21.3Sensorimotor Demyelinating Polyneuropathy (CIDP)

acquired demyelinating neuropathy, can occur in patients with Sjögren’s syndrome and should be always sought for and excluded because it is a treatable form of neuropathy responding to intravenous immunoglobulin (IVIg) and glucorticoids [22].

21.4Multiple Mononeuropathy or Mononeuritis Multiplex

Mononeuropathy and multiple mononeuropathy are rare manifestations of Sjögren’s syndrome. Patients present with acute or subacute onset of sensory and motor deficits in the distribution of single nerves. Deficits are almost invariably accompanied by pain over the same area. The symptoms are usually due to vasculitis of the vasa nervorum [15, 17]. Vessel wall inflammation, due to cellular infiltrates, results in endothelial damage, which in turn leads to vessel lumen occlusion and nerve infarction. Multiple deficits can give rise to an asymmetric, multifocal pattern. If the neurologic deficits become confluent, the resulting symmetric pattern may lead to the clinical impression of a generalized polyneuropathy [23]. Constitutional symptoms often accompany mononeuropathy or multiple mononeuropathy, reflecting the vasculitic involvement of other organs. Typical laboratory findings include an elevated erythrocyte sedimentation rate and C-reactive protein levels. Electrodiagnostic studies reveal an axonal pattern of nerve dysfunction with “pseudo-blocks” at the sites of nerve infarctions.

Nerve biopsy can be helpful in the diagnostically challenging cases [24]. Pathognomonic findings include damage of the vasa nervorum wall with fibrinoid necrosis and cellular infiltrates, mainly T cells and macrophages. We always recommend the combination of muscle and nerve biopsy if there is strong suspicion of vasculitis, because the focal nature of vasculitis often leads to false-negative nerve biopsies. The highly vascular nature of muscle tissues increases the yield of biopsy substantially. A number of studies have shown that dual biopsies of both muscle and nerve are associated with a sensitivity of up to 85% for vasculitis [25]. Necrotizing vasculitis usually responds well to immunosuppression, particularly if the diagnosis is made at an early stage [26].

Prompt recognition and treatment of this condition is needed in order to prevent the progression of neurological damage. Glucocorticoids and adjuvant immunosuppressive agents are the mainstay of treatment (Table 21.3). Cyclophosphamide plus glucocorticoids is presently the first-line therapy for remission induction in the setting of necrotizing vasculitis associated with Sjögren’s syndrome [27]. After remission is achieved, safer agents such as azathioprine, methotrexate, or mycophenolate mofetil can be used as maintenance treatment [28, 29]. Rituximab is a highly promising approach to the treatment of this form of vasculitis, as B cell depletion has been proven to be as effective as cyclophosphamide for remission induction in forms of vasculitis associated with antineutrophil cytoplasmic antibodies (ANCA) [30]. Of interest are the results of another study, in which patients with Sjögren’s syndrome and lymphoma were treated with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) [31]. Despite the use of vincristine, a potentially neurotoxic agent, complete remission of peripheral neuropathy was induced.

21.5Sensory Ataxic Neuronopathy

Sensory ataxic neuropathy, also known by the names of ataxic neuropathy, sensory neuronopathy, or ganglionopathy, is a sensory neuropathy encountered in a number of different diseases, one of them being Sjögren’s syndrome. The term “neuronopathy” is used to denote dysfunction of the sensory ganglionic neuronal cell body, located at the dorsal root. Because of the location of the lesion, a pure sensory neuropathy results. Muscle strength and motor electrodiagnostic studies are normal or nearly so, but sensory potentials are typically absent.

Sensory ataxic neuronopathy is the most disabling of all peripheral neuropathies encountered in Sjögren’s syndrome. Its onset is usually subacute, although acute cases have also been described [32, 33]. Although all sensory modalities are affected, losses of position sense and vibration predominate because of involvement of largesize fibers [33]. Patients often present with paresthesias and unsteadiness of gait, due to deafferentiation [33]. Ataxic gait, Romberg sign, impaired proprioception and vibration sensation, as well as absent tendon reflexes are typical neurological findings [15, 17, 34].

