2 Clinical evaluation and differential diagnosis R. Kiefer, E.B. Ringelstein

Introduction

Many clinicians experience the evaluation of patients with peripheral neuro- pathy as challenging and sometimes non-rewarding. While the clinical diag- nosis of a length-dependent sensorimotor is easily made by experienced neurologists, the cause of the disorder may remain un- resolved in many cases despite extensive workup. Furthermore, some periph- eral neuropathies may present with clinical features which are not easily rec- ognized to be derived from disorders of the peripheral nerve at all. Thus, mul- tifocal and pure motor neuropathic syndromes may be confused with myopa- thies or motor neuron disease, and neuropathies involving the cranial nerves may mimic brainstem diseases. Others may have additional involvement of central nervous system structures or may be accompanied by specific features in the general examination of the body such as facial stigmata or alterations of the skin and internal organs. Therefore, even the localization of the patient's problem to the peripheral nervous system may not be obvious in some cases. The structure of peripheral nerves is relatively simple. The cellular com- ponents directly related to the innate function of peripheral nerves, which is transmission of signals from the central nervous system to the periphery of the body and back, are only axons and Schwann cells orientated longi- tudinally along the nerve. As a consequence, damage to peripheral nerves can result in only a limited number of clinical and pathological phenotypes despite a great variability of causes. It is this seemingly homogenous pre- sentation of peripheral neuropathy which makes the differential diagnosis appear difficult to many. However, not all peripheral neuropathies look the same. A careful clini- cal look and an organized approach offer many possibilities to structure the differential diagnosis and narrow down possible causes of the patient's disease. Hereditary neuropathies, in particular, often have clinical features that are fairly specific and are easily recognized. This chapter offers a gen- eral approach to the patient with peripheral neuropathy, elaborates on spe- cific aspects of the history and clinical examination of patients with var- ious forms of hereditary neuropathies, and suggests a logical approach to establish a differential diagnosis in these patients [3, 5, 7]. 16 z R. Kiefer, E.B. Ringelstein

2.1 General approach to the patient with peripheral neuropathy

Patients with peripheral neuropathy are first evaluated on clinical grounds. History and physical examination are the cornerstones on which a first clinical differential diagnosis is based. Diagnosticians of peripheral nerve disorders assess the patient's symptoms and signs along a pathway provid- ing answers to the following questions (see also Table 2.1): 1. At what age were the first symptoms noted? 2. What is the time course of the disease? 3. Which fiber types are involved? 4. Which is the distribution of the deficits? 5. Is there any indication of inheritance? 6. Is there evidence of other concomitant diseases or specific non-neuro- logical features?

Each type of neuropathy is associated with specific features described by these six major categories, and each combination of answers to these six questions forms a clinical syndrome with a specific differential diagnosis. Three examples are given: A person of any age with acute and rapidly progressive proximal sym- metric weakness, with little sensory involvement, without other affected family members, and with a preceding diarrhea may suffer from Guillain- Barr syndrome. Another person with subacute onset of weakness and sen- sory deficits first in the distribution of the on one side and the on the other followed by progressive involvement of additional individual nerves has multiple mononeuropathy and may suffer from vas- culitis, to name just one possible cause of this syndrome. In contrast, if the onset of the multiple mononeuropathy started years ago, the course was re- lapsing-remitting, the deficits were triggered by repetitive movements in affected limbs, an underlying existed, and other family members were also suffering from a similar disease, the patient may rather have hereditary neuropathy with pressure palsies (HNPP). There are many other neuropathic clinical syndromes. A complete listing of the differential diagnoses of the various neuropathy syndromes is beyond the scope of this chapter focusing on hereditary neuropathies. Obviously, the clinical syn- drome of lifelong disease (item 2), first noted in youth or early adulthood (item 1), weakness and sensory loss (item 3) in a distal and symmetric dis- tribution with peroneal preponderance (item 5), evidence of autosomal dominant inheritance (item 4) and the presence of hammertoes and pes cavus suggests a hereditary neuropathy, most likely CMT1 or 2. Once a clinical differential diagnosis is made, neurophysiological tests are applied next. Their aims are threefold: to confirm the presence of a polyneuropathy, to assess fiber type involvement and distribution patterns, and to determine the relative degree of demyelination and axonal damage. 2 Clinical evaluation and differential diagnosis z 17

