and symptoms of intoxication. Neurophysiological methods, including EEG and EMG, are strongly recommended to determine the level of peripheral and/or central nervous system impairment.

Progressive encephalomyelitis with rigidity and myoclonus: a new variant with DPPX antibodies.

OBJECTIVE: To describe a novel and distinct variant of progressive encephalomyelitis with rigidity and myoclonus (PERM) associated with antibodies directed against dipeptidyl peptidase-like protein 6 (DPPX), a regulatory subunit of the Kv4.2 potassium channels on the surface of neurons. METHODS: Case series describing the clinical, paraclinical, and serologic features of 3 patients with PERM. A recombinant, cell-based indirect immunofluorescence assay with DPPX-expressing HEK293 cells was used to detect DPPX antibodies in conjunction with mammalian tissues. RESULTS: All patients presented with a distinct syndrome involving hyperekplexia, prominent cerebellar ataxia with marked eye movement disorder, and trunk stiffness of variable intensity. Additional symptoms comprised allodynia, neurogenic pruritus, and gastrointestinal symptoms. Symptoms began insidiously and progressed slowly. An inflammatory CSF profile with mild pleocytosis and intrathecal immunoglobulin G synthesis was found in all patients. High DPPX antibody titers were detected in the patients' serum and CSF, with specific antibody indices suggestive of intrathecal synthesis of DPPX antibodies. Response to immunotherapy was good, but constant and aggressive treatment may be required. CONCLUSION: These cases highlight the expanding spectrum of both PERM and anti-neuronal antibodies. Testing for DPPX antibodies should be considered in the diagnostic workup of patients with acquired hyperekplexia, cerebellar ataxia, and stiffness, because such patients might benefit from immunotherapy. Further studies are needed to elucidate both the entire clinical spectrum associated with DPPX antibodies and their role in pathogenesis.

Hypoventilation in glycine-receptor antibody related progressive encephalomyelitis, rigidity and myoclonus.

Glycine receptor (GlyR) antibodies have been identified in patients with rigidity and hyperekplexia, but the clinical phenotype associated with these antibodies has not been fully elucidated. The clinical features in two additional patients with GlyR antibodies are described. A 55-year-old man presented with stimulus-induced hyperekplexia and rigidity in the lower limbs and trunk. He initially responded to benzodiazepines, but presented after 18 months with severe, painful, prolonged spasms associated with supraventricular and ventricular arrhythmias, hypoventilation and oxygen desaturation requiring intubation. He improved following treatment with clonazepam, baclofen and immunomodulatory therapies. A 58-year-old woman presented with stiffness in the legs and hyperekplexia associated with hypoventilation, at times leading to loss of consciousness. She responded to benzodiazepines and has remained in remission. The clinical picture associated with GlyR antibodies includes autonomic dysfunction, cardiac arrhythmias and hypoventilation. It is important to recognise these serious complications early to limit mortality from this treatable condition.

Caspr2 antibodies in limbic encephalitis with cerebellar ataxia, dyskinesias and myoclonus.

Here we report on a case of contactin-associated protein-2 (Caspr2) antibody positive but voltage gated potassium channel (VGKC) antibody negative limbic encephalitis associated with cerebellar ataxia, myoclonus and dyskinesias with favorable response to immunotherapy. This case underlines the importance of Caspr2-specific antibody testing and demonstrates that Caspr2 antibodies are associated with a broader clinical spectrum than hitherto described.

Progressive encephalomyelitis with rigidity and myoclonus: the first pediatric case with glycine receptor antibodies.

IMPORTANCE: Progressive encephalomyelitis with rigidity and myoclonus is characterized by rigidity, painful muscle spasms, hyperekplexia, and brainstem signs. Recently, glycine receptor alpha 1 antibodies have been described in adult patients with progressive encephalomyelitis with rigidity and myoclonus. We describe a pediatric case. OBSERVATIONS: A 14-month-old child developed startle-induced episodes of generalized rigidity and myoclonus, axial hyperextension, and trismus, without impairment of consciousness. Episodes occurred during wakefulness and sleep, lasted seconds, and were accompanied by moaning, tachypnea, and oxygen desaturation. Imaging, cerebrospinal fluid, endocrine, metabolic, and genetic screening findings were normal or negative. She was treated with intravenous steroids and immunoglobulins with resolution of symptoms, but she relapsed weeks later. At this time, episodes were more severe. Glycine receptor alpha 1 antibodies were found in serum (titer of 1:200, later 1:320) and cerebrospinal fluid (titer of 1:2). Treatment was restarted with intravenous steroids and immunoglobulins, with major improvement, and she began treatment with oral steroids. She had 4 milder relapses, with improvement after treatment adjustments. CONCLUSIONS AND RELEVANCE: To our knowledge, this is the first pediatric case of progressive encephalomyelitis with rigidity and myoclonus associated with glycine receptor alpha 1 antibodies, a potentially severe but treatable antibody-mediated neurological disorder.

