Brain 2006 129(2):285-287; doi:10.1093/brain/awh732
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From the Archives
Sensory radicular neuropathy associated with muscle wasting in two cases. By A.M.G. Campbell and the late H.L. Hoffman (From the Bristol Royal Hospital, Bristol, and the Royal United Hospital, Bath). Brain 1964: 87; 67–74.
First, Drs Campbell and Hoffman briefly rehearse clinical and pathological accounts of conditions manifesting as hereditary perforating ulcer of the foot since the disorder was first described in the mid-19th century French literature as acropathie ulcéro-mutilante. Little was known of the pathological substrate for this condition until Dr Derek Denny-Brown correlated primary degeneration in the dorsal root ganglia with secondary involvement of the posterior roots, peripheral nerves and posterior columns of the spinal cord in one such case—designating the condition as ‘hereditary sensory radicular neuropathy’ (Denny-Brown D. Hereditary sensory radicular neuropathy Journal of Neurology Neurosurgery and Psychiatry 1951: 14; 237–252). This report was based on one of 10 affected individuals from a family first reported 30 years earlier (Hicks EP. Hereditary perforating ulcer of the foot. Lancet 1922: i; 319–321), in whom the cardinal features were ‘perforating ulcers of the feet, shooting pains about the body and deafness, with clinical signs of dissociated sensory loss and areflexia in the feet’. In the following year, England and Denny-Brown described a pedigree in which 57 individuals amongst 303 family members had peroneal muscular atrophy, but two also showed trophic lesions of the feet for which each subsequently required leg amputation (England AC and Denny-Brown D. Severe sensory changes and trophic disorder in peroneal muscular atrophy: Charcot-Marie-Tooth Type. Archives of Neurology 1952: 67; 1–22). Denny-Brown distinguished these examples of peroneal muscular atrophy from his earlier description of hereditary sensory radicular neuropathy, but Campbell and Hoffman seemed not so sure; and the purpose of their report was to clarify the nosology of this group of disorders and to nail the pathological substrate. They describe two families and one sporadic case.
Family X, with nine definite and three partially affected individuals in four generations, showed a rather uniform phenotype confined to the lower limbs and manifesting as hyperkeratosis on the soles of the feet, starting in early adult life, that later ulcerated, enlarged, became infected and proved destructive of the metatarsals and pedal anatomy (see Figs 1 and 2). And yet, the patients remained ambulant, not noticing (in three instances) that one had a nail impaled through the foot, another a gramophone needle driven deep into the sole and a third was carrying around a large glass marble trapped in the shoe, since the lesions were painless and associated with dissociated sensory loss—pain and (usually but not invariably) temperature being preferentially affected below the knees compared to touch. Although bed rest and surgical debridement sometimes allowed the ulcers to heal, one patient had required amputation of a chronically ulcerated leg, observers being astonished that this man had been able to walk on such a deformed limb. Only one patient had lost the tendon reflexes and that individual was the only person also to show involvement of the upper limbs.
Family Y included three definite and two possible affected individuals.
Case 2 suffered ulcerated feet for 40 years, always wore surgical
boots and later had several toes amputated. Confined to bed
for several years in his late 70s, he found the appearance of
his left little toe so unpleasant that he himself cut it off,
without discomfort, but gangrene supervened, the leg was amputated
(this time by surgeons) and he died post-operatively, aged 81.
Case 7 lost his hallux to ‘frost-bite’ during the
Second World War and was noted to have areflexia with dissociated
sensory loss when first assessed in 1953; but he remained fully
ambulant over the next 8 years and, when seen in 1961, had normal
tendon reflexes and a history of one foot ulcer that had healed
in a few weeks. Case 5, the older brother of case 7, presented
when he discovered that a missing shoe-horn was wedged in the
shoes he had been wearing for several days. Campbell and Hoffman
point out that, despite having drunk Guinness since he was a
small child and with a later preference for whisky, Case 5 nonetheless
won the 1953 President's Cup and Club Championship of the Bath
Bowling Club. But despite admission to this sporting Hall of
Fame, by 1956 he suffered infected foot ulceration and required
serial amputation of several toes. Progressive weakness and
wasting of the hands (
see Fig. 3) with areflexia and loss both
of cutaneous and proprioceptive sensation in all four limbs,
together with enthusiastic maintenance of his former dietary
habits, led to deterioration in personal care and Case 5 died
from pneumonia in 1961.
In Patient Z, excision of a plantar wart led to ulceration on
the sole of that foot and the demonstration of pain and temperature
loss, with preserved proprioception, in the legs. The clawed
and ulcerated toes of both feet were removed in stages over
the next 2 years. His feet remained numb and paraesthetic with
blue discolouration. Later, painless cuts and burns developed
in his hands and these were seen to be wasted, weak and clumsy.