Table 2.1. Important clinical features for the initial categorization of a patient's neuropathy Item 1: Age at onset Item 2: Course

z birth z acute z infancy z subacute z childhood z chronic-progressive z adolescence z lifelong z young adulthood z relapsing-remitting z midlife z advanced age Item 3: Fiber types involved Item 4: Inheritance

z pure motor z autosomal dominant z pure sensory z autosomal recessive ± pain and temperature z X-linked ± light touch, vibration and position senses z none z pure autonomic z combinations of the above Item 5: Distribution of deficits Item 6: Concomitant conditions

z length-dependent (distal-symmetric) z diabetes mellitus z proximal symmetric z renal or liver disease z marked asymmetry z rheumatic disease and vasculitis z one nerve or multiple individual nerves z malignancy z radicular z gastrointestinal disorders z nerve plexus z malnutrition z cranial nerves z ocular disorders z additional CNS symptoms and signs z hearing loss z combinations of the above z alcohol and drug abuse z neurotoxic drugs z others

The role of clinical neurophysiology is discussed in detail in the next chap- ter. Once the neurophysiological examination is completed, a clearer pic- ture of the differential diagnosis should have emerged, and discrimination between an axonal and a demyelinating neuropathy might have been achieved. In the third step, the cause of the neuropathy is sought. Based on the differential diagnosis drawn from the recognition of the specific clinical neuropathy syndrome and neurophysiological tests, laboratory studies, in- 18 z R. Kiefer, E.B. Ringelstein

vestigations of other organ systems to determine concomitant disease, ge- netic studies, and nerve or skin biopsy are performed as needed. In certain hereditary neuropathies, the clinical picture together with the results from neurophysiological tests is already sufficiently clear to suggest a specific di- agnosis [4, 6]. In such cases, one single genetic test may be all that is needed to confirm the diagnosis. A rational approach to genetic testing is described in the chapter ªMolecular genetic diagnosis of hereditary neuro- pathiesº of this book. In the fourth and final step of this general approach, the consequences of the now established diagnosis are structured and discussed with the pa- tient. Whenever possible, specific treatments and symptomatic measures are initiated. Examples are immunotherapy for inflammatory neuropathies and treatment of neuropathic pain. When no specific therapy is available, the patient still needs to be informed about the nature of his or her illness and the perspectives. Physiotherapy and specific rehabilitative measures may be needed. In patients with hereditary neuropathy, genetic advice needs to be provided (see chapter: ªGenetic Counselingº).

2.2 Specific features in the history of patients with hereditary neuropathies 2.2.1 Chief complaint and functional deficits noted by the patient

Patients may seek medical advice for a number of different reasons which vary depending on the type of hereditary neuropathy. The most common causes of seeking medical advice are summarized in Table 2.2. It should al- ways be remembered that only CMT1A and B, CMTX, CMT2 and HNPP are diseases which are regularly encountered in neurological practice, while all other forms are extremely rare and may occur only in certain populations. The most common chief complaint in patients with hereditary neuropa- thy is disturbance of gait. Gait may be impaired due to weakness, proprio- ceptive loss, foot deformity or contracture of the Achilles tendon. Patients may fall over their feet due to weakness of peroneal muscles, while the ability to stand on the toes is usually preserved for some time. Walking on uneven ground may become difficult with distal weakness, and frequent ankle sprains may be another consequence of distal weakness. Proximal weakness is indicated by complaints of difficulties climbing stairs or raising from a chair. Proximal weakness, however, is an unusual feature of hereditary neuropathy and occurs only late in the disease in few cases, with the exception of the most severe forms such as Djerine-Sottas syndrome (DSS), some forms of CMT4 and the very rare hereditary motor and sensory neuropathy proximal type (HMSN-P) and is otherwise rather suggestive of acquired inflammatory . 2 Clinical evaluation and differential diagnosis z 19

