Metabolic, Toxic, Hereditary, and Rare Causes of Spinal Cord Disease

Category

Examples

Recommended diagnostics

Structural abnormalities of the brain and spinal cord

Spinal cord compression from neoplasm or spondylosis, tethered cord syndrome, spinal cord arteriovenous malformation

MRI of entire neuraxis

Leukodystrophy

Adrenomyeloneuropathy, Krabbe disease, metachromatic leukodystrophy, vitamin B12 deficiency, mitochondrial disorders

Vitamin B12, methylmalonic acid, serum very long chain fatty acids (VLCFA), beta-galactosidase, arylsulfatase, serum lactate, and pyruvate

Chronic inflammatory disease

Multiple sclerosis (primary progressive, secondary progressive)

Cerebrospinal fluid analysis for immunoglobulin index and polyclonal bands

Infectious diseases

Tropical spastic paraplegia due to HTLV-1 infection, tertiary syphilis

HTLV-1, syphilis serology, (HIV)

Other motoneuron disorders

Amyotrophic lateral sclerosis, primary lateral sclerosis, distal hereditary motor neuropathy

Serial electromyography (for the first 2–5 years of adult-onset and progressive spastic paraparesis)

Other degenerative neurological disorders

Friedreich ataxia, spinocerebellar ataxia type 3 (SCA 3)

Friedreich ataxia and SCA3 gene analysis

Environmental toxins

Hypocupremia, lathyrism, konzo, organophosphate-induced neuropathy

Serum copper, serum zinc

Other

Spastic diplegic cerebral palsy, dopa-responsive dystonia, stiff person syndrome

Trial of low-dose levodopa (2–4 weeks)

Adapted from [50]

Diagnostic steps include individual and family history to detect the type of transmission. Moreover, a careful neurological examination, neurophysiological testing (nerve conduction studies, EMG, MEP, somatosensory evoked potential (SSEP), visual evoked potential (VEP)), imaging studies (spinal MRI, CT), and laboratory tests are needed for diagnosis, in particular to identify pure and complicated forms prior to genetic testing (Table 8.1). Screening for SPG mutations is usually carried out by direct Sanger sequencing and needs to be coupled with multiplex ligation-dependent probe amplification [39]. Recent improvements analyzing large panels of SPG genes by next-generation sequencing (NGS) permit confirmation of diagnosis in many patients; nevertheless this approach does not cover all SPG genes and may not identify all gene copy variants, including exon deletions [51]. Genetic testing is most useful to confirm a clinical diagnosis of HSP, and results of genetic testing need to be interpreted in the light of the clinical context (Table 8.2). Importantly, HSP gene variations with unknown clinical significance need careful consideration, in particular when the clinical diagnosis does not conform to HSP [49]. Genetic counseling is recommended for affected families, and the gene test results must consider mode of inheritance, and the possible degree of genetic penetrance, which is not very well known in most types of HSP [52].

Table 8.2

Common genetic types of HSP

SPG locus	Gene/protein	Onset	Phenotype	Additional clinical features
Autosomal dominant HSP
SPG3A	ATL1/atlastin-1	EO	P or C	Ataxia, sensorimotor axonal neuropathy, intellectual disability, optic atrophy, lower limb muscle atrophy
SPG4	SPAST/spastin	VO	P or C	Cognitive impairment, amyotrophy of small hand muscles, epilepsy, upper limb spasticity, pes cavus
SPG6	NIPA1/NIPA1	EO	P or C	Idiopathic generalized epilepsy, polyneuropathy, atrophy of small hand muscles, upper limb spasticity, pes cavus
SPG8	KIAA0196/strumpellin	AO	P	–
SPG10	KIF5A/kinesin HC5A	EO	P or C	Distal muscle atrophy, cognitive decline, polyneuropathy, deafness, retinitis pigmentosa
SPG17	BSCL2/seipin	EO	C	Amyotrophy of hand muscles (Silver syndrome)
SPG31	REEP1/REEP1	EO	P or C	Peripheral neuropathy, cerebellar ataxia, tremor, dementia, amyotrophy of small hand muscles
Autosomal recessive HSP
SPG5A	CYP7B1/OAH1	VO	P or C	Axonal neuropathy, WMLs, optic atrophy, cerebellar ataxia
SPG7	PGN/paraplegin	VO	P or C	Cerebellar atrophy, PNP, optic atrophy, TCC, axonal neuropathy Caution: AD inheritance possible!
SPG11	KIAA1840/spatacsin	VO	P or C	TCC, seizures, cognitive decline, upper extremity weakness, parkinsonism, dysarthria, slowly progressive familial ALS
SPG15	ZFYVE26/spastizin	EO	C	Pigmented maculopathy, distal amyotrophy, dysarthria, intellectual deterioration
SPG20	SPG20/spartin	EO	C	Distal muscle wasting (Troyer syndrome), intellectual disability, dysarthria, cerebellar signs, WMLs
SPG23	Unknown	EO	C	Pigmentary abnormalities, cognitive impairment, facial and skeletal dysmorphism
SPG46	GBA2/GBA2	EO	C	Dementia, cataract, cerebellar atrophy, TCC, hypogonadism in males
SPG54	DDHD2/DDHD2	EO	C	Dysarthria, cognitive decline, TCC, WMLs, dysarthria, strabismus
SPG56	CYP2U1/CYP2U1	EO	P or C	Dystonia, WMLs, cognitive impairment, TCC, axonal neuropathy, basal ganglia calcifications
X-linked HSP
SPG1	LICAM1/NCAM	EO	C	Cognitive impairment, adducted thumbs, aphasia
SPG2	PLP1/MPLP	EO	P or C	Cognitive impairment, polyneuropathy, nystagmus, seizures
SPG22	SLC16A2/MCT8	EO	C	Neck muscle hypotonia in infancy, cognitive impairment, distal muscle wasting, ataxia, dysarthria, abnormal facies
Maternal (mitochondrial) inheritance HSP
ATPase6 gene	Mitochondrial ATP6	AO	C	Axonal neuropathy, cardiomyopathy, cerebellar syndrome

