Differential Diagnosis in Neurology

10.2. Acute Predominately Small Fiber Sensory and Autonomic Neuropathy

Diabetes Mellitus

• General features:
  • Autonomic neuropathy usually occurs with type I diabetes
  • Incidence is not determined
  • Frequently autonomic components noted in typical dying back neuropathy
• Clinical presentation:
  • Postural hypotension elicits no compensatory increase of pulse rate
  • Resting tachycardia
  • Nocturnal diarrhea
  • Light near dissociation (poor pupillary response to light with constriction to convergence)
  • Gastroparesis (slow intestinal transit time)
  • Impotence (may occur prior to overt neuropathy)
  • Patchy loss of sweating
• EMG:
  • Lower extremities involved earliest
  • Abnormalities may occur while the patient is asymptomatic
  • Axonal neuropathy with reduced CMAP and SNAP; fibrillations
  • Decreased sympathic skin responses
  • In time:
    • Segmental demyelination with prolonged distal latencies
    • Conduction block
    • Temporal dispersion
    • Prolonged F waves
    • Slowed conduction velocities
• Pathology:
  • Degeneration of autonomic nerves and ganglia
  • Microangiopathy

Dimethylamino Propionitrile (DMAPN)

• General features:
  • Catalyst in polymerization reaction for polyurethane foam
  • Toxic distal axonopathy
• Clinical features:
  • Earliest sign may be urinary hesitancy and sexual dysfunction
  • Numbness develops in the feet and spreads proximally to the legs and hands
  • Weakness develops first in the toe and foot extensors
  • Atrophy of involved muscles is rare
  • Tendon reflexes are preserved
  • Often affects small fibers selectively

Pandysautonomia

• General features:
  • Follows acute viral infection (10–14 days). Rarely it is paraneoplastic.
  • Severe postural hypotension
  • Wildly fluctuating heart rate; no RR variation with breathing
  • Patchy or generalized hypohidrosis
  • Light near dissociation of pupillary function; 3–4 mm pupils
  • Normal strength
  • Retained deep tendon reflexes
  • Bowel, bladder and sexual dysfunction
  • May have associated decreased motor and sensory NCVs
• Pathology:
  • Degeneration of autonomic ganglia and nerve

Acute Idiopathic Small-Fiber Sensory Neuropathy

• General features:
  • Loss of pain and temperature sensation in a stocking glove distribution
  • Suffused fingers and toes (early autonomic dysregulation)
  • Anhidrosis
  • Livedo reticularis (mottling of the skin)
  • Normal or minimal distal weakness
  • Retained deep tendon reflexes
  • Severe generalized fatigue (often signals an exacerbation)

Chronic Small Fiber Neuropathies

• General features:
  • Hereditary Sensory Autonomic Neuropathy (HSAN) I
    • Genetics:
      • AD
      • Chromosome 9q 22
• Clinical presentation:
  • Onset in the second decade
  • Loss of pain and temperature distally in the lower limbs which progresses to the upper limbs
  • Later touch vibration and position sense are affected
  • Slight distal motor weakness
  • Spontaneous lancinating pain or generalized deep ache of muscles
  • No autonomic signs or symptoms
  • Neuropathic joint degeneration (Charcot joints)
  • Persistent foot ulceration (volar first and second metatarsal)
• EMG:
  • Normal nerve conduction velocity
  • HSAN II
    • AR
  • Similar clinical presentation

Hereditary Sensory Autonomic Neuropathy III (Riley–Day Syndrome)

• General features:
  • Genetics:
    • AR; primarily Jewish children
    • Chromosome 9q 31–33
    • Incidence 1:50,000 people
• Clinical presentation:
  • Noted in infancy with recurrent vomiting, feeding problems, pulmonary infections
  • Autonomic dysfunction:
    • Defective temperature regulation
    • Livedo reticularis of the skin
    • Episodic hypertension and postural hypotension
  • Absent fungiform tongue papillae
  • Kyphoscoliosis
  • Congenital insensitivity to pain
  • Excessive sweating from emotional stimuli
  • Progressive deficits
  • Renal complications
• EMG
  • Normal motor and sensory nerve conduction velocities
• Pathology

Congential Sensory Neuropathy with Anhidrosis (HSAN IV)

• General features:
  • Genetics: AR
• Clinical features:
  • Presents in infancy
  • Delayed motor development
  • Episodic hyperpyrexia
  • Insensitivity to pain and decreased temperature sensibility
  • Cutaneous ulceration; bone fractures
  • Self-mutilation
• Pathology:
  • Selective loss of small myelinated fibers in sensory nerves; absence of unmyelinated fibers

Hereditary Sensory and Autonomic Neuropathy (Type V)

• General features:
  • Genetics: AR (very rare)
    • Mutations in the NGF gene
• Clinical features:
  • Selective loss of pain sensibility
  • Decreased sweating
• Pathology: Loss of small myelinated fibers; large unmyelinated fibers and large myelinated fibers

