2742'ournal ofNeurology, Neurosurgery, and Psychiatry 1995;58:274-283 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. Downloaded from NEUROLOGICAL INVESTIGATIONS

Investigation of

J G McLeod

Peripheral neuropathy is a common condition Sensory symptoms are usually the presenting that is associated with many systemic dis- features of neuropathy and include numb- eases. Its exact prevalence in the community ness, tingling, pins and needles in the hands is not known although epidemiological stud- and feet, burning sensations, pain in the ies have established the frequency of certain extremities, sensations of walking on cotton subtypes-for example, Guillain-Barre syn- wool, band like sensations around the wrists drome,' diabetic neuropathy,' and Charcot- or ankles, unsteadiness on the feet, or stum- Marie-Tooth disease.3 Because of the bling. Motor symptoms are usually those of numerous causes (well over 100) of periph- weakness and patients may find it difficult to eral neuropathy and the likelihood of finding turn keys in locks, unfasten buttons, and an underlying treatable condition, it is impor- remove the tops of bottles and jars. In the tant to take a systematic approach to the early stages of peripheral neuropathy, weak- diagnosis. Diagnostic algorithms for evalua- ness is usually distal; however, early proximal tion of neuropathies have been published.4 weakness is a feature of inflammatory neu- Although it used to be believed that in more ropathies and porphyric neuropathy. than half the cases a cause was not found,6 Autonomic symptoms, particularly postural several large series have shown that after hypotension, impotence, sphincter distur- intensive investigation only about 20% of bances, diarrhoea, constipation, and dryness cases remain undiagnosed and these tend to or excessive sweating of the extremities point have a relatively good prognosis.7- to damage of small myelinated and unmyeli- nated fibres. In the history, attention should be paid to recent upper respiratory tract or Pathological types ofperipheral other infections, alcohol and drug intake, neuropathy diet, possible exposure to industrial and envi- There are three major pathological processes ronmental toxins, family history, and symp- that affect the peripheral nervous system: toms of systemic diseases. It is important to http://jnnp.bmj.com/ axonal degeneration, segmental demyelina- note the tempo of the disease-acute, suba- tion, and neuronopathy. It is important in the cute or insidious onset; rapid or slow progres- investigation of a peripheral neuropathy to be sion; progressive, stepwise or relapsing and able to recognise the underlying pathological remitting course. Table 1 shows some of the nature of the condition as it influences subse- more common causes of peripheral neuro- quent management. Axonal degeneration is the pathy with acute onset.

most common pathology seen in systemic, Signs are usually those of distal muscle on September 30, 2021 by guest. Protected copyright. metabolic, toxic, and nutritional disorders. It wasting and weakness, and sensory impair- characteristically has a predilection for large ment, predominantly over distal regions and diameter and long fibres-distal axonopathy often in a glove and stocking distribution. In or dying back neuropathy. Segmental demyeli- distal axonopathies, particularly in diabetes, nation is primary destruction of the myelin there may be loss of sensation over the ventral sheath leaving the axon intact, although regions of the trunk due to distal degenera- axonal degeneration may also be present in tion of the intercostal nerves. A truncal neu- demyelinating neuropathies and secondary ropathy, with a dermatomal distribution of segmental demyelination may be seen in dysaesthesia and sensory loss, may also be axonal degeneration. Electrophysiological seen in diabetes'0 as well as in Lyme disease" studies are helpful in differentiating primary and Sjogren's syndrome'2 (table 1). In condi- demyelination from axonal degeneration. tions that affect predominantly small fibres Neuronopathies are those conditions in which (amyloid neuropathy, Tangier disease, and the cell bodies of axons-anterior horn cells some cases of diabetic neuropathy) there may or dorsal root ganglia are primarily affected. be dissociated loss of sensation with loss of pain and temperature sensation and preserva- tion of tactile sensation. Reflexes are usually Clinical evaluation depressed or absent but in mild cases, in Department of The most important parts of the investigation small fibre neuropathies, and when peripheral Medicine, University neuropathy is associated with pyramidal tract of Sydney, Sydney, of suspected peripheral neuropathy are the NSW 2006, Australia taking of an accurate history and the perfor- lesions, reflexes may be preserved. Careful J G McLeod mance of a careful clinical examination. general examination should seek evidence of Investigation ofperipheral neuropathy 275 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. Downloaded from Table 1 Clinical types ofperipheral neuropathy investigation will depend on the results