Table 2.2. Common presenting complaints in patients with hereditaryneuropathies CMT and distal HMN phenotype z Disturbance of gait z Weakness z Sensoryloss (not distal HMN) z Foot deformities HNPP and HNA phenotype z Recurrent focal weakness z Foot deformities z Shoulder pain (HNA) HSAN phenotype (rare) z Pain z Excessive or lost sweating All hereditary neuropathies z Affected familymembers

Weakness of the hands with difficulties in writing, turning a key or grasp- ing fine objects is rarely the presenting complaint in hereditary neuropathy but may occur later in the course of the disease. Exceptions are patients with CMT2D and the hereditary motor neuropathies type 5(HMN V) as well as HMN VIIB whose illness begins in the hands with initially normal function of the legs. Progressive muscle wasting of the lower legs or hands may be another chief complaint while weakness may not have been noted. While the above complaints are typical for CMT and distal HMN patients, patients with HNPP usually report disturbances of gait due to uni- or bilateral peroneal palsy. Other peripheral nerves of the lower limb are less frequently af- fected, and quadriceps weakness is not a usual feature of this disease. Pa- tients with HNPP may also complain of acute weakness and sensory loss in one or both arms which only on physical examination turn out to follow the distribution of individual nerves, mostly the ulnar nerve. Weakness is frequently triggered by repetitive movements, forced positions of the af- fected limbs for a prolonged period of time, or minor pressure on the nerve along its course. Further questioning may reveal similar insults at earlier times and evidence of an additional generalized neuropathy, the symptoms of which may only be reported when specifically asked for. Also, the history may reveal the preexisting diagnoses of multiple entrapment syndromes or surgery for . In hereditary neuralgic amyotrophy (HNA), weakness is rarely the presenting complaint, but rather severe shoulder pain, followed by weakness and atrophy within days to weeks. Usually the pain subsides while weakness and atrophy set in. Sensory deficits in CMT patients add to postural imbalance and gait dis- turbance which are accentuated in the dark. Sensory loss may, however, go 20 z R. Kiefer, E.B. Ringelstein

unnoticed for many patients with CMT, particularly in CMT2. Some pa- tients may even insist on feeling normal sensation despite having total loss of vibration sense at the toes and severe sensory abnormalities on neuro- physiological testing. The history alone may therefore not provide the nec- essary clues to differentiate between CMT and distal SMA. The very slow occurrence of deficits is the likely cause of unnoticed sensory loss in CMT and is a suggestive feature differentiating it from acquired neuropathies of shorter duration. In HNPP, sensory loss is focally distributed along the sensory fields of individual peripheral nerves. In addition, there may be distal sensory loss similar to that in CMT patients due to the underlying generalized neuropathy in HNPP. Pain is a prominent complaint in hereditary sensory and autonomic neuropathy type 1 (HSAN1). Also, it is highly characteristic of HNA where acute onset of uni- or bilateral shoulder pain is the chief complaint fol- lowed by weakness. Specific questioning may reveal similar episodes in the past. Loss of pain and distal loss of sweating are characteristics of HSAN ex- cept HSAN3 where excessive sweating is a feature. Some HSAN patients may also present because of poor wound healing and painless ulcers, or mutilations. Foot deformities including hammertoes and pes cavus are another fre- quent cause to seek medical advice, and such patients may first be seen by orthopedic surgeons rather than neurologists. When evaluating patients with longstanding polyneuropathy, a history of orthopedic surgery on the feet and ankles in earlier days may suggest a hereditary neuropathy. Foot deformities are seen in CMT1 and 2, CMTX, distal HMN patients and less frequently in HNPP. Finally, patients with affected family members may seek medical advice despite the absence of any physical complaints to find out whether they are also affected, and to obtain genetic counseling. In some individuals, the ill- ness may then be detected by physical examination and neurophysiological testing.

