Subacute Horizontal Diplopia, Jaw Dystonia, and Laryngospasm.

Jaw dystonia and laryngospasm in the context of subacute brainstem dysfunction have been described in a small number of diseases, including antineuronal nuclear antibody type 2 (ANNA-2, also known as anti-Ri) paraneoplastic neurologic syndrome. Severe episodes of laryngospasms causing cyanosis are potentially fatal. Jaw dystonia can also cause eating difficulty, resulting in severe weight loss and malnutrition. In this report, we highlight the multidisciplinary management of this syndrome associated with ANNA-2/anti-Ri paraneoplastic neurologic syndrome and discuss its pathogenesis.

Large kindred evaluation of mitofusin 2 novel mutation, extremes of neurologic presentations, and preserved nerve mitochondria.

BACKGROUND: Mitofusin 2 (MFN2) is a mitochondrial membrane protein mediating mitochondrial fusion and function. Mutated MFN2 is responsible for Charcot-Marie-Tooth type 2A2. In small kindreds, specific MFN2 mutations have been reported to associate with severity of axonal neuropathy, optic atrophy, and involvement of the central nervous system. The results of the nerve biopsy specimens suggested that the mitochondria are structurally abnormal in patients with MFN2 mutations. OBJECTIVE: To study a newly identified MFN2 mutation, Leu146Phe, and the associated phenotypes in a large kindred. PATIENTS: An American kindred of Northern European and Cherokee American Indian descent. RESULTS: Genetic analysis revealed a novel GTPase domain MFN2 mutation Leu146Phe that associated with clinical status of 15 studied persons (10 affected and 5 unaffected) and not found in 800 control persons. Clinical manifestations were markedly different. In 1 affected person, optic atrophy and brain magnetic resonance imaging abnormalities led to multiple sclerosis diagnosis and interferon ß-1a treatment when neuropathy was initially unrecognized. Age of onset ranged from 1 to 45 years. In some affected family members, severe and rapid-onset motor sensory neuropathy led to early loss of ambulation, whereas other family members experienced minimal neuropathic sensory symptoms. Despite histologically significant loss of nerve fibers, the mitochondria were not distinguishable from diseased sural nerve biopsy specimens and healthy controls. CONCLUSIONS: Novel MFN2 mutation Leu146Phe causes Charcot-Marie-Tooth type 2A2. Intrafamilial clinical phenotype variability is emphasized and has important implications in genetic counseling. The clinical phenotype may mimic multiple sclerosis when optic atrophy and the characteristic brain lesions of MFN2 on magnetic resonance imaging are present and neuropathy is mild or unrecognized. The predicted molecular pathogenesis may occur without evident histological abnormalities of mitochondria in nerve.

Paraneoplastic jaw dystonia and laryngospasm with antineuronal nuclear autoantibody type 2 (anti-Ri).

BACKGROUND: Opsoclonus-myoclonus syndrome and breast carcinoma were initially described as neurologic and oncologic accompaniments of antineuronal nuclear autoantibody type 2 (ANNA-2, also known as anti-Ri). However, the neurologic spectrum of ANNA-2 autoimmunity is broader, includes a syndrome of jaw dystonia and laryngospasm, and can be accompanied by lung carcinoma. OBJECTIVE: To describe clinically (with a video) ANNA-2-associated jaw dystonia and laryngospasm, its pathologic correlates, and therapeutic outcomes. DESIGN: Retrospective case series with prospective clinical follow-up. SETTING: Mayo Clinic's Neuroimmunology Laboratory, Rochester, Minnesota. PATIENTS: Consecutive patients with ANNA-2 seropositivity identified since January 1, 1990. MAIN OUTCOME METHODS: Clinical (in 9 patients) and neuropathologic (in 2 patients) findings were reviewed. RESULTS: Of 48 patients with ANNA-2 seropositivity, 9 (19%) had multifocal neurologic manifestations that included jaw dystonia and laryngospasm. Among 6 patients with jaw dystonia, 5 had severely impaired nutrition, causing profound weight loss. Five patients had documented laryngospasm, which contributed to 1 patient's death. Neuropathologic examination revealed diffuse infiltration by CD8(+) T lymphocytes, with axonal loss and gliosis in brainstem and descending spinal cord tracts. Some patients improved symptomatically after immunosuppressant or cytotoxic therapies; 1 patient improved after treatment with botulinum toxin. One patient who underwent tracheostomy because of recurrent laryngospasm was alive and well longer than 3 years after symptom onset. CONCLUSIONS: Jaw dystonia and laryngospasm are common accompaniments of ANNA-2 autoimmunity and are associated with significant morbidity. We propose that selective damage to antigen-containing inhibitory fibers innervating bulbar motor nuclei by CD8(+) T lymphocytes (histopathologically observed infiltrating brainstem reticular formation) is the proximal cause of this syndrome. Early and aggressive therapy offers the prospect of neurologic improvement or stabilization.

Anti-neuronal nuclear autoantibody type 2: paraneoplastic accompaniments.

We identified the IgG autoantibody ANNA-2 ("anti-Ri") in 34 patients in a 12-year period by immunofluorescence screening of sera from approximately 75000 patients with subacute neurological disorders that were suspected to be paraneoplastic. Detailed clinical information was available for 28 patients (10 men, 18 women). Cancer was diagnosed in 24 patients (86%); 21 had histologically proven carcinoma (10 lung, 9 breast, 1 cervical, 1 bladder), and 3 had an intrathoracic imaging abnormality. Cancer anteceded neurological symptoms in 4 of 28 patients. Cancer detection frequency increased with continued surveillance. Neurological disorders, in decreasing frequency, were brainstem syndrome (including opsoclonus, myoclonus, or both), cerebellar syndrome, myelopathy, peripheral neuropathy, cranial neuropathy, movement disorder, encephalopathy, Lambert-Eaton syndrome, and seizures. Four patients had laryngospasm and four had jaw opening dystonia (two with neck dystonia). Nine (32%) were wheelchair-bound 1 month after neurological symptom onset. Most improved neurologically after immunomodulatory or tumor-directed therapy. Accompanying autoantibodies, found in 73% of sera, included ANNA-1, ANNA-3, CRMP-5-IgG, P/Q-type and N-type Ca(2+) channel antibodies, and muscle-type acetylcholine receptor antibody. Some neurological accompaniments of ANNA-2 may reflect potentially pathogenic humoral or cell-mediated responses to coimmunogenic tumor antigens, for example, Lambert-Eaton syndrome (P/Q-type Ca(2+) channel antibody) and peripheral neuropathy (ANNA-1 effector T cells).