of Acute onset: these initial studies. Guillain-Barre syndrome Porphyria Toxic (for example, arsenic, nitrofurantoin) GENERAL LABORATORY TESTS Serum sickness (postimmunisation) Basic laboratory investigations that should be Diphtheria Malignancy performed on all patients with peripheral Critical illness neuropathy of undetermined aetiology Diabetes, uraemia (rarely) Predominantly motor: include urinalysis, haemoglobin, white cell Guillain-Barre syndrome count, platelets, erythrocyte sedimentation Porphyria Diphtheria rate, fasting blood glucose, serum elec- Lead trolytes, serum proteins, serum protein elec- Charcot-Marie-Tooth disease Diabetes (diabetic amyotrophy) trophoresis and immunoelectrophoresis, Predominantly sensory: serum creatinine, liver function tests, chest Leprosy Diabetes (distal sensory polyneuropathy) radiographs, and electrophysiological studies Vitamin B12 or thiamine deficiency (see later). If these do not provide a diagno- Malignancy Hereditary sensory and autonomic neuropathy sis, other special investigations may include Primary of familial amyloidosis thyroid function tests, serum vitamin E con- Uraemia Lyme disease centrations, serum cholesterol and triglyc- Sj6gren's syndrome erides, cryoglobulins, urinary heavy metals Radicular: Diabetic truncal neuropathy and porphyrins, antinuclear antibodies, Lyme disease rheumatoid factor, Sj6gren's syndrome (SS) Sjogren's syndrome Painful neuropathies: antibodies, (SS-A (anti-Ro) and SS-B (anti- Alcohol, nutritional deficiencies La)), serology for Lyme disease and HIV, Diabetes (acute painful neuropathy) Hereditary sensory and autonomic neuropathy antiganglioside GM1 antibodies, Schirmer's (HSAN type 1) test, and screening for occult malignancy with Arsenic Cryoglobulinaemia endoscopic and radiological examinations Lyme disease including skeletal surveys (table 3). Paraneoplastic sensory neuropathy Vasculitic neuropathies NERVE CONDUCTION STUDIES Nerve conduction studies play a key part in confirming the presence of peripheral neu- pes cavus or other skeletal deformities, ropathy and in establishing its cause. They enlarged nerves, skin lesions, arthritis, dry assist in determining whether the patient has mucous membranes, and enlargement of a mononeuropathy, mononeuritis multiplex, liver, spleen, and lymph glands. or a generalised peripheral neuropathy, and if The clinical features of the neuropathy so, whether it is symmetric or asymmetric, may indicate the underlying cause and enable whether both sensory and motor fibres are the most appropriate investigations to be affected, and whether the underlying pathol- undertaken (table 1). Mononeuropathy is ogy is that of axonal degeneration or segmen- usually due to direct compression or entrap- tal demyelination as there is a correlation ment but may be the first manifestation of between the conduction velocity and the http://jnnp.bmj.com/ diabetic or vasculitic neuropathy. Mono- underlying pathological process."1'7 Table 4 multiplex (multiple mononeuro- shows the causes of segmental demyelination pathy) is caused by vasculitis, leprosy, and conduction velocities in the demyelinat- sarcoidosis, and some other conditions (table ing range. 2). Nerve conduction studies should be per- formed on nerves that are clinically unaf- fected as well as those that are clinically

Laboratory investigations affected. In general, several nerves should be on September 30, 2021 by guest. Protected copyright. General laboratory tests and nerve conduc- studied in upper and lower limbs-for exam- tion studies will be performed as the first ple, motor and sensory conduction in median stage of investigation in all patients unless the and ulnar nerves, motor conduction in com- diagnosis is clinically obvious-for example, mon peroneal and posterior tibial nerves, and diabetic or alcoholic neuropathy; subsequent sensory conduction in sural nerves. In some cases it may be appropriate to perform sen- Table 2 Causes ofmononeuritis multiplex sory conduction on radial, tibial, and saphe- nous nerves and to record mixed nerve action Vascular: Diabetes potentials in ulnar and common peroneal Polyarteritis nodosa nerves. Every clinical neurophysiology labora- Rheumatoid arthritis Systemic lupus erythematosus tory should have established its own control Wegener's granulomatosis values. The age of the patient needs to be Sjogren's syndrome Non-systemic vasculitis taken into account because nerve conduction Inflammatory: velocities in full term infants are about half Leprosy Sarcoidosis the adult values but increase to the adult Lyme disease range at 3 to 5 years of age; there is also a Infiltrations: Malignancy reduction in conduction velocity after the age Amyloidosis of 40. Temperature of the limbs must be con- Immune reactions: Immunisation, foreign serum and proteins trolled or a temperature correction applied Trauma: because the conduction velocity changes by Multiple nerve injuries 2-4 m/s/IC from 29 to 380C.'8-19 276 McLeod J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. Downloaded from Table 3 General laboratory investigations Table 4 Demyelinating neuropathies