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The human spinal cord contains segregated sensory and motor pathways that have been difficult to quantify using conventional magnetic resonance imaging (MRI) techniques. Multiple sclerosis is characterized by both focal and spatially diffuse spinal cord lesions with heterogeneous pathologies that have limited attempts at linking MRI and behaviour. We used a novel magnetization-transfer-weighted imaging approach to quantify damage to spinal white matter columns and tested its association with sensorimotor impairment. We studied 42 participants with multiple sclerosis who each underwent MRI at 3 Tesla and quantitative tests of sensorimotor function. We measured cerebrospinal-fluid-normalized magnetization-transfer signals in the dorsal and lateral columns and grey matter of the cervical cord. We also measured brain lesion volume, cervical spinal cord lesion number and cross-sectional area, vibration sensation, strength, walking velocity and standing balance. We used linear regression to assess the relationship between sensorimotor impairment and MRI abnormalities. We found that the dorsal column cerebrospinal-fluid-normalized magnetization-transfer signal specifically correlated with vibration sensation (R = 0.58, P < 0.001) and the lateral column signal with strength (R = -0.45, P = 0.003). Spinal cord signal measures also correlated with walking and balance dysfunction. A stepwise multiple regression showed that the dorsal column signal and diagnosis subtype alone explained a significant portion of the variance in sensation (R(2) = 0.54, P < 0.001), whereas the lateral column signal and diagnosis subtype explained a significant portion of the variance in strength (R(2) = 0.30, P < 0.001). These results help to understand the anatomic basis of sensorimotor disability in multiple sclerosis and have implications for testing the effects of neuroprotective and reparative interventions.

Small fibre neuropathy (SFN), a condition dominated by neuropathic pain, is frequently encountered in clinical practise either as prevalent manifestation of more diffuse neuropathy or distinct nosologic entity. Aetiology of SFN includes pre-diabetes status and immune-mediated diseases, though it remains frequently unknown. Due to their physiologic characteristics, small nerve fibres cannot be investigated by routine electrophysiological tests, making the diagnosis particularly difficult. Quantitative sensory testing (QST) to assess the psychophysical thresholds for cold and warm sensations and skin biopsy with quantification of somatic intraepidermal nerve fibres (IENF) have been used to determine the damage to small nerve fibres. Nevertheless, the diagnostic criteria for SFN have not been defined yet and a 'gold standard' for clinical practise and research is not available. We screened 486 patients referred to our institutions and collected 124 patients with sensory neuropathy. Among them, we identified 67 patients with pure SFN using a new diagnostic 'gold standard', based on the presence of at least two abnormal results at clinical, QST and skin biopsy examination. The diagnosis of SFN was achieved by abnormal clinical and skin biopsy findings in 43.3% of patients, abnormal skin biopsy and QST findings in 37.3% of patients, abnormal clinical and QST findings in 11.9% of patients, whereas 7.5% patients had abnormal results at all the examinations. Skin biopsy showed a diagnostic efficiency of 88.4%, clinical examination of 54.6% and QST of 46.9%. Receiver operating characteristic curve analysis confirmed the significantly higher performance of skin biopsy comparing with QST. However, we found a significant inverse correlation between IENF density and both cold and warm thresholds at the leg. Clinical examination revealed pinprick and thermal hypoesthesia in about 50% patients, and signs of peripheral vascular autonomic dysfunction in about 70% of patients. Spontaneous pain dominated the clinical picture in most SFN patients. Neuropathic pain intensity was more severe in patients with SFN than in patients with large or mixed fibre neuropathy, but there was no significant correlation with IENF density. The aetiology of SFN was initially unknown in 41.8% of patients and at 2-year follow-up a potential cause could be determined in 25% of them. Over the same period, 13% of SFN patients showed the involvement of large nerve fibres, whereas in 45.6% of them the clinical picture did not change. Spontaneous remission of neuropathic pain occurred in 10.9% of SFN patients, while it worsened in 30.4% of them.

Sensory disturbances are part of the clinical picture of Parkinson's disease. Abnormalities in sensory processing, through a basal ganglia involvement, are thought to be responsible for the sensory dysfunction since sensory nerve conduction velocity (NCV) is usually normal. However, NCV does not examine small fibres or terminal endings of large sensory fibres, whereas skin biopsy is more suitable for these purposes. To evaluate peripheral sensory nerves in Parkinson's disease, we studied cutaneous free and encapsulated sensory nerve endings in 18 patients and 30 healthy controls using 3-mm punch biopsies from glabrous and hairy skin. Ten patients had additional skin biopsies from the contralateral side. Further evaluation included NCV and Quantitative Sensory Testing. Parkinson's disease patients showed a significant increase in tactile and thermal thresholds (P < 0.01), a significant reduction in mechanical pain perception (P < 0.01) and significant loss of epidermal nerve fibres (ENFs) and Meissner corpuscles (MCs) (P < 0.01). In patients with bilateral biopsies, loss of pain perception and ENFs was higher on the more affected side (P < 0.01). We found evidence suggesting attempts at counteracting degenerative processes as increased branching, sprouting of nerves and enlargement of the vascular bed. Morphological and functional findings did not correlate with age or disease duration. Disease severity correlated with loss of MCs and reduction in cold perception and pain perception. We demonstrated a peripheral deafferentation in Parkinson's disease that could play a major role in the pathogenesis of the sensory dysfunction.