An interesting and often misleading clinical finding in patients with sensory ataxic neuronopathy are pseudoathetoid movements of the hands. [33] This results from proprioceptive loss in the fingers. Neurological deficits are usually present bilaterally but involvement of the dorsal root ganglia can be asymmetric, affecting one side more than the other. Involvement of the upper limbs and trunk as well as the lower extremities is highly characteristic of sensory ataxic neuronopathies, in contrast to mononeuritis multiplex, for example. Patients usually progress to a wheel-chair confinement due to lack of proprioception, in spite of having normal strength [33]. Characteristic electrodiagnostic findings include absent sensory nerve action potentials, normal motor nerve action potentials, normal nerve conduction velocities, F-wave latencies, and a normal EMG (Table 21.2) [15, 17, 33, 34]. The F-wave latencies can be however prolonged when the roots are affected.

The main differential diagnostic entity of concern is paraneoplastic sensory ataxic neuropathy and the neuropathy associated with IgM monoclonal antimyelinassociated glycoprotein (MAG) antibodies [33]. Paraneoplastic neuronopathy most often accompanies or precedes small cell carcinoma of the lung, and rarely breast cancer or lymphoma [35]. Seropositivity for anti-Hu antibodies in these cases is a highly specific (99%) laboratory finding. The absence of anti-Hu antibodies, however, does not rule out a malignancy [36]. Immunofixation electrophoresis should be always performed to exclude an IgM monoclonal gammopathy. Other causes of sensory neuronopathy are listed in Table 21.3.

The pathogenesis of dorsal root ganglionopathy in Sjögren’s syndrome is unclear. On the rare occasions when dorsal root ganglion tissue has been obtained through an open biopsy, neuronal degeneration and T cell infiltration of the dorsal root ganglia has been demonstrated [17, 34, 37]. However, the role of the other components of the immune system, namely B cells and autoantibodies, remains unknown.

Table 21.3 Sensory neuronopathy causes

Paraneoplastic (lung cancer, Hodgkin’s lymphoma, neuroendocrine tumors, breast cancer, ovarian cancer, sarcoma)

Immune-mediated (Sjögren’s syndrome, MGUS)a Infectious (AIDS, HTLV-1)b,c

Iatrogenic (platin analogues, doxorubicin, bortezomib)

Vitamin related (pyridoxine intoxication, nicotinic acid deficiency, vitamin E deficiency, riboflavin deficiency)

Hereditary (Friedreich’s ataxia) Idiopathic

aMGUS: Monoclonal gammopathy of unknown significance bAIDS: Acquired immune deficiency syndrome

cHTLV-1: Human T lymphotropic virus – 1

Treatment regimens including IVIg [38], plasmapheresis [39], D-penicillamine [40], infliximab [41], and interferon-a [42], have been employed, but none in a randomized clinical trial. The results are usually disappointing and the treatment of this neuronopathy remains challenging, particularly if treatment is not begun until an advanced stage. However, some cases with subacute onset appear to respond to immunotherapy. A case of IVIg-dependent sensory neuronopathy has been reported to respond to treatment with rituximab [43]. We recently treated five cases of autoimmune ataxic neuropathy with rituximab and, although there was not any dramatic change, minimal benefits were noted in four [44].

21.6Small Fiber Painful Sensory Neuropathy

Small fiber neuropathy is the most common sensory neuropathy encountered in patients with Sjögren’s syndrome. Small-diameter lightly myelinated Ad and unmyelinated C fibers, which relay superficial sensation, are predominantly affected. Painful, burning dysesthesias, usually of the distal limbs is the presenting symptom. These patients are often labeled as having psychosomatic disorder, because they do not have any objective abnormal findings in the neurological examination. Reflexes, sensory examination, and nerve conduction studies are normal [45]. Two distinct patterns of small fiber neuropathy have been described in patients with Sjögren’s syndrome [46, 47]. The first involves a distal, symmetric (length-dependent) pattern of neurologic involvement with centripetal progression, which is attributed to loss of small axons (“dying-back axonopathy”). The second involves an asymmetric, non- length-dependent distribution of symptoms, which may reflect a neuronopathy affecting small sensory neurons located in the dorsal root ganglia, which give rise to small diameter nerve fibers [48]. Mixed, small and large fiber dysfunction has also been described, as well as progression from small fiber to large fiber dysfunction. The implication of this is that a patient with a nonlength-dependent small fiber neuropathy