2.2.2 Onset and time course of disease

Although a lifelong disease, patients with CMT and distal HMN usually do not seek medical advice before the end of the first decade or in the second decade. Earlier onset points towards severe disease such as DSS, in which weakness is often present from birth, or one of the forms of CMT4. On the other hand, onset may be so insidious and progression so slow that it may remain unnoticed for many years. Some symptoms may only retrospec- tively be recognized when specifically asked for. In neuropathy patients with suspected hereditary neuropathy, it is therefore very important to spe- cifically ask for early symptoms during childhood and adolescence and in- quire about indirect hints for abnormal function. Low physical activity as 2 Clinical evaluation and differential diagnosis z 21 a child or a dislike for wild play may provide clues, as do poor grades in sports at school. Affected persons will frequently report that they always had been slower than their peers. A child regularly assigned as goalkeeper when playing soccer may indicate poor running abilities. It may also be re- membered that the feet looked funny from the early days and that shoes that fit were always difficult to buy, indicating that foot deformities had preexisted for years. In contrast, patients with HNPP and HNA may have been healthy until the first bout of disease, but again, this needs to be specifically asked for and may have gone unnoticed at first.

2.2.3 Concomitant diseases

Medical conditions causing acquired peripheral neuropathy should be sought for as part of establishing a differential diagnosis. Their existence does, however, not preclude hereditary neuropathy. The time course of the disease and characteristic elements of the physical examination may help distinguish between the two.

2.2.4 Family history

A considerable number of patients have no family history of neuropathy, amounting to 20% in CMT1. A negative family history, therefore, does not preclude the diagnosis of hereditary neuropathy. Also, affected family members may not have even noted their disease. It is therefore necessary to specifically ask for weakness, gait disturbance, foot deformities and other features of the disease in family members. It is also mandatory to ex- plore a complete family tree including brothers and sisters, the parents and their brothers and sisters, the cousins, and the grandparents. A large family who all lived until old age will be informative. On the other hand, the ab- sence of affected family members does not exclude even an autosomal dominant genetic trait. Potentially informative family members may have died early or were lost for other reasons. This may be particularly true in populations where families were destroyed or dispersed during war times. Finally, adoption or false paternity may obscure a genetic trait. Another not uncommon possibility is that the disease is caused by a de novo muta- tion and therefore the patient is the first affected member of the family. 22 z R. Kiefer, E.B. Ringelstein

2.3 Specific features in the clinical examination of patients with suspected hereditary neuropathy 2.3.1 Neurological examination

The most prominent abnormalities refer to the motor and sensory systems affecting the extremities. Cranial nerve abnormalities, vocal cord and respi- ratory problems and additional CNS features are rare but nevertheless rep- resent important and informative findings in classifying hereditary neuro- pathy. Among the cranial nerve abnormalities, optic atrophy may rarely occur in CMT patients. Sensorineural hearing loss can be associated with CMTX, some forms of CMT4 and in very rare cases in patients with CMT1A. Vocal cord paralysis is a peculiar attribute of CMT2C as well as some forms of CMT4 and distal HMN. These conditions are also associated with early re- spiratory failure. Weakness and muscle atrophy in CMT occurs typically in a length-de- pendent pattern and shows a preponderance of peroneal muscles. The small muscles of the foot and the peroneal muscles of the lower leg are af- fected first, followed by the thigh muscles. As an exception to that rule, CMT2D, HMN V and HMN VIIB patients show initial weakness in the hands. Weakness in the distribution pattern of one or more peripheral nerves suggesting multiple entrapment syndromes is the typical finding in HNPP. In addition, distal weakness is often found in older patients due to the underlying generalized neuropathy in HNPP. A careful and detailed ex- amination is required to recognize asymmetry in such patients and to de- tect the preponderance of weakness in selected peripheral nerves. Proximal weakness occurs only in the most severe forms of disease such as in DSS, in some families with CMT4, in the extremely rare HMSN-P and in very advanced cases of distal hereditary neuropathies late in life. Weakness of respiratory muscles is also infrequent, but occurs in certain rare forms as mentioned above, or in advanced cases of the more common hereditary neuropathies. In HNA, the pattern of weakness is rather different. The asymmetric brachial associated with HNA is best appreciated after a de- tailed examination of all proximal and distal muscles of the arm and shoulder region. Head flexors and extensors are not affected. There is, however, often marked winging of the scapula due to involvement of one or both long thoracic nerves. Sensory abnormalities are absent in distal HMN and follow the distribu- tion of weakness in CMT and HNPP. In CMT, there is a length dependent loss of all modalities. Perception of vibration sense is reduced first, fol- lowed by loss of perception of light touch. In many cases, affected patients deny any sensory abnormalities which may only be detected by careful testing of vibration sense. 2 Clinical evaluation and differential diagnosis z 23