Ross syndrome is described as a rare disorder of sweating associated with areflexia and tonic pupil. Since Ross's first description in 1958, approximately 40 cases have been described. We assessed the involvement of cutaneous innervation in 12 subjects with Ross syndrome using quantitative sensory testing, sweating assessment and immunohistochemical study of anhidrotic and hyperhidrotic skin. This evaluation was repeated over time in 4 out of 12 subjects. In addition, we enrolled four subjects with Holmes-Adie syndrome (areflexia and tonic pupil) to investigate similarities between the two conditions. We found in Ross patients a complex and progressive involvement of cutaneous sensory and autonomic innervation underlying the impairment of heat production and heat dissipation through both loss of sweating and loss of cutaneous blood flow regulation. In Holmes-Adie subjects we found a mild impairment of sweating without thermoregulatory problems. The persistence of a sudomotor vasoactive intestinal peptide-immunoreactive (VIP-ir) innervation, although deranged and poor, definitely differentiated Holmes-Adie from Ross patients. Ross syndrome is a progressive and complex disorder of thermoregulation difficult to differentiate from the probably pathogenetically related Holmes-Adie syndrome. Sweating assessment and skin biopsy are suitable tools to define a boundary between them. Owing to the large number of Ross patients observed in only 5 years, and to the long and complex medical history of most of them, doubts arise on the effective rarity of this condition, and we warn family doctors and other specialists, besides neurologists, to become aware of this complex disorder.

We assessed the clinicopathological features of 92 patients with primary Sjögren's syndrome-associated neuropathy (76 women, 16 men, 54.7 years, age at onset). The majority of patients (93%) were diagnosed with Sjögren's syndrome after neuropathic symptoms appeared. We classified these patients into seven forms of neuropathy: sensory ataxic neuropathy (n = 36), painful sensory neuropathy without sensory ataxia (n = 18), multiple mononeuropathy (n = 11), multiple cranial neuropathy (n = 5), trigeminal neuropathy (n = 15), autonomic neuropathy (n = 3) and radiculoneuropathy (n = 4), based on the predominant neuropathic symptoms. Acute or subacute onset was seen more frequently in multiple mononeuropathy and multiple cranial neuropathy, whereas chronic progression was predominant in other forms of neuropathy. Sensory symptoms without substantial motor involvement were seen predominantly in sensory ataxic, painful sensory, trigeminal and autonomic neuropathy, although the affected sensory modalities and distribution pattern varied. In contrast, motor weakness and muscle atrophy were observed in multiple mononeuropathy, multiple cranial neuropathy and radiculoneuropathy. Autonomic symptoms were often seen in all forms of neuropathy. Abnormal pupils and orthostatic hypotension were particularly frequent in sensory ataxic, painful, trigeminal and autonomic neuropathy. Unelicited somatosensory evoked potentials and spinal cord posterior column abnormalities in MRI were observed in sensory ataxic, painful and autonomic neuropathy. Sural nerve biopsy specimens (n = 55) revealed variable degrees of axon loss. Predominantly large fibre loss was observed in sensory ataxic neuropathy, whereas predominantly small fibre loss occurred in painful sensory neuropathy. Angiitis and perivascular cell invasion were seen most frequently in multiple mononeuropathy, followed by sensory ataxic neuropathy. The autopsy findings of one patient with sensory ataxic neuropathy showed severe large sensory neuron loss paralleling to dorsal root and posterior column involvement of the spinal cord, and severe sympathetic neuron loss. Degrees of neuron loss in the dorsal and sympathetic ganglion corresponded to segmental distribution of sensory and sweating impairment. Multifocal T-cell invasion was seen in the dorsal root and sympathetic ganglion, perineurial space and vessel walls in the nerve trunks. Differential therapeutic responses for corticosteroids and IVIg were seen among the neuropathic forms. These clinicopathological observations suggest that sensory ataxic, painful and perhaps trigeminal neuropathy are related to ganglioneuronopathic process, whereas multiple mononeuropathy and multiple cranial neuropathy would be more closely associated with vasculitic process.

