R. Kiefer, E.B. Ringelstein
2.4 Differential diagnosis in patients
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 polyneuropathies.
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 ichthyosis of the skin, retinitis pigmentosa 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 z R. Kiefer, E.B. Ringelstein
24
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 myopaneuropa-thies 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 ataxia 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.
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 median nerve 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 cliniclini-cally 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 long thoracic nerve causes scapular winging, but no other evidence of plexopathy is found. Tangier disease has also been reported to present in this way.
z R. Kiefer, E.B. Ringelstein 26
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
1. Adams D (2001) Hereditary and acquired amyloid neuropathies. J Neurol 248:647±
2. Brady RO, Schiffmann R (2000) Clinical features of and recent advances in therapy657 for Fabry disease. JAMA 284:2771±2775
3. Dyck PJ, Grant IA, Fealey RD (1996) Ten steps in characterizing and diagnosing pa-tients with peripheral neuropathy. Neurology 47:10±17
4. Kuhlenbåumer G, Young P, Hunermund G, Ringelstein B, Stogbauer F (2002) Clini-cal features and molecular genetics of hereditary peripheral neuropathies. J Neurol 249:1629±1650
5. McLeod JG (1995) Investigation of peripheral neuropathy. J Neurol Neurosurg Psy-chiatry 58:274±283
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: evaluainvestiga-tion 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
28 z R. Kiefer, E.B. Ringelstein: 2 Clinical evaluation and differential diagnosis
This chapter will first give some general considerations of electrodiagnos-tics in hereditary polyneuropathies. The electrophysiological features of different types of hereditary polyneuropathies will then be discussed.
3.1 General considerations
An electrophysiological examination is an important step in assessing a pa-tient with suspected hereditary neuropathy and is necessary to plan ra-tional genetic testing. Nerve conduction studies are the cornerstones of the electrophysiological investigation if a hereditary neuropathy is suspected.
The main goal is to distinguish between a demyelinating and an axonal type of pathology or to provide evidence for an intermediate process [6, 13]. Together with the clinical examination and the patient's history, the electrophysiology should also help to exclude acquired neuropathies. A complete neuromuscular examination is necessary to plan the electrophy-siological tests and to choose the right nerves and muscles to examine.
3.2 Electrodiagnostic evaluation of hereditary polyneuropathies
Physical examination and a comprehensive history of a patient with a sus-pected hereditary neuropathy are fundamental in order to plan the follow-ing electrophysiological evaluation. Detailed information can be found in the previous chapter of this book. The complete electrodiagnostic evalua-tion should provide necessary informaevalua-tion to determine whether the disor-der primarily affects the axon, the myelin sheath or both. In addition, the involvement of sensory nerve fibers, motor fibers or both types of fibers should be clarified. This is essential to choose reasonable genetic tests for the patient (Table 3.1).
Nerve conduction studies are the most important part of the electro-diagnostic workup. At least three sensory nerves (e.g., sural, median and