Pain and temperature sensation are preferentially lost in HSAN1 and CMT2B, and are selectively absent in HSAN4. In contrast, all sensory mo- dalities are affected in HSAN2. Spontaneous pain is very rare in CMT1, most forms of CMT2 and CMTX but is prominent in CMT2B and HSAN1. Thickening of peripheral nerves due to a hypertrophic neuropathy should always be sought for in suspected hereditary neuropathy. It is best palpated and seen at the greater auricular nerve in the neck and at the ul- nar and peroneal nerves. It is sometimes a prominent feature in DSS and about one half of patients with CMT1, but not in CMT2 and CMTX. A postural tremor is observed in about one third of patients with CMT1. Autonomic disturbances may affect sweating, blood pressure control, urinary and fecal continence and sexual functions. They are features of some forms of HSAN and are rare in CMT. Muscle tendon reflexes are commonly lost. Ankle reflexes are lost first in most types of hereditary neuropathy. In CMT1, generalized reflex loss is found early, while in CMT2, the more proximal reflexes are preserved long- er. In HNPP, distal or generalized reflex loss indicates advanced generalized neuropathy, while early cases may show reflex loss only in affected nerves. Exaggerated muscle tendon reflexes with positive pyramidal signs indicate additional pyramidal tract involvement and can be found in giant axonal neuropathy (GAN) and some forms of distal HMN.

2.3.2 General examination z Skin changes Painless ulcerations of the skin, unnoticed burns and painless injuries can be found in patients with HSAN as well as patients with CMT2B where the perception of pain may be severely impaired or absent. To detect such changes, it is important to carefully examine the feet and particularly the soles. Cases of HSAN may show severe disturbances of sweating, ranging from distal anhidrosis in HSAN2 to complete inability to sweat in HSAN4. Alter- nating hyperhidrosis and anhidrosis occurs in HSAN3. Absent fungiform papillae of the tongue are a feature of HSAN3. Curly hair reminiscent of little corkscrews in a child with neuropathy is highly suggestive of GAN. z Skeletal abnormalities Foot deformities are almost universally present in CMT. Pes cavus and hammertoes are both observed but do not necessarily need to occur to- gether. Absence of foot deformities makes CMT unlikely but does not en- tirely exclude the diagnosis. The reason for these deformities are tone im- 24 z R. Kiefer, E.B. Ringelstein

balances of the small foot muscles as well as the long flexor and extensor muscles of the lower leg. While the toe extensors innervated by the pero- neal nerve are disproportionately weak, the muscles at the sole of the foot and particularly the long toe flexors innervated by the tibial nerve are bet- ter preserved, leading to a high-arched foot and hammertoes. The hands may be deformed in a similar way, with a claw like appearance. Deformi- ties of the spine with severe kyphoscoliosis point towards tone imbalance of the paraspinal muscles and are associated with very severe forms of CMT including DSS and some forms of CMT4. A high-arched palate points towards weak palatal muscles during early development and is rarely seen in hereditary neuropathy. It may, though, occur in GAN. Neurogenic arthropathy, stress fractures, osteolysis and osteomyelitis due to uncontrolled skin infection are consequences of impaired pain sen- sation in HSAN. In HSAN2 in particular, this may lead to severe distal de- formities.

z Ocular features and hearing loss Ocular manifestations are not a frequent feature of the hereditary neuropa- thies covered in this book. However, optic atrophy may occur in CMT. Sen- sorineural hearing loss may be found rarely in CMTX, some rare forms of CMT4 and in rare cases of CMT1A.