EO early onset, VO variable onset, AO adult onset, P pure, C complicated, WML white matter lesion, TCC thin corpus callosum, PNP polyneuropathy. Adapted from [39, 50]

Genetic counseling aims to inform affected patients and unaffected family members at risk about the nature and inheritance of the disorder. In case of AD transmission, most affected individuals have an affected parent, depending on genetic penetrance. Nevertheless, the frequency of de novo mutations causing AD HSP is unknown. In general, caution must be exercised in providing genetic counseling and prognosis for many HSP types, due to unclear genetic penetrance and insufficient information about the full phenotypic spectrum. In particular, the clinical description of the majority of genetic types of HSP is limited to one or a few families (Table 8.2).

Therapy

Currently, no specific treatments to prevent, halt, or reverse the pathological processes underlying HSP are available. Treatment options are exclusively symptomatic. Spasticity is managed by regular physical therapy, occupational therapy, assistive walking devices, orthotics, or drugs reducing muscle tone, in particular baclofen or tizanidine [41]. Chemodenervation with botulinum toxin A or B can be an alternative option [53, 54], as well as intrathecal baclofen therapy in selected cases. Secondary complications, such as tendon contractures, scoliosis, or foot deformities, may be delayed or even prevented by intense and regular physical therapy. Urinary urgency can be treated with anticholinergic drugs. Pain, a quite common symptom in HSP, should be treated according to general guidelines. Neuropathic pain benefits from gabapentin and pregabalin. In complicated forms patients with cognitive decline or dementia may profit from cholinergic drugs, while epilepsy should be treated according to established guidelines. If parkinsonism is a feature of the clinical phenotype, L-DOPA or dopamine-receptor agonists may be a treatment option. If dystonia is a prominent presentation of the HSP, botulinum toxin or even deep brain stimulation may be beneficial. In patients with SPG1 who develop hydrocephalus, shunt implantation is required [39, 40]. Regular clinical reevaluations of patients once or twice yearly are recommended to identify complications and progression of the disease.

8.5 Rare Cases

8.5.1 Cervical Flexion Myelopathy

A number of cases of spinal cord disease due to protracted fixed cervical spine positions – predominantly in young individuals – have been reported in the course of surgeries requiring a flexed cervical spine position, unconsciousness due to medication overdose, or after an assault forcing the victim into a flexed cervical spine position for a prolonged period of time [55].

Pathophysiology

In the literature, the term cervical flexion myelopathy is reserved for a chronic disease condition also known as Hirayama syndrome [56]. In case of Hirayama syndrome, the hypermobile dura compresses the cord microcirculation repeatedly for a short duration. As a consequence only highly susceptible neural cells within the spinal cord namely motoneurons, in the ventral horn are affected with isolated lower motoneuron signs and minimal MRI changes. In contrast, in case of subacute cervical flexion myelopathy, the shift of the dura over longer periods of time (hours to days) may compromise larger-caliber blood vessels (posterior spinal artery, epidural veins), causing more extensive circulatory problems affecting the white matter structures predominantly in the dorsal half of the spinal cord.

Clinical Presentation

After a protracted period of fixed cervical spine position, patients present with tetraparesis/tetraplegia meaning bilateral sensorimotor dysfunction in the upper and lower extremities including bladder and bowel dysfunction.

Diagnostics

If a subacute flexion myelopathy is suspected, spinal MRI should be performed to exclude compressive causes of spinal cord disease, in particular intraspinal hemorrhage. Within the cord parenchyma MRI longitudinally extending, dorsally accentuated signal changes with signs of cord swelling can be observed in T2-weighted sequences.

Therapy

Effective treatment options are not available. The existence of such a pathomechanisms potentially leading to irreversible neurological dysfunction should raise the awareness to check the necessity for surgeries requiring intra- or postoperative flexed cervical spine positions very carefully, particularly in young individuals, who are predominantly affected by subacute cervical flexion myelopathy. In cases where respective positions cannot be avoided, intra-/postoperative neuromonitoring should be considered to detect spinal cord dysfunction before irreversible damage to neural tissue occurs [55].

8.5.2 Epidural Lipomatosis

The spinal epidural lipomatosis is a rare entity. A majority of male patients and a mean manifestation at the age of 43 are described in the literature. Most of the cases are associated with obesity, chronic use of steroids, Cushing’s syndrome, and other endocrinopathies. Only a small group of patients without relevant concomitant diseases (idiopathic spinal epidural lipomatosis) are described so far. In all these cases, manifestation of the lipomatosis was restricted to the thoracic and lumbar segments of the spinal cord especially in the dorsal and lateral parts of the myelin [57].

Pathophysiology

Excess adipose tissue deposits in the spinal canal cause radiculopathy or spinal cord compression.

Clinical Presentation

Main symptoms are back pain, followed by a slowly progressive weakness of the legs, sensory loss, and sometimes a radicular manifestation or a claudication mainly seen with a lumbar affection of the spinal cord. An autonomic dysfunction with bowel and urinary incontinence is not typical.

Diagnostics

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