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When symptoms and signs indicate involvement of only one of the three fiber types the differential diagnosis is narrowed, e.g. severe sensory neuropathies associated with sensory limb or gait ataxia are caused by only a few conditions (mainly paraneoplastic, Sjögren’s syndrome, a few toxins, and rare hereditary neuropathies). Peripheral causes of isolated muscle weakness are limited and include motor neuronopathy, multifocal motor neuropathy, or some forms of acute and chronic inflammatory demyelinating polyneuropathy (AIDP and CIDP). Pure autonomic dysfunction is seen in acute panautonomic neuropathy (sometimes post-infectious), pure autonomic failure, or as an immune mediated syndrome.
Case 1
A 65-year-old woman with asthma presents with a progressive right foot drop along with numbness and pain in the lateral calf and dorsum of the right foot; 14 days later, she develops weakness of the left hand with numbness and pain of the ulnar border. There is low-grade fever, weight loss of 10 kg, and a nonproductive cough. Examination confirms a right peroneal and a left ulnar neuropathy, both of moderate clinical severity. Her complete blood count is normal other than eosinophilia, and the erythrocyte sedimentation rate is elevated at 90 mm/h. A chest radiograph demonstrates a hazy interstitial infiltrate. Electrodiagnostic examination confirms a multifocal axonal polyneuropathy with low-amplitude right peroneal and left ulnar motor and sensory responses, normal conduction velocities, without motor conduction block.
Discussion
The diagnostic algorithm in peripheral nerve disorders follows a logical and stepwise approach in which the following questions are addressed:
1. What is the localization for the patient’s symptoms (e.g. central, peripheral, or both)?
2. Is the onset acute, subacute, or chronic, and is the course relapsing–remitting, progressive, or static?
3. What is the pattern and clinical severity of deficits (e.g. sensory, motor, or autonomic)?
4. What is the pattern of involvement (e.g. symmetric or asymmetric; proximal, distal, or mixed)?
5. Are there associated systemic features (e.g. weight loss, rash, joint swelling, fever)?
6. Are there clues to a hereditary cause in the family history?
7. Is there exposure to neurotoxins (drugs, occupational toxins, alcohol), or inadequate nutrition?
8. Is the past medical history notable for diseases associated with neuropathy (diabetes, cancer, connective tissue disease, etc)?
Involvement of individual named nerve territories with both motor and sensory involvement is due to a peripheral neuropathy, not a central disorder. The onset is subacute, stepwise in nature, and clearly asymmetric. Such a presentation is typical of mononeuropathy multiplex, in which motor and sensory fibers of individual peripheral nerves are affected in sequential fashion. Although this is a typical presentation of a vasculitic illness, other causes are listed in Table 20.1. This patient’s asthmatic symptoms, peripheral eosinophilia, and pulmonary infiltrates all suggest a new diagnosis of Churg–Strauss syndrome. See Table 20.2 for examples of other systemic manifestations of diseases known to cause neuropathy. Nerve conduction studies disclosed axon loss physiology; biopsy of superficial peroneal nerve and adjacent peroneus brevis muscle confirmed a necrotizing vasculitis, and laboratory studies confirmed markedly elevated p-ANCA (perinuclear anti-neutrophil cytoplasmic antibodies) titers (anti-myeloperoxidase or anti-MPO positive).
