Consensus Paper: Ataxic Gait.

The aim of this consensus paper is to discuss the roles of the cerebellum in human gait, as well as its assessment and therapy. Cerebellar vermis is critical for postural control. The cerebellum ensures the mapping of sensory information into temporally relevant motor commands. Mental imagery of gait involves intrinsically connected fronto-parietal networks comprising the cerebellum. Muscular activities in cerebellar patients show impaired timing of discharges, affecting the patterning of the synergies subserving locomotion. Ataxia of stance/gait is amongst the first cerebellar deficits in cerebellar disorders such as degenerative ataxias and is a disabling symptom with a high risk of falls. Prolonged discharges and increased muscle coactivation may be related to compensatory mechanisms and enhanced body sway, respectively. Essential tremor is frequently associated with mild gait ataxia. There is growing evidence for an important role of the cerebellar cortex in the pathogenesis of essential tremor. In multiple sclerosis, balance and gait are affected due to cerebellar and spinal cord involvement, as a result of disseminated demyelination and neurodegeneration impairing proprioception. In orthostatic tremor, patients often show mild-to-moderate limb and gait ataxia. The tremor generator is likely located in the posterior fossa. Tandem gait is impaired in the early stages of cerebellar disorders and may be particularly useful in the evaluation of pre-ataxic stages of progressive ataxias. Impaired inter-joint coordination and enhanced variability of gait temporal and kinetic parameters can be grasped by wearable devices such as accelerometers. Kinect is a promising low cost technology to obtain reliable measurements and remote assessments of gait. Deep learning methods are being developed in order to help clinicians in the diagnosis and decision-making process. Locomotor adaptation is impaired in cerebellar patients. Coordinative training aims to improve the coordinative strategy and foot placements across strides, cerebellar patients benefiting from intense rehabilitation therapies. Robotic training is a promising approach to complement conventional rehabilitation and neuromodulation of the cerebellum. Wearable dynamic orthoses represent a potential aid to assist gait. The panel of experts agree that the understanding of the cerebellar contribution to gait control will lead to a better management of cerebellar ataxias in general and will likely contribute to use gait parameters as robust biomarkers of future clinical trials.

Adult-onset methylenetetrahydrofolate reductase deficiency.

Severe hyperhomocysteinemia (>100 µmol/L) is often associated with inborn errors of homocysteine metabolism. It manifests typically in neonatal period with developmental delay, hypotonia, feeding problems or failure to thrive. Adult-onset forms are rare and include less severe manifestations. Early diagnosis is crucial because effective treatment is available. A 23-year-old man presented with a 3-week history of speech and gait impairment, and numbness in lower limbs. Neurological examination revealed dysarthria, decreased vibratory sensation in both legs and appendicular and gait ataxia. Brain MRI revealed T2-hyperintense symmetric white matter lesions and cortical atrophy. He had folate and vitamin B12 deficiency, a markedly elevated serum homocysteine and low methionine. Despite vitamin supplementation homocysteine levels remained elevated. Molecular studies of 5,10-methylenetetrahydrofolate reductase (MTHFR) gene revealed a new pathogenic mutation (c.1003C>T (p.Arg335Cys)) and a polymorphism (C677T (p.Ala222Val)) associated with hyperhomocysteinemia, both in homozygosity. The patient started betaine with clinical and biochemical improvement.

Progressive gait ataxia following deep brain stimulation for essential tremor: adverse effect or lack of efficacy?