Condition Investigations Inflammatory neuropathies: Guillain-Barre Syndrome Metabolic: Chronic inflammatory demyelinating Diabetes Urinalysis, fasting blood glucose, glucose tolerance test Motor neuropathy with multifocal conduction block Hypoglycaemia Fasting blood glucose, serum insulin, or Chronic inflammatory neuropathy associated with C peptide concentrations paraproteinaemia Uraemia Blood urea, serum creatine, urinalysis Inflammatory neuropathy associated with HIV infection Porphyria Urinary porphyrins, ALA, porphobilinogen. Hereditary neuropathies: Total faecal porphyrins. Erythrocyte HMSN type I porphobilinogen deaminase HMSN type III Hypothyroidism Serum free thyroxine, serum TSH Refsum's syndrome Acromegaly Serum growth hormone concentrations Metachromatic Deficiencies: Krabbe's disease B1 (thiamine) Erythrocyte transketolase activity + Metabolic neuropathies: enhancement with thiamine pyrophosphate Diabetes (sometimes) Vitamin B6 (pyridoxine) Erythrocyte aspartate amino transferase + Uraemia (sometimes) enhancement with pyridoxal-5-phosphate Toxic neuropathies: Vitamin B 12 Serum B 12, Schilling test Perhexiline maleate Vitamin E Serum vitamin E Amiodorone Toxic: Hexacarbons Arsenic, lead, mercury, thallium 24 hour urinary heavy metals Infections: Paraproteinaemias, dysproteinaemias: Diphtheria Multiple myeloma, Waldenstrom's Hb, WCC, platelets, ESR, macroglobulinaemia, plasma Malignancy cryoglobulinaemia, immunoelectrophoresis, urinary Bence- Some acute or subacute neuropathies associated with monoclonal gammopathy of uncertain Jones protein, radiological skeletal Iymphoma, carcinoma significance survey, bone marrow biopsy, plasma cryoglobulins Connective tissue disorders: Systemic lupus erythematosus, mixed Hb, WCC, platelets, ESR, serum connective tissue disease, scleroderma, immunoelectrophoresis, antinuclear rheumatoid arthritis, polyarteritis antibodies, antidouble stranded tion).22 in or nodosa, Sjogren's syndrome, DNA antibodies, rheumatoid factor, serum Abrupt change area, amplitude, Wegener's granulomatosis complement (C3, C4, CH50), or both over a short segment of nerve, rather antineutrophil cytoplasmic antibodies than a reduction over a dis- Sjogren's syndrome All above + anti-Sjogren's syndrome gradual longer antibodies, Schirmer's test, lip biopsy tance, is strong evidence of conduction Inflammatory neuropathies: Further evidence of Acute inflammatory neuropathy HIV, blood glucose, urinary porphyrins, block.22 demyelination is Epstein-Barr virus, Campylobacter temporal dispersion (increased duration of infections, cytomegalovirus, mycoplasma the muscle action Chronic inflammatory demyelinating ESR, serum immunoelectrophoresis, anti- potential), prolonged distal polyradiculoneuropathy ganglioside GMI antibodies, antinuclear latencies, and reduction in conduction veloc- antibodies, antineutrophil to less than 80% of the cytoplasmic antibodies ity lower limit of nor- Infections: mal in two or more motor nerves.2' 23 HIV HIV serology In axonal Lyme disease Lyme serology degeneration there is normal or Leprosy Lepromin tests; skin, nasal scrapings; only mild slowing of conduction due to fall skin, nerve biopsy Hereditary neuropathies with known out of the damaged large diameter fibres, the biochemical abnormalities: remaining intact fibres having normal con- Primary amyloid neuropathy Rectal, liver, renal, abdominal fat, nerve duction velocities. Other evidence of axonal biopsy; serum immunoelectrophoresis; urinary Bence-Jones protein degeneration is a reduced muscle action Familial amyloid polyneuropathy Serum, tissue transthyretin and Metachromatic leukodystrophy Blood leucocyte, skin fibroblast potential electromyographic evidence of arylsulphatase denervation. It should be noted that mild Krabbe's disease Blood leucocyte, skin fibroblast degrees of slowing of conduction do not (globoid cell leukodystrophy) galactosylceramide ,B galactisidase http://jnnp.bmj.com/ A ,B lipoproteinaemia (Bassen- Acanthocytes in blood, serum cholesterol, exclude the possibility of underlying segmen- Kornzweig disease) plasma low density and very low density tal in 17 lipoproteins demyelination peripheral nerves.'5 An a lipoproteinaemia (Tangier disease) Serum cholesterol Sensory conduction is usually impaired, with Plasma high density lipoproteins reduced of action in Refsum's disease Serum . a oxidation of amplitudes potentials phytanic acid in skin fibroblasts both axonal degeneration and segmental action Hb = haemoglobin; WCC = white cell count; ESR = erythrocyte sedimentation rate. demyelination. Although sensory potentials are difficult to record over long dis-

