Finger extension weakness and downbeat nystagmus motor neuron disease syndrome: A novel motor neuron disorder?

Disturbances of eye movements are rarely encountered in motor neuron diseases (MNDs) or motor neuropathies.1-3 Limited upgaze, saccadic intrusions, and slow saccades have been reported, most commonly seen in MND patients with bulbar onset or frontal impairment.4-9 Nystagmus is extremely rare in MNDs.4, 10 In 2006, we first reported 3 cases with the exceptional combination of a motor neuron syndrome and downbeat nystagmus.11 Here we describe 3 additional cases with the same condition and provide follow-up information on the previously reported cases, confirming that this is a novel clinical disease entity, an MND with distal upper extremity extensor muscle weakness and downbeat nystagmus.

METHODS

A retrospective chart review was performed on the identified cases. Clinical parameters and the results of investigations were collected and analyzed. The study was approved by institutional ethics committees, and the patients provided written informed consent.

RESULTS

Detailed descriptions of the clinical presentations and the results of investigations of 3 novel patients and follow-up information on 2 of the 3 earlier reported patients11 are given in the Supporting Information online. The combination of a slowly progressive motor syndrome with prominent early finger extensor weakness and the eventual development of downbeat nystagmus characterize this syndrome. The core clinical characteristics and investigation results of the 6 patients are presented in Table 1.

The age at onset was during adolescence or early adulthood in all patients. All patients presented with unilateral finger extension paresis, slowly spreading to other muscle groups in the arms but also with progression to the legs. Over time, all patients developed gait difficulties, with reduced stability during walking. Over more than 30 years of follow-up, none of the patients experienced functionally important bulbar or respiratory involvement, pseudobulbar affect, or cognitive impairment.

Symptoms were always purely motor; none of the patients reported sensory symptoms or pain. Disease progression was slow in all patients. All patients with current follow-up information (5/6) were still alive after a disease duration ranging from 3 to 43 years. Family history was negative for MNDs in all patients.

Ocular manifestations of the syndrome were asymptomatic or absent in early disease stages in 3/6 patients. The other 3 patients noticed oscillopsia or mild diplopia, which coincided with the onset of muscle weakness. After a disease duration ranging from less than 1 year to 7 years, 5/6 patients reported visual symptoms, and only 1 patient remained asymptomatic. The most distinctive feature of the disease was downbeat nystagmus in all patients (see Supporting Information video). Most accompanying oculomotor findings were also attributable to cerebellar dysfunction and included skew deviation, comitant esophoria, saccadic dysmetria, abnormal smooth pursuit, impaired suppression of the vestibulo-ocular reflex (VOR), and gaze-evoked nystagmus. Less localizing was the presence of excessive saccadic intrusions in 2 patients.

Muscle weakness was most pronounced in distal arm and leg muscles, with extensor muscles generally more affected than flexor muscles. In 4 patients, the disease progressed to involve proximal musculature as well. The weakest muscles were usually atrophic with visible fasciculations, suggesting lower motor neuron involvement. Many patients had brisk reflexes at least in some body regions, sometimes with a slight increase in muscle tone, but manifest upper motor neuron involvement with spasticity or extensor plantar responses was not encountered. No signs of upper or lower motor neuron involvement were seen in the bulbar region except for patient 3 with tongue fasciculations. Results of the sensory exam were normal for all patients. There was no truncal or appendicular ataxia.

Electrodiagnostic testing confirmed lower motor neuron involvement, with signs of denervation (positive sharp waves and fibrillation potentials) and fasciculation potentials, in combination with signs of reinnervation (large amplitude-long duration motor unit potentials with reduced recruitment) in multiple regions.

Eye movement recordings were performed in 3 patients. Downbeat nystagmus was confirmed in all patients. Other clinical findings are detailed in Table 1.

Laboratory investigations did not reveal consistent abnormalities. Aside from variably increased antinuclear antigen (ANA) titers in 3 patients, low level of antiglutamic acid decarboxylase (GAD) and antigliadin antibodies in 1 patient, and antithyroglobulin/thyroperoxidase antibodies in another patient, autoimmune screening results were normal. Genetic testing for spinal muscular atrophy (SMA; assessing SMN1), amyotrophic lateral sclerosis (ALS; assessing C9ORF72, superoxide dismutase 1, TAR DNA-binding protein 43, fused in sarcoma, senataxin), Kennedy disease, and episodic ataxia type 2 (each performed in some of the patients) did not reveal pathogenic mutations.