Thalamic deep brain stimulation is a mainstay treatment for severe and drug-refractory essential tremor, but postoperative management may be complicated in some patients by a progressive cerebellar syndrome including gait ataxia, dysmetria, worsening of intention tremor and dysarthria. Typically, this syndrome manifests several months after an initially effective therapy and necessitates frequent adjustments in stimulation parameters. There is an ongoing debate as to whether progressive ataxia reflects a delayed therapeutic failure due to disease progression or an adverse effect related to repeated increases of stimulation intensity. In this study we used a multimodal approach comparing clinical stimulation responses, modelling of volume of tissue activated and metabolic brain maps in essential tremor patients with and without progressive ataxia to disentangle a disease-related from a stimulation-induced aetiology. Ten subjects with stable and effective bilateral thalamic stimulation were stratified according to the presence (five subjects) of severe chronic-progressive gait ataxia. We quantified stimulated brain areas and identified the stimulation-induced brain metabolic changes by multiple 18 F-fluorodeoxyglucose positron emission tomography performed with and without active neurostimulation. Three days after deactivating thalamic stimulation and following an initial rebound of symptom severity, gait ataxia had dramatically improved in all affected patients, while tremor had worsened to the presurgical severity, thus indicating a stimulation rather than disease-related phenomenon. Models of the volume of tissue activated revealed a more ventrocaudal stimulation in the (sub)thalamic area of patients with progressive gait ataxia. Metabolic maps of both patient groups differed by an increased glucose uptake in the cerebellar nodule of patients with gait ataxia. Our data suggest that chronic progressive gait ataxia in essential tremor is a reversible cerebellar syndrome caused by a maladaptive response to neurostimulation of the (sub)thalamic area. The metabolic signature of progressive gait ataxia is an activation of the cerebellar nodule, which may be caused by inadvertent current spread and antidromic stimulation of a cerebellar outflow pathway originating in the vermis. An anatomical candidate could be the ascending limb of the uncinate tract in the subthalamic area. Adjustments in programming and precise placement of the electrode may prevent this adverse effect and help fine-tuning deep brain stimulation to ameliorate tremor without negative cerebellar signs.

Transcranial direct current stimulation (tDCS) of the cortical motor areas in three cases of cerebellar ataxia.

The excitability of the motor areas of the cerebral cortex is reduced in ataxia. Since transcranial direct current stimulation (tDCS) is a noninvasive neuromodulation technique able to increase the cortical excitability, we assessed the effect of anodal tDCS over the motor cortex in three patients with ataxia. A clinical evaluation, a video-taped SARA rating scale and a gait analysis with cinematic parameters, were performed pre- and post-sham and anodal tDCS cycle. The full cycle was composed by five consecutive constant current sessions of stimulation. Anodal tDCS (2.0 mA, 20 min,max current density: 0.0278 mA/cm2, max total charge:0.033 C/cm2) was performed on the M1 area of the most affected side. The contralateral primary motor cortex underwent cathodal stimulation (2.0 mA, 20 min, max current density:0.0278 mA/cm2, max total charge: 0.033 C/cm2). After anodal tDCS, gait analysis revealed an improvement of the symmetry of step execution and reduction of base-width lasting 30 days associated to patients' perception of amelioration. No relevant changes were found after sham stimulation. Our results suggest tDCS can improve gait symmetry in patients with ataxia for a short-term period. Future researches are needed in order to standardize time, amplitude, and area of stimulation in order to reach a long lasting effect on cerebellar ataxia.

Gait impairment and optimizing mobility in multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated disease that causes demyelination and degeneration within the brain and spinal cord. This may result in many impairments, including impaired ambulation, muscle weakness, abnormal tone, visual disturbances, decreased sensation, and fatigue. Rehabilitation helps patients with MS maximize independence by helping to manage and minimize impairments. Deficits seen in ambulation should be addressed to improve energy efficiency and reduce falls. Compensation through appropriate prescription of assistive devices, bracing, and wheelchairs will help improve safety. Rehabilitation can make a significant impact on achieving and maintaining quality of life and independence.

Adrenomyeloneuropathy.

A 29-year-old male patient presented with progressive spastic paraparesis of three years duration. He also had gait ataxia which led to recurrent falls. In addition, there was pigmentation of the skin creases, tongue and buccal mucosa. His clinical course was remarkable by recurrent episodes of diarrhea, pulmonary tuberculosis. The investigatory work up showed a normal MRI scan of the brain, spinal cord and normal abdominal structures. The basal serum cortisol levels were low. Adrenomyeloneuropathy was diagnosed and he was started on corticosteroid supplementation. Mineralocorticoid supplementation also is planned in the follow up. The case is being presented for its rarity.

Difficulty in walking 10 years after gastric surgery.

A 65-year-old gentleman presented with a history of abdominal distension and difficulty in walking 10 years after a Polya partial gastrectomy. Clinical history and neurological examination suggested an axonal sensory neuropathy. A computed tomographic scan of the abdomen showed a large afferent jejunal loop, and a hydrogen breath test confirmed small-bowel bacterial overgrowth secondary to the blind loop syndrome. Serological tests revealed low copper levels, which are a cause of a myeloneuropathy. The trace element deficiency occurred as a consequence of small-bowel bacterial overgrowth, and with antibiotic treatment of the bacterial overgrowth and copper supplementation his symptoms markedly improved.