tances in diseased nerves, slowed conduction on September 30, 2021 by guest. Protected copyright. and dispersion of the action potentials can be recorded in segmental demyelination with Motor conduction velocities should be appropriate techniques. Because motor and recorded from surface electrodes to measure sensory conductions are routinely measured the amplitudes of the muscle action potential only in large diameter fibres with standard after stimulation at distal and proximal sites; nerve conduction techniques, they may be reduced amplitude of the muscle action normal in small fibre neuropathies. potential at distal stimulation sites is indica- tive of axonal degeneration, or, rarely, F waves demyelination in distal motor fibres. A signifi- F waves are late waves that can be recorded cant reduction in the amplitude of the muscle from muscles after supramaximal stimulation action potential on moving the stimulating of the nerve and result from antidromic nerve electrode from a distal to a more proximal impulses causing anterior horn cells to back- site is supportive evidence of conduction fire.24 They provide a measure of conduction block.20 Conduction block is suspected if over the whole length of the motor nerve and there is greater than 20% reduction in ampli- are therefore a useful way of recording con- tude (provided there is less than a 15% duction in proximal segments.'9 change in duration of the muscle action potential between proximal and distal sites of H reflex stimulation2' as dispersion and polyphasic The H reflex measures the conduction action potentials can cause phase cancella- through afferent and efferent fibres in the Investigation ofperipheral neuropathy 277 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. Downloaded from monosynaptic reflex arc. It is most easily useful in detecting early sensory abnormali- recorded from the calf muscles. It is usually ties in people exposed to occupational and absent when the F wave and other nerve con- environmental toxins, in controlled clinical duction studies are abnormal.'9 trials, and in epidemiological studies.3'

Needle electromyography AUTONOMIC FUNCTION STUDIES When muscles are denervated, spontaneous Autonomic dysfunction is a common compli- fibrillation, positive sharp waves, and a cation of peripheral neuropathies although reduced interference pattern are recorded on often it is mild and of little relevance. In some needle electromyography. Electromyography conditions, however, there may be profound is useful in confirming the presence of axonal disturbance of autonomic function including degeneration in the Guillain-Barre syn- orthostatic hypotension, impairment of blood drome.25 It should be borne in mind that den- pressure, heart rate and bladder control, and ervation potentials may not appear until three impotence. Diseases that primarily affect weeks after the onset of axonal degeneration. small fibres in peripheral nerves or cause acute demyelination of small myelinated Somatosensory evokedpotentials fibres are those most likely to cause auto- Somatosensory potentials may be useful in nomic dysfunction. These include acute detecting abnormalities of conduction in dysautonomia, familial and primary amyloi- proximal segments when conventional nerve dosis, Guillain-Barre syndrome, diabetes, conduction studies are normal.25 Walsh et aP6 porphyria, Chagas' disease, and some heredi- found them more useful than the F waves in tary sensory and autonomic neuropathies.'2" the Guillain-Barre syndrome although others There are many available tests from which have had a different experience.27 to select; tests of both sympathetic and parasympathetic function should be included EXAMINATION OF CSF and it is generally necessary to find abnormal- A lumbar puncture with examination of CSF ities in two or more of these tests to confirm is unrewarding in most cases of axonal neu- the presence of autonomic dysfunction.33 ropathy but should be performed in demyeli- Tests of autonomic function that can be read- nating neuropathies. In the Guillain-Barre ily undertaken in the clinical neurophysiology syndrome the CSF protein rises during the laboratory are heart rate variation with respi- first week. The white cell count varies with ration, Valsalva ratio, heart rate response to the time of lumbar puncture and is raised in standing or tilting, blood pressure response to about 10% of cases.2829 An increased white sustained hand grip, and the sympathetic skin cell count raises the possibility of HIV infec- response.34 Autonomic function studies, tion or Lyme disease.2830 CSF protein is also together with quantitative sensory testing and raised in chronic inflammatory demyelinating sural nerve biopsy, are the most useful ways polyradiculoneuropathy (CIDP) and may of confirming a diagnosis of small fibre help to distinguish this condition from hered- neuropathy.'6 itary demyelinating neuropathies. A high CSF protein suggests inflammatory causes and MOLECULAR GENETICS demyelination of spinal roots or both. In my There are now several hereditary neu- http://jnnp.bmj.com/ experience, oligoclonal IgG bands are present ropathies in which the gene locus has been in the CSF of about 6% of cases of Guillain- identified and the number is rapidly increas- Barre syndrome, and 16% of cases of CIDP. ing with advances in recombinant DNA tech- nology. The types of genetic analysis available QUANTITATTVE SENSORY TESTING to the clinician fall into two groups: linkage Quantitative sensory testing is the use of psy- studies for conditions in which the region of