2.4 Differential diagnosis in patients with suspected hereditary neuropathy 2.4.1 Distal symmetric leg weakness with peroneal preponderance

This is the most common and characteristic clinical presentation of CMT. Together with peroneal atrophy, hammertoes and pes cavus and in the presence of sensory abnormalities, this presentation is highly suggestive for CMT and argues against most other forms of acquired or inherited sen- sorimotor . Among the hereditary forms, the neuropathy of Refsum's disease may present in a similar way, although there is also a relapsing-remitting pre- sentation. A diagnosis of Refsum's disease can be suggested clinically by the presence of of the skin, and other ocu- lar signs, shortened phalanges of the fingers and toes, and cardiac arrhyth- mias [8]. A distinctive feature of CMT compared with acquired neuropathies is the observation that sensory deficits are frequently not noted by the patients. In many cases, they are only detected by careful sensory testing on physi- cal examination. This is likely due to the extremely slow progression and 2 Clinical evaluation and differential diagnosis z 25 long-standing disease. In contrast, acquired neuropathies with sensory in- volvement cause notable sensory deficits which frequently form the pre- senting complaint. Also, pain is hardly ever a feature of CMT, and the pres- ence of a painful neuropathy raises doubts about this diagnosis. Weakness in acquired length-dependent neuropathies may also affect foot elevators more than foot flexors. However, the difference between the anterior and posterior compartment muscles of the lower leg is frequently not as marked as in inherited neuropathy. Apart from the presence of a high-arched foot and hammertoes (see below), contractures of the Achilles tendon are highly unusual in acquired neuropathies but are a distinctive feature of inherited neuropathies. Also, the time course of the disease, age at onset and the presence of concomitant medical conditions may help to distinguish acquired from inherited neuropathies. If sensory symptoms and signs are completely absent, a diagnosis of dis- tal HMN is suggested. In such purely motor cases, certain myopathies af- fecting peroneal muscles need to be excluded. These include facioscapulo- humeral muscular dystrophy, myotonic dystrophy, central core disease, other congenital myopathies, and Nonaka myopathy. In most cases, these disorders are easily distinguished because of other characteristic features in the history and physical examination. A helpful sign is the absence of atrophy of the extensor digitorum brevis muscle and the small muscles at the sole of the foot in many peroneal myopathies, while atrophy is always present in distal HMN.

2.4.2 Pes cavus and hammertoes

Foot deformities typical for CMT are not unique for this group of disor- ders, nor are they always present. Pes cavus und hammertoes do not neces- sarily need to occur together. Since the deformities are caused by long- standing dysbalance of muscle tone between peroneal and tibial muscles of the lower leg, other conditions causing such an imbalance may also result in pes cavus and/or hammertoes. These include other inherited neuropa- thies like Refsum's disease and certain myopathies as mentioned above, but also central nervous system disorders. Since central paraparesis of the lower legs leaves muscle force acting against gravity better preserved, foot flexors are stronger than foot elevators in a centrally paretic leg. Hence, ge- netic disorders causing slow degeneration of pyramidal tracts such as he- reditary spastic paraplegia and Friedreich may also cause high- arched feet and hammertoes. Although these deformities are characteristic of genetic disorders, they can also rarely occur in acquired disease. Very occasionally, patients with acquired distal polyneuropathy and peroneal involvement will report that their toes become slowly bent with time and the interphalangeal joints come up. Pes cavus is not a usual feature of acquired spasticity due to spinal cord or cerebral lesions. 26 z R. Kiefer, E.B. Ringelstein

Pes cavus and hammertoes can also occur in the absence of any detect- able neurological deficit. In rare cases, familial foot deformities have been described.

