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We read with interest the article by Klein et al1 providing pathological evidence that the neuropathic attacks in hereditary brachial plexus neuropathy (HBPN) are secondary to an inflammatory process. As a possible pathogenetic mechanism the authors suggest altered immune modulation. In the absence of controlled clinical trials they treated patients with intravenous methyl prednisolone. This treatment—in their experience—relieved the symptoms, particularly the pain, for a brief time, but as they tapered the corticosteroid dose the signs and symptoms reappeared. The authors concluded that in some cases of HBPN an inflammatory multifocal response arising from an immune dysfunction in the brachial plexus and upper limb nerves causes nerve abnormalities and axonal degeneration. Treatments based on immune modulation may therefore be useful in the management of HBPN.
To further support the immunological pathogenesis we describe a 13 year old girl who since childhood had suffered from recurrent episodes of severe asymmetric pain and weakness of the shoulder and arm involving the same as well as the opposite side. Her father had similar attacks and genetic testing for hereditary neuropathy with liability to pressure palsy was negative. At the age of 4 years the girl experienced severe left shoulder pain that lasted for 20 days and was treated with corticosteroids. Three years later, a left deltoid muscle hypotrophy was still present. At the age of 11 years she had a similar episode associated with marked weakness of left upper limb and was treated with non-steroid anti-inflammatory drugs. The shoulder pain improved in four weeks but muscle strength recovered only after about four months. We observed the girl during a further episode that occurred in July 2002: she complained of severe neck pain that lasted for one day then spontaneously disappeared. One week later she suddenly experienced severe neck and right shoulder pain and mild weakness of the right limb girdle. The neurological examination disclosed bilateral hypotrophy and weakness of the deltoids, secondary to previous episodes, and mild weakness of right subscapular and both spinate muscles. Tendon jerks were absent in the upper limbs. Magnetic resonance imaging (MRI) of the cervical spinal cord yelded normal findings. MRI scans of the brachial plexus and shoulder muscles showed mild abnormalities in the supraspinatus muscle. The cerebrospinal fluid examination disclosed 38 mononuclear cells/mm3 with normal glucose and proteins; oligoclonal bands were absent. Neurophysiological tests showed a mild reduction in the amplitude of the compound motor action potential elicited by both axillary and musculocutaneous nerve; the right median nerve sensory action potential was abnormally small and the F wave was delayed. Needle EMG found no denervation. The standard neuroimmunological screening (anti-GM1, -GM2, -GD1a, -GD1b, -sulfatide, -MAG IgM antibodies) was normal. Because the previous episode failed to respond to corticosteroid treatment, and considering the severity of the episode, the lengthy period needed for a partial recovery in previous episodes, the severity of the patient’s pain, her young age, and the muscular atrophy, we started treatment with intravenous immunoglobulin (IG Vena N IV, Sclavo, Siena, Italy, 0.4 g/kg/day for five days). After two days of IVIg treatment the patient reported a dramatic reduction of pain and a progressive improvement in muscle strength. One week after the onset she achieved a complete clinical recovery and no muscle atrophy developed. Two months after the treatment stopped she is still asymptomatic.
The case reported here has two potentially important implications. Firstly, the epineural mononuclear cell infiltrates observed by Klein et al1 in nerve biopsy specimens, the presence of mononuclear cells in our patient’s CSF, and her response to IVIg together strongly support an immune mediated inflammation in the pathogenesis of HBPN. Among others, possible mechanisms underlying the efficacy of IVIg in HBPN include attenuation of complement mediated damage, induction of anti-inflammatory cytokines, inhibition of endothelial cell activation, regulation of helper T cell cytokine production, and neutralisation of T cell superantigens.2 Secondly, individual episodes of HBPN are undistinguishable from Parsonage-Turner syndrome and pain can be very severe for weeks. Complete recovery from each episode is frequent although cumulative disability may develop.3 Although Klein et al1 proposed corticosteroid treatment, others report that this treatment produces no definite improvement.4 Also our patient in a previous episode had no benefit from corticosteroid treatment. The rapid benefit and the long term efficacy of IVIg in our patient suggest that episodes may be safely and effectively treated with this drug. To our knowledge this is the first report of a patient treated with IVIg. The encouraging results prompt controlled therapeutic trials at least for patients with severe forms of HBPN and, possibly even for those with Parsonage-Turner syndrome.
The patient described by Ardolino and colleagues provides an example of a hereditary episodic illness of the upper extremities, which may have responded favourably to IVIg. The patient’s young age of onset, tendency to recurrent events, and a reported family history would all support the diagnosis of hereditary brachial plexus neuropathy (HBPN). We note, however, the unusual feature of an increase in the CSF mononuclear cells (38/mm3), and therefore request further information; that is, concordant exacerbating infection or immunisation and precise timing of CSF examination given that IVIg may increase CSF white cell blood count. It would also be helpful to know more details of the EMG needle examination in support of the multifocal neurogenic axonal process characteristic of this disorder. Her father was reported to have the disorder, but details of his history are not provided. Lastly, because they are commenting on the absence of response to corticosteroids the dose and route used in the previous episode should be specified. We noted in our patients that low dose oral corticosteroids were not as effective as high dose 1.0 g/treatment IV methylprednisilone.1 Because our pathological studies of nerve during episodes showed features characteristic of microvasculits we elected to use methylprednisolone.
As with all anecdotal reports their patient’s improvements must be interpreted cautiously. This is especially true in disorders such as HBPN where individual episodes have a considerably varied course.2 The morbidity of this disorder, the pathological observations, and the results of open trials with IV methylprednisolone and possibly IVIg warrant clinical trials. It will be necessary to carefully distinguish inherited from cryptogenic variants to ensure that a potentially non-responsive group does not interfere with recognition of a responding group. We believe this condition is more common then appreciated and therefore clinical trials are feasible. Knowing if such treatments are beneficial is important as correction of the underlying gene(s) defect is currently not possible.