Progressive encephalomyelitis with rigidity and myoclonus: a syndrome with diverse clinical features and antibody responses.

BACKGROUND/AIMS: To better characterize progressive encephalomyelitis with rigidity and myoclonus (PERM) syndrome and identify novel PERM phenotypes. METHODS: The clinical features and antibody status of PERM patients were investigated using immunoblots, cell-based assays, RIA, protein macroarray and ELISA. RESULTS: Two patients with supratentorial involvement showed abnormal PET or EEG findings. One patient was discovered to have renal cell carcinoma, and protein macroarray revealed Ma3-antibodies. Another patient with leucine-rich, glioma-inactivated 1 (LGI1) and glutamic acid decarboxylase (GAD) antibodies showed a good response to immunotherapy. CONCLUSION: The heterogeneity of the immunological features suggests that PERM is caused by diverse pathogenic mechanisms. Seropositivity to well-characterized neuronal cell surface antigens might indicate a good treatment response.

Progressive encephalomyelitis with rigidity and myoclonus: glycine and NMDA receptor antibodies.

BACKGROUND: The syndrome of progressive encephalopathy with limb rigidity has been historically termed progressive encephalomyelitis with rigidity and myoclonus (PERM) or stiff-person syndrome plus. METHODS: The case is presented of a previously healthy 28-year-old man with a rapidly fatal form of PERM developing over 2 months. RESULTS: Serum antibodies to both NMDA receptors (NMDAR) and glycine receptors (GlyR) were detected postmortem, and examination of the brain confirmed an autoimmune encephalomyelitis, with particular involvement of hippocampal pyramidal and cerebellar Purkinje cells and relative sparing of the neocortex. No evidence for an underlying systemic neoplasm was found. CONCLUSION: This case displayed not only the clinical features of PERM, previously associated with GlyR antibodies, but also some of the features associated with NMDAR antibodies. This unusual combination of antibodies may be responsible for the particularly progressive course and sudden death.

Myoclonus after dextromethorphan administration in peritoneal dialysis.

OBJECTIVE: To report a case of myoclonus that developed after administration of dextromethorphan. CASE SUMMARY: A 64-year-old man was diagnosed with chronic renal failure due to diabetic nephropathy. The patient started on peritoneal dialysis 6 months before he was hospitalized. Two days before hospitalization, he developed cough and sputum and he visited an outpatient clinic, where dextromethorphan was prescribed. After taking a total of 30 mg of dextromethorphan, the patient developed myoclonus, tremor, agitation, slurred speech, and diaphoresis, which continued after he stopped taking the prescribed medicine. He visited an emergency department and was hospitalized for examination and treatment of myoclonus. DISCUSSION: As the patient's dialysis schedule was adequate, these symptoms were likely not due to uremia. The blood concentration of dextromethorphan (2.68 ng/mL) 60 hours after the 30-mg dose was higher than expected, and the blood concentration of dextrorphan, a metabolite, was lower than expected. We suspected that myoclonus was due to dextromethorphan-related symptoms induced by CYP2D6, which primarily metabolizes dextromethorphan. We analyzed the CYP2D6 gene for polymorphisms and identified CYP2D6 (*)1/(*)10. The patient had been taking metoprolol 40 mg/day for 2 years. The blood concentration of metoprolol 6 hours after administration was 13 ng/mL, which suggests that it was metabolized normally. Metoprolol has another metabolic pathway, via CYP2C19, and this may have led to its lack of accumulation. Moreover, metoprolol may have bound to active CYP2D6. Thus, affinity for CYP2D6, protein-binding rate, and lipid solubility may influence these drug interactions. Total scores for the Adverse Drug Reaction (ADR) probability scale and the Drug Interaction Probability Scale (DIPS) were 9 (highly probable) and 3 (possible), respectively. CONCLUSIONS: Myoclonus and other symptoms in this patient may have been caused by a prolonged high concentration of dextromethorphan due to CYP2D6 polymorphisms and drug interactions.