Gait ataxia in essential tremor is differentially modulated by thalamic stimulation.

Patients with advanced stages of essential tremor frequently exhibit tandem gait ataxia with impaired balance control and imprecise foot placement, resembling patients with a cerebellar deficit. Thalamic deep brain stimulation, a surgical therapy for otherwise intractable cases, has been shown to improve tremor, but its impact on cerebellar-like gait difficulties remains to be elucidated. Eleven patients affected by essential tremor (five females; age 69.8 ± 3.9 years; disease duration 24.4 ± 11.2 years; follow-up after surgery 24.7 ± 20.3 months) were evaluated during the following conditions: stimulation off, stimulation on and supra-therapeutic stimulation. Ten age-matched healthy controls served as the comparison group. Locomotion by patients and controls was assessed with (i) overground gait and tandem gait; (ii) balance-assisted treadmill tandem gait and (iii) unassisted treadmill gait. The two treadmill paradigms were kinematically analysed using a 3D opto-electronic motion analysis system. Established clinical and kinesiological measures of ataxia were computed. During stimulation off, the patients exhibited ataxia in all assessment paradigms, which improved during stimulation on and worsened again during supra-therapeutic stimulation. During over ground tandem gait, patients had more missteps and slower gait velocities during stimulation off and supra-therapeutic stimulation than during stimulation on. During balance-assisted tandem gait, stimulation on reduced the temporospatial variability in foot trajectories to nearly normal values, while highly variable (ataxic) foot trajectories were observed during stimulation off and supra-therapeutic stimulation. During unassisted treadmill gait, stimulation on improved gait stability compared with stimulation off and supra-therapeutic stimulation, as demonstrated by increased gait velocity and ankle rotation. These improvements in ataxia were not a function of reduced tremor in the lower limbs or torso. In conclusion, we demonstrate the impact of thalamic stimulation on gait ataxia in patients with essential tremor with improvement by stimulation on and deterioration by supra-therapeutic stimulation, despite continued control of tremor. Thus, cerebellar dysfunction in these patients can be differentially modulated with optimal versus supra-therapeutic stimulation. The cerebellar movement disorder of essential tremor is due to a typical cerebellar deficit, not to trembling extremities. We hypothesize that deep brain stimulation affects two major regulating circuits: the cortico-thalamo-cortical loop for tremor reduction and the cerebello-thalamo-cortical pathway for ataxia reduction (stimulation on) and ataxia induction (supra-therapeutic stimulation).

Studies of "unsteady gait disease" of the Tibetan gazelle (Procapra picticaudata).

Clinical signs of a disease locally referred to as "unsteady gait disease" for the Tibetan gazelle (Procapra picticaudata) were observed in the Qinghai Lake watershed area, China. The objective of this study was to determine if there was a relationship between the disease and copper (Cu) deficiency. Chemical examinations showed that Cu concentrations in soil and forage samples were similar from areas where gazelles were affected and unaffected. However, concentrations of sulfur (S) and molybdenum (Mo) in the soil and forage samples from the affected area were significantly higher than those from the unaffected areas (P<0.01). Copper concentrations in samples of blood, hair, and liver from the affected gazelles were significantly lower than those in unaffected animals (P<0.01). Supplementation of CuSO(4) in affected gazelles improved their appetite and vigor. We conclude that the disorder of Tibetan gazelles was caused by Cu deficiency, attributable to the high S and Mo content in forage.

[Acquired copper deficiency myelopathy]. / Myélopathie postérieure par carence en cuivre acquise.

INTRODUCTION: The hematological manifestations of acquired copper deficiency are well known. But the neurological manifestations have only been recognised in the past few years. The most common neurological manifestation in adults is a myeloneuropathy with prominent sensory ataxia and spastic gait. Electrophysiological tests reveal an axonal sensorimotor peripheral neuropathy. Spinal MRI shows an augmented T2 signal involving the dorsal column. The causes of acquired copper deficiency include gastric surgery, excessive zinc ingestion, and malabsorption but in most cases, the cause remains unclear. Early recognition and treatment may prevent neurological deterioration but improvement seems to be slight and inconstant. OBSERVATION: We report two new cases of acquired copper deficiency myeloneuropathy associated with a nephrotic syndrome and, in one case, with a major iron overload syndrome. Biological abnormalities disappeared under copper supplementation. A significant neurological improvement with disappearance of ataxia occurred in one patient who received copper supplementation eight months after symptom onset. CONCLUSIONS: Nephrotic syndrome might be another complication of acquired copper deficiency. Delayed treatment is not necessarily associated with a deleterious neurological prognosis. Significant neurological improvement under copper supplementation is possible.