Table 20.1. Causes of neuropathy
| Neuropathy type | Acute | Subacute or chronic |
| Demyelinating | ||
| Symmetric | Immune-mediated, AIDP, SLE, HIV-associated AIDP, Lyme disease-associated AIDP Infectious, e.g. diphtheria Toxic, hexacarbons (n-hexane) | Immune-mediated, CIDP, anti-MAG, POEMS/Castleman’s syndrome Hereditary, CMT type 1A, 1B (childhood), CMT3, CMT4, CMTX Drugs, e.g. amiodarone, perhexilene Toxic, e.g. n-hexane, gold, arsenic Leukodystophies, e.g. Krabbe’s, metachromatic, adrenomyelopathy Mitochondrial |
| Asymmetric/Multifocal | Immune-mediated, AIDP (rarely) Hereditary, e.g. HNPP Inflammatory, vasculitisa | Immune-mediated, e.g. MADSAM, MMNCB, CIDP (upper extremity variant) Hereditary, e.g. HNPP |
| Axonal | ||
| Symmetric | Immune-mediated, e.g. AMAN, AMSAN Hereditary, porphyria Toxic, e.g. alcohol, arsenic, thallium, hexacarbon, pyrinuron Drugs, e.g. vincristine, cisplatin, high-dose pyridoxine Critical illness Inflammatory, vasculitis (rarely), cryoglobulinemia | Metabolic, e.g. diabetes, renal failure, hypothyroidism Toxic, e.g. alcohol, arsenic, thallium, acrylamide, organophosphates, hexacarbon Hereditary, e.g. CMT type II (“axonal” CMT) Infectious, e.g. Lyme, HIV Paraneoplastic Infiltrative, e.g. amyloidosis Drugs, e.g. vincristine, cisplatin, thalidomide, dapsone, nucleoside analogs Inflammatory, e.g. connective-tissue disease, Sjögren’s syndrome, cryoglobulinemia, celiac disease |
| Asymmetric/Multifocal | Inflammatory, vasculitis, perineuritis Infectious, e.g. leprosy, Lyme disease Toxic, e.g. lead Paraneoplastic (sensory only) Metabolic, e.g. diabetes | Inflammatory, e.g. vasculitis, sarcoidosis Infectious, e.g. leprosy, Lyme disease Infiltrative disorders, e.g. amyloidosis, neurolymphomatosis Inflammatory, Sjögren’s syndrome, cryoglobulinemia |
aMay be associated with acute motor conduction block, but axon loss then predominates.
AIDP/CIDP, acute/chronic inflammatory demyelinating polyradiculoneuropathy; AMAN/AMSAN, acute motor/sensorimotor axonal neuropathy; CMT, Charcot–Marie–Tooth disease; HNPP, hereditary neuropathy with pressure palsies; MADSAM, multifocal acquired demyelinating sensorimotor polyneuropathy; MMNCB, multifocal motor neuropathy with conduction block; POEMS, peripheral neuropathy, organomegaly, endocrinopathy, M-protein, skin changes.
Table 20.2. Systemic manifestations of diseases associated with neuropathy
| Systemic manifestation | Disease |
| Rheumatological | |
| Arthritis | Lyme disease, lupus, rheumatoid arthritis, sarcoidosis |
| Destructive arthropathy | Diabetes, leprosy, hereditary neuropathy |
| Hematological | |
| Hepatosplenomegaly | POEMS, myeloma, amyloidosis |
| Lymphadenopathy | POEMS, Castleman’s disease, lymphoma, HIV, sarcoidosis |
| Macrocytosis – with or without anemia | Arsenic poisoning, vitamin B12 deficiency |
| Renal | HIV disease |
| Fabry’s disease | |
| Hepatitis B and C | |
| Diabetes | |
| Systemic vasculitis | |
| Lupus | |
| Amyloid | |
| Gastrointestinal | Celiac disease |
| Arsenic, thallium, or lead poisoning | |
| Porphyria | |
| Vitamin deficiency associated with malabsorption (e.g. thiamin, vitamin B12, copper) | |
| Dermatological | |
| Purpura | Systemic vasculitis, cryoglobulinemia |
| Hypopigmentation | Leprosy |
| Hyperpigmentation | Adrenomyeloneuropathy, POEMS |
| Ichthyosis | Refsum’s disease |
| Angiokeratoma | Fabry’s disease |
| Mees’ lines | Arsenic, thallium poisoning |
| Alopecia | Thallium poisoning |
| Erythema nodosum | Sarcoidosis, connective tissue disease |
| Macroglossia | Amyloidosis, vitamin B12deficiency |
| Thickened nerves | Hereditary neuropathy, leprosy |
| Raynaud’s phenomenon | Cryoglobulinemia, connective tissue disease |
| Nodules | Rheumatoid arthritis |
| Kaposi’s sarcoma | HIV |
| Cardiovascular | |
| Cardiac failure | Amyloidosis |
| Hypertrophic cardiomyopathy | Freidreich’s ataxia |