Correlation between myoclonus and the 3-glucuronide metabolites in patients treated with morphine or hydromorphone: a pilot study.

BACKGROUND: The 3-glucuronide metabolites of morphine and hydromorphone have been implicated as a causative factor for patients exhibiting myoclonus. OBJECTIVE: The primary goal of this study was to determine plasma levels of morphine-3-glucuronide (M3G) or hydromorphone-3-glucuronide (H3G) in patients demonstrating myoclonus and identify any trends or associations between the two. SETTING: Patients were recruited from San Diego Hospice and the Institute for Palliative Medicine's inpatient unit. DESIGN: A prospective convenience sample comprised of 17 subjects, 12 with myoclonus and 5 without myoclonus. Analysis included demographic, metabolic and clinical variables. Plasma was assayed via high performance liquid chromatography for morphine, M3G, and morphine-6-glucuronide or hydromorphone and hydromorphone-3-glucuronide. RESULTS: No trends or associations were identified between plasma levels of M3G or H3G and myoclonus. Ratio levels of 3-glucuronide metabolite to their corresponding parent opioid were dramatically lower than anticipated. CONCLUSION: In this small pilot study, it appears that the serum levels of metabolites M3G and H3G do not correlate with myoclonus.

[Myoclonia in an oldest old woman: a frequent and reversible etiology]. / Myoclonies chez une personne très âgée; une cause fréquente et réversible.

A 98-year-old woman was referred to our hospital because of myoclonia. The concentration of calcium and vitamin D in the serum was low. In this context, we concluded of neuromuscular irritability secondary to hypocalcaemia. The symptoms disappeared after a treatment of intravenous calcium. This case shows how important it is to investigate electrolytes in case of neuromuscular irritability symptoms in elderly people.

A retrospective evaluation of the impact of total smoking cessation on psychiatric inpatients taking clozapine.

OBJECTIVE: To investigate the effect of a complete smoking ban on a group of psychiatric inpatients maintained on the antipsychotic medication clozapine. METHOD: Retrospective data on clozapine dose and plasma levels were collected from a three month period before and a six month period after the introduction of the smoking ban. RESULTS: Before the ban only 4.2% of patients who smoked had a plasma clozapine level > or =1000 microg/l but after the ban this increased to 41.7% of the sample within the six month period following the ban despite dose reductions. CONCLUSION: Abrupt cessation of smoking is associated with a potentially serious risk of toxicity in patients taking clozapine. Plasma clozapine levels must be monitored closely and adjustments made in dosage, if necessary, for at least six months after cessation.

Alpha-synuclein multiplications with parkinsonism, dementia or progressive myoclonus?

Duplications and triplications of the alpha-synuclein (SNCA) gene have been reported in Parkinson's disease patients belonging to the Southern Swedish "Lister family". Further genealogical research has now shown that these individuals are descended from a large kindred characterized by Herman Lundborg in 1901-1913. In the expanded pedigree, a total of 25 individuals had Parkinson's disease with an autosomal dominant pattern of inheritance. Hereditary dementia, and, historically, dementia praecox have been described in other family members. Furthermore, an autosomal recessively inherited pediatric disease with nocturnal tonic-clonic fits, subsequent progressive myoclonus, startle reactions, tremor and muscle rigidity was described by Lundborg in the same pedigree. The entity was later designated Unverricht-Lundborg disease (ULD) or progressive myoclonus epilepsy type 1 (EPM1). However, Lundborg's clinical description of this disease, based on 17 patients within this kindred, differs from the modern definition of EPM1, which relies on patients with a mutation in the cystatin B (CSTB) gene. We hypothesize that the former pediatric disease, as well as the parkinsonism and dementia phenotypes, are associated with duplications, triplications and possibly higher-order multiplications of the alpha-synuclein (SNCA) gene. This hypothesis is supported by the distribution of afflicted family members within the pedigree and by recently obtained genealogical information.

Ocular flutter, generalized myoclonus, and trunk ataxia associated with anti-GQ1b antibodies.