chophysical methods for measuring abnor- the gene on the chromosome has been identi- on September 30, 2021 by guest. Protected copyright. malities of the different modalities of fied but the defective gene has not been sensation. With these techniques, quantitative cloned, and mutation analysis or positional values for thresholds of vibration, touch- cloning in those conditions in which the gene pressure, and warm and cold sensation may has been cloned.'7-'9 be obtained on individual patients and com- Table 5 shows the hereditary peripheral pared with control values. These investiga- neuropathies in which the gene has been tions are not routinely employed in the identified. investigation of peripheral neuropathy but are SURAL NERVE BIOPSY Nerve biopsy is a valuable method for estab- Table S Genetic tests for hereditary neuropathies lishing a cause of peripheral neuropathy in Chromosome Gene specific circumstances.'404' It should not be Disease location product Genetic defect performed simply to establish the presence of CMT Ia (HMSN Isa) 17pl 1.2-12 PMP22 Duplication peripheral neuropathy as clinical evaluation Point mutation and nerve conduction studies are nearly CMT Tb (HMSN Ib) 1q21.2, 23 Po Point mutation CMT X (HMSN-X) Xql3 Connexin-32 Point mutation always adequate for this purpose. It should Hereditary liability to pressure 1 7p. 1 1.2,12 PMP22 Deletion only be undertaken where the biopsy can be palsies (Tomaculous Point mutation neuropathy) evaluated by a laboratory experienced in the Familial amyloid polyneuropathy 18ql 1.2,12.1 Transthyretin, Apo Al Point mutations techniques of light and electron microscopy, (most types) + 2 unidentified genes teased fibre studies, and the use of immuno- on chromosomes 9 and 11 histochemical methods of staining. Biopsies 278 McLeod J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. Downloaded from should only be undertaken after full clinical (25-45 m/s) and intermediate changes on and electrophysiological assessment and nerve biopsy. It is likely that some of these when other laboratory investigations have cases were CMT-X as slow conduction veloci- been completed. It is usually performed on ties are found in affected males with CMT-X the sural nerve but sometimes the radial sen- (< 40 m/s) and intermediate range motor con- sory nerve is more appropriate. Whole nerve duction velocities (> 40 mIs) in affected or or fascicular biopsies are undertaken in differ- obligate female carriers.75 In HMSN III ent centres. Although not required in those (Dejerine-Sottas disease) motor conduction cases where the diagnosis is certain from fam- velocities are typically grossly slowed (< 12 ily history or from other investigations, nerve m/s). 47 487 It may be a genetically heteroge- biopsy may confirm a diagnosis of chronic neous condition.76 inflammatory demyelinating polyradiculoneu- Sural nerve biopsy-Sural nerve biopsy is help- ropathy (CIDP),42 43 hereditary motor and ful in distinguishing the different types of sensory neuropathy (HMSN),448 hereditary HMSN when they are not clearly separated on sensory and autonomic neuropathy the basis of electrophysiological studies.44 487 (HSAN),49 primary and familial amyloid neu- In HMSN la and b there is a reduction in the ropathy,50-53 vasculitis,54 57 sarcoidosis,98 giant density of fibres, evidence of segmental axonal neuropathy,5960 hereditary liability to demyelination on light and electron micro- pressure palsies (tomaculous neuropathy),6' scopy and teased nerve fibres, and in most and hexacarbon (n-hexane and methyl n- myelinated fibres the myelin sheath is of butyl ketone) neuropathy.62 Specific appear- appropriate diameter for the axon. In HMSN ances may be seen in the nerve biopsy in IgM II there is a reduction in the density of myeli- K paraproteinaemic neuropathy,63 metachro- nated fibres but no evidence of demyelination. matic leukodystrophy,64 66 Krabbe's dis- In HMSN III onion bulbs are prominent and ease,6667 Fabry's disease,6869 and Friedreich's the myelin sheath is abnormally thin relative to .70 In some cases of vasculitis, sarcoido- the axon diameter. sis, amyloidosis, sensory perineuritis, and Genetic studies-Most cases of HMSN I are chronic inflammatory neuropathy, the biopsy type la, which is linked to chromosome 17. is essential for diagnosis. There is usually a duplication on In general, nerve biopsy is of little diagnos- 17pll.2-1279-8' in which region the PMP22 tic value in metabolic disorders and alcoholic gene is located. In some cases of the disease, a and nutritional neuropathies, in which the point mutation of the coding region of PMP22 appearances are non-specific. There is a case has been demonstrated where an identical for performing biopsies in patients with mutation also occurs in the trembler chronic neuropathies of undetermined cause mouse.8-84 Duplication in this region has also when all other investigations have been com- been shown in nine out of 10 sporadic cases pleted. The morphometry of peripheral that had been considered to be recessive.85 It nerves is related to age and every laboratory has been suggested that overdosage of PMP22 should have its own