Hereditary Amyloidosis

• General features:
  • Andrade Variant Type I:
    • Genetics:
      • AD
      • Mutation of the transthyretin gene
      • Chromosome 18q11–12
      • Most common form of hereditary amyloid neuropathy
• Clinical features:
  • Onset in the 3rd and 4th decade
  • Insidious loss of pain and temperature in the leg
  • Associated pain and paresthesias
  • Loss of position and vibratory sensation in the upper extremities
  • Distal wasting, weakness and areflexia appear later; AJ may be spared
  • Autonomic dysfunction is seen early:
    • Postural hypotension
    • Impotence
    • Distal anhidrosis
    • Large poorly reactive pupils; light near dissociation
    • Bowel and bladder dysfunction
    • Neuropathic arthropathy and foot ulcers
    • Amyloid deposits in the vitreous (primary uveal veil)
    • Cardiomyopathy (dilatated)
    • Renal involvement
    • Slowly progressive
    • Death within 10 years of onset

Type II (Rukavina variant)

• General features:
  • Genetics: AD
• Clinical features:
  • Often presents with carpal tunnel syndrome
  • Similar to Type I amyloid in regard to sensory, motor and autonomic signs
  • Insidiously progressive
  • Visceral deposition of amyloid

Type III (Van Allen Variant)

• General features:
  • Genetics: AD
• Clinical features:
  • Autonomic features less conspicuous than those noted with Type I
  • High incidence of duodena ulcers

Type IV (Meretoja Variant)

• General features:
  • Genetics: AD
• Clinical features:
  • Cranial neuropathy
  • Lattice corneal dystrophy
  • Skin laxity
  • Onset with corneal opacities is usually in the 3rd decade
  • Neuropathy in distal extremities develops later

Tangier Disease

• General features:
  • Genetics: AR
    • Mutation in the gene encoding the ATP binding cassette reporter ABC-1
    • Chromosome 9q31
    • Protein encoded: cholesterol efflux regulatory protein:
      • Putatively important for intracellular cholesterol transport
    • Allelic to AD, HDL deficiency
    • Described from Tangier Island in Chesapeake Bay; less than 100 patients described
• Clinical features:
  • Approximately 50% of patients have peripheral nerve involvement
  • Onset may be in childhood or during adult life
  • Deposition of cholesterol esters in the tonsils, spleen, lymph nodes, thymus, intestinal mucosal, cornea and peripheral nerves; most often asymptomatic
  • Enlarged orange tonsils; slight hypersplenism; premature coronary artery disease in some patients
• Patterns of Clinical neuropathy:
  • Mononeuritis, relapsing, asymmetric:
    • EMG: normal NCV; rare prolonged distal latencies
    • Pathology: de and re-myelination
  • Symmetric polyneuropathy:
    • Legs greater than arms
    • EMG: normal NCV
    • Pathology: clear vacuoles in Schwann cells of unmyelinated and thinly myelinated fibers
  • Symmetric polyneuropathy:
    • Slowly progressive
    • Facial and intrinsic hand muscle involvement
    • Loss of pain and temperature sensation that may spare the distal extremities
• EMG:
  • Low or absent SNAPs
  • Low motor amplitudes in the arms; denervation of the hands and face
• Pathology:
  • Axonal degeneration of unmyelinated and thinly myelinated fibers
  • Loss of small DRG cells, anterior horn cells and facial nuclei neurons
• Laboratory features:
  • Very low plasma HDL (α-lipoproteins)
  • Low plasma cholesterol
  • Normal or increased triglyceride levels

Fabry's Disease (α-Galactosidase Deficiency)

• General features:
  • Genetics:
    • X-linked recessive
    • Deficiency of lysosomal hydrolase α-galactosidase
    • Gene for α-galactosidase located on Xq22
    • 25–33% of patients have spontaneous mutations
    • Mutations described are: gene rearrangements, splice junction deficits and point mutations
    • Deposition of globotriaosylceramide in vascular lysosomes
• General presentation:
  • Presents in childhood or adolescence
  • Hypohidrosis with severe heat intolerance may occur
  • Angiokeratoma corporis diffusum (telangiectatic skin lesions):
    • Bathing suit distribution
    • Conjunctival
    • Under the nail beds
    • Oral mucosa
• Associated medical conditions:
  • Renal failure (in the forties)
  • Easy bruisability
  • Stroke
  • Hypertension
  • Myocardial infarction
  • Corneal opacification
  • Carrier females: lumbosacral disc degeneration
• Neuropathy:
  • Characteristically burning pain distally in the extremities; associated with anhidrosis
  • Pain may be triggered by physical exertion and emotional stress
  • Facial swelling and coma due to hyperpyrexia
• Laboratory:
  • Decreased α-galactosidase activity in leukocytes or cultured skin fibroblasts
  • Globotriaosylceramide in the urine
• Pathology:
  • Deposition of globotriaosylceramide in autonomic and dorsal root ganglia of the peripheral nervous system
  • Globotriaosylceramide deposits in vascular lysosomes