OBJECTIVE: To describe a movement disorder characterized by ocular flutter, trunk ataxia, and mild generalized myoclonus associated with anti-GQ1b antibodies. DESIGN: Case report. SETTING: University hospital. PATIENT: A 37-year-old woman presented with rapid, conjugated, and periodic oscillations of the eyes with a strict preponderance for the horizontal plane (ocular flutter); trunk ataxia; and occasional arrhythmic muscle jerks (myoclonus) most pronounced at the neck. RESULTS: Brain magnetic resonance imaging results were normal. Cerebrospinal fluid examination revealed mild lymphocytic pleocytosis. Results of extensive serological tests on viral, bacterial, and fungal infections from blood and cerebrospinal fluid samples were unremarkable. Results of screening examinations for neoplasms and paraneoplastic antibodies, including whole-body fludeoxyglucose F18 positron emission tomography, were normal. Positive titers of IgG and IgM anti-GQ1b antibodies were found. CONCLUSIONS: This is the first description of an association between the clinical syndrome of ocular flutter, mild stimulus sensitive myoclonus, and trunk ataxia and anti-GQ1b antibodies. The association with ganglioside antibodies lends further support to the notion of an autoimmune-associated pathology of the syndrome.

Detection of herpesvirus-6A in a case of subacute cerebellitis and myoclonic dystonia.

This is a case study of a child who developed roseola infantum first, then varicella, and was later affected by acute cerebellar syndrome, severe truncal ataxia, and myoclonic dystonia. Human herpesvirus 6 (HHV-6) A and B were detected in the cerebrospinal fluid (CSF) and peripheral blood, respectively, upon ataxia onset. The intricacy of this case suggests multifaceted conclusions ranging from the need for a multidirectional approach to neurological diseases, to confirmation of a more pronounced neurotropism of HHV-6A and a possible role of viruses in myoclonic dystonia syndrome, although this last hypothesis should be confirmed by larger studies.

The role of carnitine supplementation during valproic acid therapy.

OBJECTIVE: To review the pathophysiology and significance of valproic acid-induced carnitine deficiency; to present and evaluate the literature pertaining to carnitine supplementation in pediatric patients receiving valproic acid; and to present the consensus guidelines for carnitine supplementation during valproic acid therapy. DATA SOURCES: A MEDLINE search (1966-December 1998) restricted to English-language literature, using MeSH headings of carnitine and valproic acid, was conducted to identify clinically relevant articles. Selected articles and references focusing on the pediatric population were included for review. DATA EXTRACTION: Study design, patient population, methods, and clinical outcomes were evaluated. DATA SYNTHESIS: Valproic acid, a widely used antiepileptic agent in the pediatric population, is limited by a 1/800 incidence of fatal hepatotoxicity in children under the age of two years. Carnitine is an essential amino acid necessary in beta-oxidation of fatty acids and energy production in cellular mitochondria. It has been hypothesized that valproic acid may induce a carnitine deficiency in children and cause nonspecific symptoms of deficiency, hepatotoxicity, and hyperammonemia. Relevant published case reports and trials studying this relationship are evaluated, and a consensus statement by the Pediatric Neurology Advisory Committee is reviewed. CONCLUSIONS: Despite the lack of prospective, randomized clinical trials documenting efficacy of carnitine supplementation in preventing valproic acid-induced hepatotoxicity, the few limited studies available have shown carnitine supplementation to result in subjective and objective improvements along with increases in carnitine serum concentrations in patients receiving valproic acid. The Pediatric Neurology Advisory Committee in 1996 provided more concrete indications on the role of carnitine in valproic acid therapy, such as valproic acid overdose and valproic acid-induced hepatotoxicity. Carnitine was strongly recommended for children at risk of developing a carnitine deficiency. Although carnitine has been well tolerated, future studies are needed to evaluate the efficacy of prophylactic carnitine supplementation for the prevention of hepatotoxicity.

Abnormalities of antioxidant metabolism in a case of Friedreich's disease.

We report a patient with Friedreich's disease (FD) who exhibited abnormalities of antioxidant metabolism, including decreased levels of glutathione peroxidase, glutathione reductase, and selenium, and an increased lipid peroxide index. These abnormalities became normal after treatment with N-acetylcysteine, selenium, and low-dose vitamin E therapy. Treatment was associated with a decreased rate of clinical decline. FD is a neurodegenerative disorder that may be related to disturbed antioxidant metabolism; the disorder may be treatable with antioxidant compounds.