Sural nerve biopsy in the diagnosis of progressive cerebral degenerative disorders of childhood. A retrospective study

SURAL NERVE BIOPSY IN THE DIAGNOSIS OF PROGRESSIVE CEREBRAL DEGENERATIVE DISORDERS OF CHILDHOOD. A RETROSPECTIVE STUDY A. J. M. Vos*, E. M. G. Joosten***, A. A. W. M. Gabre~ls-Festen*, F. J. M. Gabre~Is*, J. B. Krijgsman*** and W. O. Renier*

SUMMARY A retrospective study of sural nerve biopsies in 105 children with progressive cerebral degeneration is presented. The indications for the procedure are discussed in relation to current views. The conclusion is that the biopsy is still useful only in occasional patients with associated peripheral neuropathy. In patients without neuropathy there is no current indication for the biopsy at all.

INTRODUCTION

Biopsy investigations still play an important role in the diagnosis of progressive cerebral degenerative disorders of childhood. Especially in those conditions in which a specific enzyme defect has not yet been demonstrated, diagnosis often still depends on biopsy. One of the procedures traditionally used in this respect is peripheral nerve biopsy. In recent years, however, the indications for this procedure seem to have become few since excellent results have been obtained with less invasive investigations like skin or conjunctival biopsy (CARPENTERet al., 1972; O'BRIEN et al., 1975; DOLMANet al., 1975; MARTINand CEUTERICK, 1978; ARSENIONUNES et al., 1981). In the current paper we present a retrospective view of our personal experience with nerve biopsy in the diagnosis of such disorders, and discuss the indications that may have remained. PERSONAL OBSERVATIONS

Since 1970 we have performed sural nerve biopsies on 105 children with progressive cerebral degeneration. The specimens were taken at midcalf level, and processed according to methods described (JOOSTENet al., 1974). The diagnostic contribution of the biopsy for the entire series is shown in Table 1, while the findings in the individual cases are presented in Table 2 (children with clinical or electrodiagnostic evidence of involvement of the peripheral nerves in the * Institute of Neurology, ** Department of Submicroscopical Morphology, *** Institute of Pediatrics, Radboud University Hospital, Nijmegen, The Netherlands Clin. Neurol. Neurosurg. 1982 Vol. 84-4 (Accepted 17-11-82)

238 TABLE I. Survey of 105 cases Number of cases Cases with peripheral neuropathy Cases without neuropathy

23 82

Diagnostic contribution of the biopsy Positive 20 27

Negative 3 55

disease process) and Table 3 (patients without neuropathy). Of course, since this is a retrospective view, the material presented does not reflect our current use of the procedure. Some of our observations deserve special comment. In Table 2: characteristic deposits but no significant demyelination were found in a juvenile case of metachromatic leukodystrophy (the child had low distal tendon jerks, distal amyotrophy but near normal nerve conduction) and in an atypical case of infantile globoid cell leukodystrophy (the infant had low distal tendon jerks, but normal nerve conduction). Specific deposits and a slight loss of thick myelinated fibers were found in three patients with long-standing juvenile Batten's disease. All three exhibited mild clinical neuropathy and all three were on anticonvulsant therapy. Segmental demyelination was a constant finding in our patients with Cockayne syndrome, but the severity of the myelinopathy varied considerably between the different cases. In Table 3: the biopsy appeared particularly reliable in the diagnosis of juvenile Batten's disease (all biopsies positive). In the late infantile group, one case was missed (diagnosis established at autopsy). In the patient with Lafora's myoclonus epilepsy a few small polyglucosan (Lafora) bodies did occur in the biopsy specimen. Examination of intramuscular nerve twigs, however, revealed the bodies much more impressively. The slight axonal degeneration observed in an infantile case of Alpers" syndrome and in a juvenile case of Leigh's disease was clinically unapparent. In 41 patients without neuropathy, no definite diagnosis could be made. Nerve biopsy in this group was normal in 34 cases, non-specific abnormalities occurred in the remaining 7. These abnormalities, which were unapparent clinically and electrodiagnostically, consisted of very mild axonal degeneration in 4 cases, degeneration of unmyelinated fibers in 2 cases, and minimal signs of segmental demyelination in 1 case. In 24 of these non-classifiable 'progressive' cases, no progression was demonstrable in the clinical follow-up study.

DISCUSSION

The question to be discussed here is whether peripheral nerve biopsy is still valuable in the diagnosis of progressive cerebral degeneration in children. Two separate categories of patients will be discussed: those who show clinical or electrodiagnostic evidence of involvement of the peripheral nerves in the disease process, and those who do not.

239 In patients with peripheral neuropathy, biopsy has been used quite successfully in the past. Our material (Table 2) illustrates some of the well-known applications. Due to recent developments, however, indications for use of biopsy in this category of patients have become few. This is evident from Table 4, which shows that diagnosis is now usually obtainable in a less invasive way. Consequently the current use of the procedure should be limited to the occasional patient in whom less invasive tests have failed to establish a definite diagnosis. Except for the possibility of a new disease entity, the differential diagnosis then includes Leigh's disease, Alpers' syndrome (which is probably related to defective pyruvate metabolism: PRICK et al., 1981) and, if there is also ophthalmoplegia, 'oculocraniosomatic disease'. As shown by the table, little diagnostic help is to be expected from the biopsy in the latter three conditions, but more data certainly is needed to support this view. If the clinical features, however, suggest that the child may be suffering from a new disease entity, a plain indication for nerve biopsy is presented since it may reveal unusual features distinct enough to suggest that a new entity has indeed been discovered. Occasionally, we still use the biopsy in the diagnosis of metachromatic leukodystrophy since low arylsulphatase A activity, found in a patient with peripheral neuropathy, may fail to discriminate between the homozygote and the heterozygote state (vos et al., 1982). Finalty~ on rare occasions, we used the biopsy for documentation of peripheral nerve involvement itself, as we did for instance in a juvenile case of metachromatic leukodystrophy and in an atypical case of infantile globoid cell leukodystrophy. In both cases, where the absence of markedly reduced nerve conduction did cast considerable doubt on the enzymatic diagnosis, the biopsy revealed characteristic deposits (confirming the diagnosis) but no significant demyelination (Table 2). In our patients with Cockayne syndrome the main purpose of the biopsies was to document that segmental demyelination of the peripheral nerves is a quite constant feature in this condition (Table 2). The diagnostic contribution of biopsy in cases without neuropathy is shown in Table 5. The conclusion drawn from this table is that the procedure has become entirely unnecessary in this category of patients, since less invasive ways of making the diagnosis are now available in all conditions where positive biopsies have been obtained in the past (see last column of table 5). This conclusion is not challenged by the positive biopsies which we have obtained (Table 3), since they only occurred in conditions where the diagnosis is now preferably made by means of other tests. Our observations also show that nerve biopsy is a useless investigation in children with static encephalopathies, since no valuable information was obtained in 24 cases (biopsied since their conditions originally seemed progressive: see Table 3 under the heading 'no definite diagnosis'). Our conclusion is that the current indications for peripheral nerve biopsy in the diagnosis of progressive cerebral degenerative disorders of childhood are limited to occasional patients with associated peripheral neuropathy. In cases without neuropathy there is no current indication for the biopsy.

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