Most of the tendon reflexes were preserved. Electrophysiological
studies favoured a neuropathy but sural nerve biopsy was considered
to be normal.
Dr Ronald Norman was able to examine material obtained at a limited post-mortem in Case 6 from Family X. The cord showed loss of myelinated fibres in the gracile tract, especially in the lumbar region; Lissaeur's tract but not Fleschig's posterior root zone was involved. Myelin pallor was apparent in outer parts of the anterolateral white matter and there was axonal loss with astrocytosis in the posterior roots. The anterior horn cells and ventral roots were normal. The one posterior tibial nerve that was sampled showed severe nerve fibre depletion. Biopsy of a digital nerve taken 6 months before death in Case 5 from Family Y, examined by Professor William Blackwood, had shown severe loss of myelin and nerve fibres with reactive changes in Schwann cells and fibrous tissue. At autopsy, there was demyelination in the posterior columns, especially the gracile tract (see Fig. 4). Dr Marion Smith demonstrated active nerve fibre degeneration in the middle laminated fibres of the posterior columns, extending to the posterior roots and sensory nerve fibres. Neurons were replaced by spindle-shaped nuclei; many of the survivors were chromatolytic with increased perineuronal satellite cells (see Fig. 5). Apart from patchy loss at C8, the anterior horn cells and their connections were normal. The tibial nerve showed demyelination and globular deposits of myelin. The changes of neurogenic atrophy were apparent in one quadriceps muscle.
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Fig. 4 Demyelination in the posterior columns of Case Y.5. Loyez. x 12. (The appearance in the cord of Case X.6 was very similar).
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Fig. 5 Third right lumbar posterior root ganglion of Case Y.5 showing loss of neurons, some of which are replaced by collections of spindle-shaped nuclei. There is overgrowth of connective tissue. Haematoxylin and Van Geison. x 78.
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So, does this small series illuminate the nature of ‘(hereditary)
perforating ulcer of the foot’? Having set out their stall
around the dilemma of overlap or absolute difference between
cases having foot mutilation with or without features of peroneal
muscular atrophy, Campbell and Hoffman approach the discussion
of their own examples by parading the relevant literature in
more detail. Thus, to the cases of Denny-Brown (1951) and England
and Denny-Brown (1952), are added those of Barraquer-Ferré
and Barraquer-Bordas (Barraquer-Ferré L, Barraquer-Bordas
L. Posterior ganglio-radicular semeiology in Charcot-Marie-Tooth
amyotrophy; trophic disorders, fulgurant pains, sensory disorders.
Acta Neurologica Belgica 1953: 53; 55–70) and van Bogaert
(van Bogaert L. Familial ulcers, mutilating lesions of the extremities
and acro-osteolysis.
British Medical Journal 1957: 17; 367–371)
who reported individuals with foot mutilation in pedigrees having
peroneal muscular atrophy and hereditary ataxia, respectively.
Conversely, examples from Riley (Riley HA. Syringomylia or Myleodysplasia.
Journal of Nervous and Mental Disease 1930: 72; 1–27)
and Passouant
et al. (Passouant P, Vallat G, Temple J. Familial
ulcero-mutilating acropathy; associated manifestations
Revue Neurologique 1951: 84; 248–252) of hereditary ulceration
of the feet accompanied by muscle wasting—formulated by
Thévenard (Thévenard A. Familial ulceromutilating
acropathy
Acta Neurologica Belgica 1953: 53; 1–24) as
‘
la forme paréto-amyotrophique d'acropathie ulcéro-mutilante’—make
the opposite point concerning transitional cases. A more complex
phenotype had been reported by Reimann and colleagues (Reimann
HA, McKechnie WG, Stanisavljevic S. Hereditary sensory radicular
neuropathy and other defects in a large family: reinvestigation
after 20 years and report of a necropsy.
American Journal of Medicine 1958: 25; 573–579) in which hereditary ulceration
of the feet was associated in two cases with cleft lip and palate,
menigocoele and subsequent wasting and weakness of the extremities,
and histological evidence for involvement of the anterior horn
cells and ventral roots in another. Lamely, in our opinion,
Campbell and Hoffman do no more by way of conclusion than to
note similarities between these accounts in the literature and
Case 5 from their Family Y, leaving open the issue of coincidental
alcoholic neuropathy, but preferring the interpretation that
these are all transitional cases linking hereditary sensory
neuropathy with peroneal muscular atrophy and drawing attention
to their more thorough histological examination. Thus, they
lump rather than split these disorders—a clinical formulation
that needed the genotype–phenotype analyses to which Henry
Houlden and colleagues from the UK now make a further important
contribution.
Alastair Compston
Cambridge
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