established control values caused by the DNA duplication is the mecha- for different age groups. nism for producing the HMSNIa phenotype. A deletion in the same region that is dupli- cated in HMSNIa is found in hereditary neu- http://jnnp.bmj.com/ Application of investigations to specific ropathy with liability to pressure palsies.8687 It types ofperipheral neuropathy has been shown that the gene involved is also HEREDITARY NEUROPATHIES PMP22. A frame shift or null mutation was Charcot-Marie-Tooth disease (hereditary motor found, indicating that underdosage of PMP22 and sensory neuropathy, peroneal muscular is the cause of this condition.88 atrophy) The gene mutation in HMSN lb has been on chromosome Charcot-Marie-Tooth disease (CMT) is a located near the Duffy locus on September 30, 2021 by guest. Protected copyright. genetically heterogeneous disorder. There are 1 where HMSN Ib was originally mapped by four major types: HMSN I (CMT la and lb), linkage analysis.8990 A point mutation in the HMSN II (CMT 2), X linked (CMT-X), and gene for Po (1q21 .2q23) was subsequently HMSN III (Dej&rine-Sottas disease).3 HMSN found when Po was mapped to this region.91 I and II are usually dominant although some HMSN type II is genetically heteroge- autosomal recessive cases have been described. neous; the gene for one of the forms of auto- Dej&rine-Sottas disease (HMSN III) is autoso- somal dominant HMSN II (CMT 2) has mal recessive. been localised to chromosome lp36.92 Nerve conduction studies-Nerve conduction The gap junction protein connexin-32 has studies are of considerable value in the initial been identified for the gene mutation in categorisation of Charcot-Marie-Tooth disease CMT X (Xql3).93 into different subtypes. Although there is some Dejerine-Sottas disease (HMSN III) now overlap, motor conduction velocities in both seems to be a heterogeneous disorder. Cases HMSN Ia and b are greatly slowed (median have been reported with mutations of PMP22 motor conduction velocity < 38 m/s) and sen- and Po genes.94 sory conduction is impaired. By contrast, there is only mildly impaired or normal motor con- Amyloid neuropathy duction velocity in HMSN II.3 4446 71-74 Bradley Peripheral neuropathy is a feature of primary et a145 suggested that there was also an inter- amyloidosis and several types of familial amy- mediate type of Charcot-Marie-Tooth disease loid polyneuropathy. Dysaesthesiae, loss of with intermediate conduction velocities pain and temperature sensation in the Investigation ofperipheral neuropathy 279 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. Downloaded from extremities, and autonomic dysfunction (pos- ing of motor conduction, and nerve biopsy tural hypotension, impotence, impaired shows segmental demyelination and loss of sweating, bladder disturbance) are character- large diameter fibres. The diagnosis can be istic features. Distal sensory loss, predomi- confirmed by laboratory investigations which nantly of pain and temperature sense, are show acanthocytes in the peripheral blood, found on examination. Nerve conduction low serum cholesterol and low density and studies and electromyography are consistent very low density lipoproteins. Genetic testing with axonal neuropathy. Autonomic function is not available. studies are abnormal. Sural nerve biopsy is An-a lipoproteinaemia (Tangier disease)- usually diagnostic and shows amyloid Peripheral neuropathy is usually present. The deposits in blood vessels and endoneurium presence of large orange tonsils is characteris- on Congo red staining and there is selective tic. Sural nerve biopsy shows reduced num- loss of small myelinated and unmyelinated bers of myelinated and unmyelinated fibres fibres. The diagnosis of amyloidosis may also and lipid droplets may be seen in Schwann be established by abdominal fat, rectum, kid- cells.96 Plasma high density lipoproteins are ney, and liver biopsy.50 53 A high proportion of greatly reduced. patients with primary amyloidosis have mon- Fabry's disease-This is associated with a oclonal proteins on immunoelectrophoresis of painful neuropathy and a selective loss of urine and blood, and some have multiple small myelinated and unmyelinated fibres myeloma. Immunohistochemical staining of may be seen in the sural nerve biopsy.68 69 It is tissue amyloid identifies protein specific an X linked recessive disorder. Glycolipid types-AL in primary amyloidosis and AF in granules may be seen in perineurial and familial types. The amyloid in familial endothelial cells in peripheral nerve.68 There polyneuropathy is not derived from immuno- is a deficiency of the enzyme ceramidetrihex- globulin and therefore abnormal immuno- sosidase that results in the accumulation of globulins are not present in the serum. In ceramidetrihexaside in tissues. Diagnosis may most, but not all, types of familial poly- be established by enzyme assay of a galactosi- neuropathy (Portuguese, Indian, German dase which is reduced on leucocyte and skin and Jewish, and Appalachian types), there fibroblast preparations.97 is a prealbumin (transthyretin) fraction in Refsum's disease-Refsum's disease is a rare the serum and a point mutation in the autosomal recessive disorder characterised by transthyretin gene (chromosome 1 8q. 11.2, demyelinating hypertrophic neuropathy, q12. 