2.4.3 The HNPP phenotype

The hallmark of HNPP is the occurrence of recurrent sensorimotor deficits in individual nerves, typically provoked by minor nerve trauma or com- pression. The most important differential diagnosis is that of common pressure palsies, e.g., of the ulnar nerve at the elbow, of the in the carpal tunnel and of the peroneal nerve at the fibular head. Hints to- wards HNPP are the mild degree of trauma causing the pressure palsy, the frequently recurring pressure palsies, and a positive family history. Furthermore, the presence of an underlying generalized demyelinating polyneuropathy points towards HNPP. It should, however, be noted that generalized neuropathies of other causes such as amyloid neuropathy and diabetic neuropathy may vice versa predispose to pressure palsies, particu- larly in the carpal tunnel. Other sensorimotor multiple mononeuropathies may need to be consid- ered. These include vasculitis of the peripheral nerve, sarcoidosis, leprosy, lymphomatous polyneuropathy, and multifocal acquired demyelinating sen- sory and motor neuropathy, a multifocal variant of chronic inflammatory demyelinating polyneuropathy. All the above disorders are usually progres- sive rather than recurrent, and do not present as pressure palsies. Also, concurrent medical disease will be indicative in some cases. Multifocal mo- tor neuropathy is easily differentiated by the lack of sensory symptoms and is a progressive disease.

2.4.4 The HNA phenotype

Recurrent shoulder pain followed by brachial plexopathy is the main clini- cal feature of HNA. A first and single episode is clinically indistinguishable from sporadic neuralgic amyotrophy or Parsonage-Turner syndrome. How- ever, neuralgic amyotrophy rarely occurs before the third decade and is seen until old age, while HNA may occur in children and in most cases the onset is before 30 years. HNA is sometimes associated with facial dys- morphic features like hypotelorism, epicanthus and cleft palate while these are not associated with Parsonage-Turner syndrome. Other conditions to be considered are infiltrative disorders of the bra- chial plexus, which are highly unlikely in bilateral disease. Myopathies af- fecting the periscapular muscles may cause secondary shoulder pain but are rarely difficult to differentiate. Compression injury of the causes scapular winging, but no other evidence of plexopathy is found. Tangier disease has also been reported to present in this way. 2 Clinical evaluation and differential diagnosis z 27

2.4.5 Pain and the sensory abnormalities of HSAN

Most acquired painful neuropathies, including diabetic neuropathy, HIV-as- sociated neuropathy, vasculitic neuropathy and acquired amyloid neuropa- thy, are usually disorders of adults. In contrast, the HSAN family of painful neuropathies manifests in nearly all cases very early in life, with the excep- tion of HSAN1 presenting not before the second or third decade. However, even in HSAN1, the clinical features are sufficiently distinct to avoid confu- sion. Transthyretin amyloid neuropathy is a rare painful neuropathy with ad- ditional autonomic involvement [1]. However, age at onset is older, and motor nerves are also affected. There are also distinctive non-neurological manifestations, including severe heart disease and various ocular manifes- tations. Fabry's disease presents in adolescence with burning limb pain in the absence of other symptoms and signs of neuropathy. The presence of cutaneous angiokeratomas, cardiac arrhythmias, characteristic ocular man- ifestations and renal failure help to identify this disease [2]. The neuropa- thy of Tangier disease may present with pain in a peculiar distribution over the chest and neck with sparing of the legs and sometimes manifests in childhood. There is multiorgan involvement with hepatomegaly and a char- acteristic yellowish-orange discoloration of enlarged and lobulated tonsils [6].

2.4.6 Nerve hypertrophy

Nerve hypertrophy belongs to the most distinctive features of CMT1 and DSS. Very few other neuropathies cause nerve hypertrophy. Lepromatous neuropathy is the most prevalent neuropathy causing enlarged peripheral nerves in some parts of the world. Refsum's disease also causes nerve thickening.

References

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6. Pareyson D (2003) Diagnosis of hereditary neuropathies in adult patients. J Neurol 250:148±160 7. Rosenberg NR, Portegies P, de Visser M, Vermeulen M (2001) Diagnostic investiga- tion of patients with chronic polyneuropathy: evaluation of a clinical guideline. J Neurol Neurosurg Psychiatry 71:205±209 8. Wanders RJ, Jansen GA, Skjeldal OH (2001) Refsum disease, peroxisomes and phy- tanic acid oxidation: a review. J Neuropathol Exp Neurol 60:1021±1031