Autonomic Variant of Guillain–Barré syndrome (GBS)

• General features:
  • Fixed tachycardia and sweating in mild form
  • Ventricular tachycardia and rare asystole
  • Shock with hypotension
  • Alteration of RR interval
  • Idioventricular arrhythmia
  • Bladder dysfunction
  • Paralytic ileus
  • Paroxysmal hypertension
  • Paroxysmal parasympathetic discharges flushing, chest tightness and bronchorrhea
  • Associated weakness often less severe than classic form
  • Minimal paresthesias and sensory deficits
• EKG:
  • ST and T wave abnormalities
  • APC and VPC (atrial and ventricular premature contractions)

Autosomal Dominant Burning Feet Syndrome

• General features:
  • Genetics: AD
• Clinical features:
  • Burning feet
• Pathology:
  • Involvement of unmyelinated nerve fibers

Differential Diagnosis of Peripheral Nervous System Disorders with Anhidrosis

• Pure autonomic failure
• Diabetes
• Amyloidosis
• Fabry's Disease
• Acute autonomic neuropathy (autoimmune/viral)
• Acute intermittent porphyria
• Acute inflammatory demyelinating polyneuropathy (autonomic variant)
• Hereditary sensory neuropathy (I, III–V)
• Tangiers's Disease
• Sjögren's Disease
• Ross's syndrome
• Holmes–Adie syndrome

Differential Diagnosis of Dermatologic Anhidrosis

• Local injury:
  • Thermal
  • X-RT
  • Scarring
  • Inflammatory conditions
• Anhidrotic ectodermal dysplasia
• Psoriasis
• Exfoliative dermatitis
• Lichens sclerosis atrophicus
• Ichthyosis
• Melioidosis
• Incontinentia pigmenti
• Dermatomally distributed vitiligo

Predominantly Small Fiber Sensory Neuropathy

• Autoimmune epitopes:
  • TTR transthyretin met 30 (amyloidosis)
  • Anti-Hu (paraneoplastic)
  • Sulfoglycuronic paragloboside SGPG (anti sulfatide epitopes)
• Inherited:
  • Fabry's Disease
  • Tangiers's Disease
  • Familial amyloid (FAP)
  • Hereditary sensory autonomic neuropathies (I, III, IV, V)
  • Hereditary thermosensitive neuropathy (AD)

Associated with Systemic Illness

• Amyloid (secondary)
• Diabetes
• Primary biliary cirrhosis
• Sjögren's (primarily ganglio neuritis)
• Rheumatoid arthritis

Associated Infections

• HIV (distal symmetrical painful neuropathy)
• Leprosy
• Cytomegalovirus (CMV)

Associated with Drugs and Toxins

• Ciguatera toxin
• Metronidazole
• Misonidazole
• Kepone
• Dimethylamino propionic acid (DMAPN)
• Vacor
• Erythromelalgia (secondary to vincristine)
• Ergotamine
• Gold

Chronic Painful Neuropathies (Small Fiber)

• Diabetes (primarily burning feet)
• Alcohol
• Pantothenic acid deficiency
• Pyridoxine B6 excess of deficiency
• CRPS I/II (RSD/causalgia)
• Amyloid (primary or secondary)
• Paraneoplastic (neuropathy/ganglioneuritis)
• TTR-met 30 (amyloidosis)
• Anti-sulfatide epitopes
• Uremia
• Arsenic
• Fabry's Disease
• Erythromelalgia
• ABC Syndrome (angry backfiring C nociceptors)
• Triple cold syndrome (cold hyperalgesia, cold hypoaesthesia and cold skin)
• Hypertriglyceridemia
• Niacin deficiency
• Thiamine deficiency

Neuropathies with Prominent Autonomic Features

• Diabetes
• Amyloidosis
• Paraneoplastic (DRG/ANs)
• SICCA complex
• Acquired generalized anhydrosis
• Acute intermittent porphyria
• Variegate porphyria
• B12 deficiency
• Uremia
• TTR-met 30 (amyloid)
• AIDP
• HSAN I, III, IV, V
• Fabry's Disease
• Pan Dysautonomia (immune/viral)
• EBV (Ebstein Barr Virus)
• Shy–Drager Disease
• Holmes–Adie Syndrome
• Familial sensory autonomic neuropathy (Navaho)
• Ross Syndrome
• Harlequin syndrome
• Vacor intoxication
• Chronic relapsing autonomic neuropathy
• NISP (non-malignant inflammatory sensory polyneuropathy)
• MISP (malignant inflammatory sensory polyneuropathy)
• Sjögren's Syndrome