1). The Finnish type of amyloidosis has , ataxia, , and been located on 9q33 and the Iowa type on deafness. Motor nerve conduction is very 1 1q33-q24. The Van Allen type is due to a slow due to demyelination; with onion bulb genetic defect of apolipoprotein Al.35 formation that may be seen on sural nerve biopsies. There is impaired a-oxidation of Hereditary disorders oflipid metabolism phytanic acid causing an accumulation of Metachromatic leukodystrophy-Metachro- phytanic acid in the tissues.98 Diagnosis is matic leukodystrophy is associated with made from the clinical picture and by peripheral neuropathy that may sometimes be increased serum phytanic acid and defective a presenting feature in adult cases. Nerve a oxidation of phytanic acid by skin fibrob- http://jnnp.bmj.com/ conduction studies are consistent with the lasts. segmental demyelination that is seen on sural Friedreich's ataxia-Friedreich's ataxia is asso- nerve biopsy together with metachromatic ciated with a sensory neuropathy. granular inclusions in Schwann cells.6466 Electrophysiological studies typically show Diagnosis may be established in the labora- small or absent sensory potentials and normal tory by determination of reduced arylsul- motor conduction and on sural nerve biopsy

phatase concentrations in blood leucocytes there is a selective loss of large diameter on September 30, 2021 by guest. Protected copyright. and skin fibroblasts, and by the finding of fibres.70 Other spinocerebellar degenerations intracellular deposits of metachromatic mate- may be associated with a mild neuropathy rial on microscopic examination of urinary affecting myelinated fibres of all diameters.99 sediment.66 There is a mutation of the gene encoding for arylsulphatase A on chromo- INFLAMMATORY NEUROPATHIES some 22q-13qter.'8 Guillain-Barre syndrome Krabbe's disease (globoid cell leukodystrophy)- In the first instance, a clinical diagnosis of Krabbe's disease is autosomal recessive, peripheral neuropathy must be established affects children in the first year of life, and is and other conditions such as transverse associated with peripheral neuropathy. Nerve myelitis, spinal cord compression, botulism biopsy shows loss of myelinated fibres, and (pure motor features), and myasthenia gravis inclusions in Schwann cells and macrophages (pure motor features) must be excluded. that are diagnostic.6667 Assay of the enzyme Other causes of acute neuropathy (toxins, galactosylceramide ,B galactosidase in leuco- drugs, nutritional deficiencies, porphyria, cytes, serum, or cultured fibroblasts will Lyme disease, acute neuropathy of the criti- establish the diagnosis without the need for cally ill, vasculitis, and malignancy) are elimi- biopsy.66 nated by clinical evaluation and appropriate A-fl lipoproteinaemia (Bassen-Kornzweig dis- tests. Antecedent precipitating factors (for ease)-Peripheral neuropathy is associated example, immunisation, Campylobacter, with a progressive ataxia resembling Epstein-Barr virus, and mycoplasma infec- Friedreich's ataxia.45 There is moderate slow- tions) should be sought. The CSF may show 280 McLeod

the typical abnormalities of increased protein Benign monoclonal gammopathy-There is an J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.58.3.274 on 1 March 1995. Downloaded from and low white cell count; a high white cell association between benign monoclonal para- count raises the suspicion of HIV, Lyme dis- proteins in the blood and peripheral neuropa- ease, and other infections.28 30 100 Nerve con- thy. 105 IgM paraproteins are particularly duction studies are essential for diagnosis but associated with a chronic demyelinating senso- may be normal in the early stages in which rimotor neuropathy, tending to occur in older case recording of F waves and somatosensory people and being accompanied by a postural evoked potentials should be undertaken to tremor.62 Sural nerve biopsy often shows seek evidence of impairment of proximal con- demyelination with widely spaced myelin duction. Three or more nerves should be lamellae being seen on electron microscopy, studied in upper and lower limbs as the particularly in the presence of IgM K.62 IgA peripheral nerve demyelination may be asym- and IgG proteins may also be associated with metric and patchy.25 Serial studies should be demyelinating neuropathies. The relation undertaken if the diagnosis is in doubt. between paraproteinemia and CIDP is uncer- Electromyography should be performed after tain. 106 107 two or three weeks if recovery is slow, or muscle wasting has developed, to ascertain Multifocal motor neuropathy with persistent the extent of axonal degeneration. Nerve con- conduction block duction studies should be repeated if recovery This is a rare condition in which there is an is delayed; persistent slowing of conduction, asymmetric chronic demyelinating neuropa- conduction block, and dispersion should raise thy affecting predominantly motor nerves and