Unsuccessful intraventricular pentosan polysulphate treatment of variant Creutzfeldt-Jakob disease.

Pentosan polysulphate, delivered by chronic intraventricular infusion, has been proposed as a potential therapy for human prion disease. The first treated patient is still alive several years after treatment started. Here we describe in detail a case of variant Creutzfeldt-Jakob disease in which this treatment was started at a relatively early stage but had no definite clinical benefit. The patient died from disease progression 16 months after diagnosis and 5 months after pentosan polysulphate treatment was commenced.

[Astasia in a patient with unilateral thalamic infarction: clinical and MRI study].

We report a 82-year-old woman who developed difficulty in standing and sitting in the morning. She had no other complaints and stayed in the bed. The next day, she was admitted to the hospital and neurological examination revealed that she was alert, with no other motor or sensory abnormalities. Finger to nose test, and knee to heel test were normal. No dysdiadochokinesia was seen. Astasia was the only observed abnormal finding. MRI showed a small infarction (14 x 8mm) in the posterolateral portion of the left thalamus (VPL-LP nucleus). During the following 15 days, her imbalance has gradually improved and then disappeared. We diagnosed the patient as astasia occurring from a small unilateral infarction in the thalamus. It is thought that thalamic astasia is caused by the disruption of afferent pathway from the vestibulocerebellum; however, this case is based on just clinical and MRI study, so physiological and pathological studies will be necessary in the future.

Immediate effect of percutaneous intramuscular stimulation during gait in children with cerebral palsy: a feasibility study.

The feasibility of percutaneous intramuscular functional electrical stimulation (P-FES) in children with cerebral palsy (CP) for immediate improvement of ankle kinematics during gait has not previously been reported. Eight children with CP (six with diplegia, two with hemiplegia; mean age 9 years 1 month [SD 1 y 4 mo; range 7 y 11 mo to 11 y 10 mo]) had percutaneous intramuscular electrodes implanted into the gastrocnemius (GA) and tibialis anterior (TA) muscles of their involved limbs. Stimulation was provided during appropriate phases of the gait cycle in three conditions (GA only, TA only, and GA/TA). immediately after a week of practice for each stimulation condition, a gait analysis was performed with and without stimulation. A significant improvement in peak dorsiflexion in swing for the more affected extremity and dorsiflexion at initial contact for the less affected extremity were found in the GA/TA condition. Clinically meaningful trends were evident for improvements in dorsiflexion kinematics for the more and less affected extremities in the TA only and GA/TA conditions. The results suggest that P-FES might immediately improve ankle kinematics in children with CP.

Paroxysmal dysarthria and ataxia after midbrain infarction.

The authors describe a patient who showed paroxysmal dysarthria and right-limb ataxia after midbrain infarction. SPECT imaging showed marked hypoperfusion in the left parietal lobe while the patient was having frequent paroxysmal attacks. After treatment with phenytoin, the symptoms and hypoperfusion in SPECT imaging improved. The authors conclude that dysfunction of the cerebellothalamocortical pathway after midbrain infarction may cause paroxysmal dysarthria and ataxia.

Copper deficiency myelopathy produces a clinical picture like subacute combined degeneration.

BACKGROUND: Copper deficiency in ruminants is known to cause an ataxic myelopathy. Copper deficiency as a cause of progressive myelopathy in adults is underrecognized. OBJECTIVE: To describe the clinical, biochemical, electrophysiologic, and imaging characteristics in 13 patients with myelopathy associated with copper deficiency. METHODS: The records of patients with a copper deficiency-associated myelopathy were reviewed. Clinical characteristics, laboratory investigations, and responses to therapeutic intervention were summarized. RESULTS: Thirteen such patients were found, 11 of them in a 15-month period. All patients presented with prominent gait difficulty, reflecting a sensory ataxia due to dorsal column dysfunction and lower limb spasticity. All patients had polyneuropathy. A high or high-normal serum zinc level was seen in 7 of the 11 patients for whom this information was available. Somatosensory evoked potential studies done in eight patients showed impaired conduction in central proprioceptive pathways. Dorsal column signal change on spine MRI was present in three patients. An initial clue to the diagnosis was a very low ceruloplasmin level; further tests of copper metabolism excluded Wilson disease. The cause remained unexplained in most patients. Oral copper supplementation restored normal or near-normal copper levels in 7 of the 12 patients in whom adequate follow-up data were available; parenteral supplementation restored normal level in 3 further patients. Copper supplementation prevented further neurologic deterioration, but the degree of actual improvement was variable. CONCLUSIONS: Unrecognized copper deficiency appears to be a common cause of idiopathic myelopathy in adults. The clinical picture bears striking similarities to the syndrome of subacute combined degeneration associated with vitamin B12 deficiency. Early recognition and copper supplementation may prevent neurologic deterioration.