Lewis-Sumner syndrome (LSS) is a dysimmune peripheral nerve disorder, characterized by a predominantly distal, asymmetric weakness mostly affecting the upper limbs with sensory impairment, and by the presence of multifocal persistent conduction blocks. The nosological position of this neuropathy in relation to multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is still debated. We report the clinical, biological and electrophysiological features, the course and the response to treatment in 23 LSS patients. The initial symptoms started in the distal part of an upper limb in 70% of patients. They were sensorimotor in 65% and purely sensory in 35% of patients. A cranial nerve involvement was observed in 26% of patients and a distal limb amyotrophy in 52%. The CSF protein level was normal in 67% of patients and mildly elevated in the remainder. None had serum anti-GM1 antibodies. There were multiple motor conduction blocks (average of 2.87/patient), predominantly located in the forearm, whereas demyelinating features outside the blocked nerves were rare. Abnormal distal sensory potentials were found in 87% of patients. The electrophysiological pattern suggests a very focal motor fibre demyelination sparing the nerve endings, whereas sensory fibre involvement was widespread. The course was chronic progressive in 71% of patients and relapsing-remitting in the others. During the follow-up study (median duration of 4 years), half of the patients progressed with a multifocal pattern and the distribution of the motor deficit remained similar to the initial presentation. The other patients showed a progression to the other limbs, suggesting a more diffuse process. Fifty-four percent of the patients treated with intravenous immunoglobulin showed an improvement, compared with 33% of the patients treated with oral steroids. Overall, 73% of patients had a positive response to immune-mediated therapy. LSS may be distinguished from MMN by the presence of sensory involvement, the absence of serum anti-GM1 antibodies and, in some cases, a positive response to steroids. In some of the patients in our study, LSS evolved into a more diffuse neuropathy sharing similarities with CIDP. Others had a clinical course characterized by a striking multifocal neuropathy, which suggests underlying mechanisms different from CIDP. Overall, whatever the clinical course, LSS responded to immune-mediated treatment in a manner similar to CIDP.

Neurofibromatosis 1 (NF1) is a common disease which is a source of various multisystemic manifestations related either to the accumulation of neurofibromas or to specific developmental abnormalities. The neurofibroma is the hallmark lesion of NF1 and develops from peripheral nerves. However, to date, the description of peripheral neuropathies of NF1 has not been investigated. To examine this question, we have evaluated 688 NF1 patients for the presentation, prognosis and associated morbidity of peripheral neuropathies in two hospital-based series. We collected 18 patients (four women and 14 men) with diffuse peripheral neuropathy (2.3%). Eight patients had a paucisymptomatic or an asymptomatic neuropathy detected only on electrophysiological study, two had minor sensory manifestations, five had moderate motor and sensory manifestations and three had severe motor and sensory manifestations. Superimposed radicular changes were observed in seven cases. Two patients had a subacute and 16 a chronic polyneuropathy. Fourteen patients had a demyelinating neuropathy with either severe axonal changes (three), moderate or minor axonal changes (four) or no axonal changes (seven). Four patients had axonal neuropathies. There was a strong association between the presence of a peripheral neuropathy and large root diffuse neurofibromas (P < 0.03) and subcutaneous neurofibromas (P < 0.0001). Severe morbidity and mortality of patients with NF1 and peripheral neuropathies was 50%, much higher than what is observed in the general population of patients with NF1, and 100% in patients with the most severe symptoms and electrophysiological changes (demyelination with severe axonal features). Four patients out of 18 (22%) developed a malignant peripheral nerve sheath tumour (MPNST), a much higher proportion than in the whole population of NF1. Two patients died. Peripheral neuropathy constitutes a potentially severe complication in patients with NF1 associated with a frequent morbidity related to spinal complications and MPNSTs. Association of proximal large neurofibromas, peripheral neuropathies and subcutaneous neurofibromas may constitute a phenotype of NF1 with a severe prognosis.

Patients with schizophrenia and related psychoses have an excess of minor neurological abnormalities (neurological soft signs) of unclear neuropathological origin. These include poor motor coordination, sensory perceptual difficulties and difficulties in sequencing complex motor tasks. Neurological soft signs seem not to reflect primary tract or nuclear pathology. It still has to be established whether neurological soft signs result from specific or diffuse brain structural abnormalities. Studying their anatomical correlates can provide not only a better understanding of the aetiopathogenesis of soft signs, but also of the pathophysiology of schizophrenia. Surprisingly few studies have investigated the brain correlates of neurological soft signs. In the present study, we investigated the relationship between brain structure and neurological soft signs in an epidemiologically based sample of 77 first-episode psychosis patients. We used the Neurological Evaluation Scale for neurological assessment and high-resolution MRI and voxel-based methods of image analysis to investigate brain structure. Higher rates of soft neurological signs (both motor and sensory) were associated with a reduction of grey matter volume of subcortical structures (putamen, globus pallidus and thalamus). Signs of sensory integration deficits were additionally associated with volume reduction in the cerebral cortex, including the precentral, superior and middle temporal, and lingual gyri. Neurological soft signs and their associated brain changes were independent of antipsychotic exposure. We conclude that neurological soft signs are associated with regional grey matter volume changes and that they may represent a clinical sign of the perturbed cortical-subcortical connectivity that putatively underlies psychotic disorders.