Cerebrospinal fluid (CSF) was normal in each of 4 patients in whom it was tested, without evidence of pleocytosis, elevated protein, or intrathecal antibody synthesis. In 1 patient, CSF neurofilaments (phosphoneurofilament heavy and neurofilament light chain) were measured and were below the cutoff for ALS.12

Results of MRI of the brain were normal in 3 patients (Table 1). Fluorodeoxyglucose-positron emission tomography was performed in 1 patient, revealing mild hypometabolism in the motor cortex, as can be seen in ALS.13-15 A trial with plasma exchange (patient 1) and intravenous immunoglobulins (patient 2) did not alter the disease course.

DISCUSSION

We describe a novel motor syndrome, characterized by progressive muscle weakness with onset in finger extensor muscles and a downbeat nystagmus. In published reports of series of patients with downbeat nystagmus, a concomitant motor syndrome is not mentioned.16, 17 As an acronym that captures the core clinical features for finger extensor weakness and downbeat nystagmus motor neuron disease, we suggest FEWDON-MND syndrome. With only 6 reported patients to date, the incidence is anticipated to be low. However, increased awareness of this clinical disease entity may lead to identification of additional patients and research into its pathophysiology.

The differential diagnosis of FEWDON-MND syndrome is broad. The initial diagnoses included ALS, SMA, multifocal motor neuropathy (MMN), and distal hereditary motor neuropathy (dHMN). MNDs or motor neuropathies often have onset in the distal upper extremities. However, onset with finger and wrist extensor muscle weakness is not frequent. MMN can start with finger extension weakness18; however, none of the patients had signs of demyelination on electrodiagnostic testing or positive monosialotetrahexosylganglioside (GM1) antibodies. Low-titer GAD antibodies were found in 1 patient. GAD antibodies can present with ataxia or eye movement disorders, including downbeat nystagmus. However, in 5 of our patients, those antibodies were negative. In addition, muscle paresis is not described in patients with GAD antibodies.19

Downbeat nystagmus has not been reported in the setting of MND.20, 21 Although downbeat nystagmus is at times clinically obvious, its presence may be more subtle. By definition, it should be present in central fixation; however, as was seen in all of our patients, it is enhanced and most clinically obvious in downward and lateral gaze (so-called “side-pocket” nystagmus).3 Provocative maneuvers such as horizontal and vertical head shaking, hyperventilation, and supine and supine head-hanging positions22-25 can increase the sensitivity of detection of downbeat nystagmus.

Several mechanisms related to impairment of the cerebellum or its inputs have been shown to result in downbeat nystagmus. These include asymmetry of vertical VOR, dysfunction of otolith-ocular reflex regulation, altered vestibulocerebellar or neural integrator function, and impaired smooth pursuit.3 They are not mutually exclusive and several may be involved, even in an individual patient. The gravitational dependence of the downbeat nystagmus in our patient 3 suggests a component of impairment of otolith-ocular reflexes in this patient,22 although it is clear that additional characterization of the downbeat nystagmus in this condition is required.

The etiology of FEWDON-MND syndrome remains unknown. We believe that infectious or postinfectious mechanisms, nutritional deficiency, intoxication, neoplastic or paraneoplastic mechanisms, and central nervous manifestation of internal organ dysfunction are unlikely. An immune-mediated or genetic origin seems most likely at this stage. Over the past decade, several neuroimmunological diseases linked to autoantibodies against neuronal proteins have been identified.26 Whether FEWDON-MND syndrome is a neuroimmunological condition remains unknown. Arguments favoring this hypothesis are the presence of elevated ANA titers, GAD antibodies, antigliadin, and antithyroglobulin/thyroperoxidase antibodies in some patients. Ataxia associated with GAD antibodies can present with downbeat nystagmus.19 However, these antibodies were present in only 1 patient in low titer, and none of the patients with FEWDON-MND syndrome had ataxia.

No support for an autoimmune hypothesis was found by examination of CSF. In addition, therapeutic trials with immune-modulating therapies, such as intravenous immunoglobulins or plasma exchange, did not affect the disease course.

A genetic origin of FEWDON-MND syndrome is also possible. Family history was negative for disease for all patients, but this would still be compatible with an autosomal recessive inheritance pattern with a rare carrier frequency or with sporadic or de novo mutations. Next-generation sequencing efforts on DNA samples from the patients and their parents are underway to explore a putative genetic cause.