the suspicion of chronic inflammatory clear electrical evidence of conduction block. demyelinating polyneuropathy with acute It presents with asymmetric weakness and onset but it should be borne in mind that wasting with a motor neuron disease-like pic- electrophysiological evidence of demyelina- ture and increased antiganglioside GM1 anti- tion may persist in typical Guillain-Barre syn- bodies in about 80% of cases.'08 109 Motor drome for many weeks. nerve conduction studies show conduction block and slowing localised to sharply cir- Chronic inflammatory demyelinating cumscribed areas in nerve trunks.1"0 Sensory polyradiculoneuropathy (CIDP) conduction is normal, at least in the early Typically the onset is subacute, the peak of stages of the disease, and sural nerve biopsy disability being reached later than four weeks; shows only minor changes.'08 1 11 112 Biopsy of however, it may have a more rapid onset. The affected segments of nerves show subperi- diagnosis is confirmed by evidence of neurial oedema, onion bulb formations, and demyelination from nerve conduction demyelinated and remyelinated axons.1"3 The studies.4243 101 These may help differentiate it relation of this condition to CIDP is unclear. from the demyelination seen in hereditary demyelinating neuropathies HMSN types I Vasculitic neuropathy and III and Refsum's syndrome in which the Vasculitic neuropathies (polyarteritis nodosa, conduction velocities are uniformly slow in all Churg-Strauss syndrome, Waldenstrom's nerves and conduction block and dispersion macroglobulinaemia, rheumatoid arthritis,

of the action potential are uncommon. 102 mixed connective tissue diseases, Sjogren's http://jnnp.bmj.com/ Protein in CSF is usually increased.4243 101 syndrome, non-systemic vasculitis, systemic Other types of demyelinating neuropathy lupus erythematosus) classically present as (paraproteinemic, vasculitic, leprosy, Lyme mononeuritis multiplex although about half disease, HIV infections) must be excluded by the patients have a clinical picture of asym- appropriate investigations. If there is doubt metric or symmetric generalised sensorimotor about the diagnosis, confirmation should be polyneuropathy.54 In most cases there will be obtained from sural nerve biopsy as the evidence of systemic disease and raised ery- patient is likely to be committed to a long throcyte sedimentation rate; the presence of on September 30, 2021 by guest. Protected copyright. course of immunotherapy with its attendant increased titres of antinuclear antibodies and risks.103 The progress can be monitored by rheumatoid factor will confirm the diagnosis. nerve conduction studies although the Nerve conduction studies are consistent with changes of improvement or deterioration will an axonal neuropathy. Nerve biopsy usually lag behind those of the clinical features. shows pathological changes of vasculitis in small vessels in the endoneurium and per- Paraproteinemic neuropathies ineurium and acute severe axonal degenera- Paraproteins may be found on immunoelec- tion. Non-systemic vasculitic neuropathy is trophoresis during the investigation of patients being increasingly recognised; up to 30% of with peripheral neuropathy, and the finding all vasculitic neuropathies fall into this should arouse suspicion of multiple myeloma, group.54-57 Some cases may have increased Waldenstrom macroglobulinaemia, cryoglobu- erythrocyte sedimentation rate and anti- linaemia, primary amyloidosis, and other dys- nuclear antibodies titres but in most there are proteinaemias. Bone marrow aspiration, no serological markers and diagnosis can be examination for urinary Bence-Jones protein, made only on sural nerve biopsy. and radiological skeletal survey should be per- formed; if these investigations are normal it is Sjogren's syndrome likely that the patient has a benign monoclonal Sjogren's syndrome is often difficult to diag- gammopathy, or monoclonal gammopathy of nose in the early stages as it may present as a undetermined significance.'04 symmetric or asymmetric predominantly Investigation ofpenipheral neuropathy 281

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NEUROLOGICAL STAMP

Atropa belladonna (deadly nightshade) Atropa belladonna is a member of the nightshade family solanaceae. Its botanical name is derived from Atropos who, in Greek mythology, cut the thread of life. The red the eye. The plant was named sap enlarges the pupils of http://jnnp.bmj.com/ at the time of the Italian Renaissance in the days of the infamous Borgia family, when the ready availability of poison was popular. The ladies of the court used one of these poisons, belladonna, not to kill their rivals but to beautify and enlarge their pupils. The solanaceous alkaloids are among the earliest effec- tive treatments for parkinsonism. Belladonna contains atropine, scopolamine, and hyoscyamine. The ripe on September 30, 2021 by guest. Protected copyright. berries are sweet tasting and poisonous and attractive to children. A medicinal plant series published and produced by Yugoslavia in 1965 shows the belladonna flower (Stanley Gibbons 1161, Scott 775). L F HAAS