| Pericarditis/pericardial effusion | Lupus, paraneoplastic syndrome |
| Cardiac conduction defects | Mitochondrial diseases |
| Respiratory | |
| Digital clubbing | Paraneoplastic syndrome, sarcoidosis, inflammatory bowel disease |
| Interstitial lung disease | Connective tissue diseases |
| Hilar adenopathy | Sarcoidosis |
| Endocrine | |
| Gynecomastia | Kennedy’s disease |
| Hypothyroidism | POEMS |
| Diabetes | Mitochondrial diseases |
| Multiple system involvement | Critical illness polyneuropathy |
Patterns of Involvement: Length Dependency
Most peripheral nerve diseases affect nerves in a “length-dependent” fashion, i.e. the longer the nerve fiber, the more severely it is affected. The result is a symmetric pattern of sensory, motor, and reflex symptoms and signs beginning in the feet, and “ascending” to the knees, fingers, etc. as the disease progresses. However, there are notable exceptions to this pattern dependent on the site of pathology; in diseases of the vasa nervorum (e.g. vasculitis), the deficits are asymmetric or multifocal as in the case above. In addition, in disease affecting proximal neural elements such as nerve roots (e.g. AIDP and CIDP), anterior horn cells (e.g. motor neuron diseases), or dorsal root ganglia cells (e.g. paraneoplastic sensory neuronopathies), proximal weakness or sensory loss may be prominent. Identification of non-length dependency is an important clinical clue limiting the broad range of differential diagnoses in peripheral nerve disorders (see Table 20.1).
Case 2
A 45-year-old man presents with slowly progressive distal weakness and wasting in his hands and feet with increasing clumsiness and several falls. He noted foot weakness as far back as he can remember, and, on focused questioning, recalls that a former schoolteacher commented on his clumsiness during childhood. He has no positive sensory symptoms or autonomic symptoms. There is no clear family history, although he recalls that many family members have high arches. Examination reveals pes cavus foot deformity, a distal–predominant pattern of weakness and wasting, and generalized areflexia. Nerve conduction studies disclose uniform slowing of motor conduction velocities (median conduction velocity or CV = 22 m/s) with reduction in motor and sensory response amplitudes in the legs more than arms.
Diagnosis: Charcot–Marie–Tooth (CMT) Disease Type 1A Due to PMP22 Duplication.
This patient exhibits many of the typical features of a hereditary neuropathy phenotype: long history with slow progression, lack of positive sensory symptoms, and skeletal deformity (pes cavus). A carefully taken history may identify subtle neuropathic symptoms before the development of frank weakness (e.g. childhood clumsiness). Weakness follows a length-dependent pattern, and may be quite severe, but only comes to medical attention when functional limitation or disability develops (e.g. falls). An exception to the length-dependent pattern of most hereditary polyneuropathy syndromes that deserves special mention is hereditary neuropathy with pressure palsies (HNPP), due to PMP22 deletions (see Chapter 21).
caution: skeletal deformities
Although common in hereditary neuropathy, foot deformities may also be seen in central nervous system (CNS) diseases such as Friedreich’s ataxia or hereditary spastic paraparesis, among others. Spinal abnormalities such as kyphosis or scoliosis, although non-specific, are clues to a hereditary neuropathy, and should be sought. Foot deformity may be in the form of “pes cavus” (high arch) or “pes planus” (fallen arch); both have similar diagnostic significance and typically reflect weakness of the intrinsic foot musculature with relative preservation of the extrinsic foot inverters and toe flexors and extensors. Finally, foot deformities may rarely be seen in chronic acquired neuropathies (e.g. longstanding CIDP).
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