Capecitabine-related neurotoxicity presenting as trismus.

Capecitabine is an oral fluoropyrimidine used for cancer treatment. It is generally well tolerated. A patient who had previously received adjuvant 5-fluorouracil without neurotoxicity had a severe adverse reaction when later given capecitabine in the metastatic setting. She presented with the acute onset of neuromuscular symptoms, the most prominent being trismus but also including slurred speech, confusion, gait abnormalities, and ocular changes. Her symptoms completely resolved with discontinuation of capecitabine.

Cutaneous stimulation improves function of a chronic patient with cerebellar damage.

The prognosis of cerebellar hemorrhage with brain stem compression is known to be poor, and patients who can usually survive are severely disabled with limited benefit from conventional rehabilitation. An innovative cutaneous stimulation was administered to a chronic patient (2 years after the incidence) who has severe ataxia, gait imbalance and limb spasticity caused by cerebellar hemorrhage. After 8 months of intervention, patient's function as evaluated by two functional measures has improved by 40%. In addition, the patient's ataxia and hypotonia have improved significantly in which he has regained the abilities to grasp objects, sit upright, control his equilibrium, and monitor an electric wheelchair. The present case study demonstrated a significant improvement of a chronic severely disabled patient who received the intervention 2 years after the accident, suggesting that the cutaneous stimulation may be a possible effective neurologic intervention.

[Two cases of thalamic infarction presenting with "thalamic astasia"].

We report two cases of so-called 'thalamic astasia', associated with thalamic infarction. A 76-year-old-man suddenly noted to fall down to the left side without severe hemiparesis. An MRI showed an infarction in the superolateral portion of the right thalamus. Over eight weeks, his astasia gradually disappeared. A 69-year-old-man suddenly noted inability to stand with loss of balance. He showed mild hemiparesis, hypesthesia and cerebellar signs on the right side. Although right hemiparesis was slight, he was unable to stand by himself. An MRI demonstrated an infarction in the ventrolateral to ventroposterior portion of the left thalamus. Three weeks later, his symptoms except for cerebellar ataxia remarkably disappeared. The overlapped MRI lesions of these two cases were localized in the ventrolateral thalamus, such as Vimi (nucleus ventrointermedii internus), Vci (nucleus ventrocaudalis internus), Cemc (nucleus centralis thalami magnocellularis). These lesions are so-called 'vestibular thalamic nuclei', in which fibers from vestibulocerebellum are terminated. Involvement of the thalamic connectivity explains that two patients noted inability to stand. Thus we concluded that these two patients had thalamic astasia, described by Masdeu and Gorelick.

Cerebellar activation during ataxic gait in olivopontocerebellar atrophy: a PET study.

OBJECTIVE: To investigate the possible abnormal regional brain metabolism during ataxic gait in olivopontocerebellar atrophy (OPCA), and to evaluate the response of the cerebellar subregions to instability during bipedal gait. MATERIAL AND METHODS: On 9 patients with OPCA in early phase and on 10 age-matched normal subjects, we performed positron emission tomography (PET) with 2-[18F]fluoro-2-deoxy-D-glucose (FDG) under two different conditions: supine resting and 30 min treadmill walking. RESULTS: Both in normals and in patients with OPCA, the FDG uptake in the walking state (Uwalk) was significantly greater than that in the resting state (Urest) in the pyramis, declive-folium-tuber and culmen of the cerebellar vermis, and in the thalamus. In the patients, the Uwalk was also significantly greater than the Urest in the posterior lobe of cerebellar hemisphere and in the pons and midbrain. In the pyramis, the activation ratio (= Uwalk/Urest) of the patients was significantly lower than that of the normals. CONCLUSIONS: We considered that these findings reflect the pathophysiology of ataxic gait in OPCA patients and the compensatory mechanism for the instability during ataxic gait.