Hereditary Neuropathy With Liability to Pressure Palsy Detected During the Use of Recreational Drugs

Abstract

Background: Nitrous oxide (N₂O) has been an increasingly popular recreational drug over the past few years. Abuse is associated with severe neurological complications and even fatal outcomes.

Purpose: Here we present a case of chronic nitric oxide abuse in a teenager presenting with rapidly progressive mixed sensory and motor polyneuropathy.

Results: The initial diagnostic workup excluded electrolyte derangement, heavy metal intoxication, autoimmune neuropathy, myopathy, hematological disorders, and thyroid disease. On further questioning, patient reported 8-months of inhalation of nitrous oxide, commonly known as “whippets”. Subsequent tests revealed low Vitamin B12 and elevated homocysteine level. Eventual genetic test demonstrated a heterozygous deletion in the gene that encodes the peripheral myelin protein 22 (PMP22), consistent with a diagnosis of Hereditary Neuropathy with Liability to Pressure Palsies (HNPP).

Conclusion: The association of neurologic and genetic findings with the timeline of nitrous oxide inhalation suggests a multifactorial etiology of her symptoms, with the N₂O acting as a trigger to the axonal degeneration and demyelination detected on electrodiagnostic studies.

Case

A 16-year-old, previously healthy, adolescent girl was admitted with progressively worsening motor weakness and paresthesia of the upper and lower extremities for several months.

Five months before admission, the patient started complaining of right leg tingling, which developed into numbness and motor weakness. Within weeks, she began experiencing similar symptoms in the contralateral leg, which then progressed to involve bilateral arms. Six weeks before admission, her symptoms were severely impairing her daily activities. She was not able to comb her hair or use her phone. She started having difficulty with ambulation and required assistance standing up and climbing stairs.

On admission, the patient appeared very thinly built (weight percentile 19th), with extensive muscle weakness involving bilateral proximal (4/5) and distal muscles (3/5) of the arms. Lower extremities revealed a similar pattern of weakness with strength of 2/5 at ankles and toes, and 4/5 at hips. Her deep tendon reflexes were normal in the arms but hypoactive (1/4) in bilateral patella and ankles. Family history was unremarkable as was rest of her medical history.

Based on the results of initial laboratory tests (including CK) and imaging- electrolyte imbalance, heavy metal intoxication, autoimmune neuropathies (Mayo AIAES Axonal Neuropathy, Autoimmune/Paraneoplastic Evaluation in serum that included: AMPHS-amphiphysin ab, ANN1S-anti-neuronal nuclear ab type 1, ANN3S-antineuronal nuclear ab type 3, AGN1S-antiglial nuclear ab type 1, CS2CS- CASPR2-IgG CBA, CRMWS-CRMP5IgG Western blot, CRMS-CRMP5IgG, LG1CS-LGI1-IgG CBA, PCABP-Purkinje cell cytoplasmic Ab Type 1, and PCAB2-Purkinje cell cytoplasmic ab type 2) or myopathies, and paraneoplastic etiologies were considered unlikely. Testing for Hepatitis, HIV, Lyme disease, diabetes and urine/serum immunofixation, Rheumatoid factor and autoimmune titers including ANA, ENA, dual stranded DNA were negative as well. As part of the paraneoplastic workup, CT abdomen and chest were completed and reported as normal. CSF glucose, protein, lactic acid, immunoglobulins, cell count and culture were also unremarkable. Nerve imaging was not performed.

Subsequently our patient was noted to have low vitamin B12 (110 pg/ml, normal values 180-914 pg/ml), low vitamin D,25OH (18 ng/ml, normal values 30-100 ng/ml), elevated homocysteine level (26 micromole/L, normal values 5-15 micromole/L) and elevated methylmalonic acid (3.09 micromole/L, normal value 0-.4 micromole/L) levels. Electromyography and nerve conduction studies results revealed multifocal sensorimotor, demyelinating and axonal polyneuropathy affecting the right upper and bilateral lower extremities, without conduction block (see Tables 1 and 2).

Table 1.

Motor Nerve Conduction Study.

Site	Latency (ms)	ND	Duration (ms)	Amp (mV)	ND	Area (mVms)	Stim. (mA)	Segment	Dist (mm)	Intvl. (ms)	NCV (m/s)
Right median
Wrist	5.4	< 4.1	8.3	6.4	> 5	16.6	60	Wrist	70	4.9
Elbow	9.2		7.8	7.3		27.1	82	Wrist-elbow	210	4.3	51.9
Right ulnar
Wrist	3.2	< 3.4	7.4	6.3	> 5	24.4	27	Wrist	75	3.2
Below elbow	7.2		7.7	8.6		35.1	65	Wrist-below elbow	160	4.0	39.8
Above elbow	10.1		8.0	7.6		32.5	79	Below elbow-above elbow	100	2.9	35.1
Left peroneal
Ankle	14.9	< 6		0.2	> 2		50	Ankle	70	14.9
Fibular head	NR						50	Ankle-fibular head	280
Popliteal fossa	NR						50	Fibular head-popliteal fossa	90
Right peroneal
Ankle	12.7	< 6		0.4	> 2		50	Ankle	70	12.7
Fibular head	NR						50	Ankle-fibular head	290
Popliteal fossa	NR						50	Fibular head-popliteal fossa	80
Left tibial
Ankle	8.4	< 5.3		2.6	> 3.5		50	Ankle	75	8.4
Popliteal fossa	23.8		11	1.2		6.9	50	Ankle-popliteal fossa	390	15.4	25.3
Right Tibial
Ankle	9.4	< 5.3		1.5	> 3.5		50	Ankle	70	9.4
Popliteal fossa	28.8		6.1	0.2		0.6	50	Ankle-popliteal fossa	400	19.4	20.6

Note: Amp, Amplitude; Dist, distance; Intvl, interval; NCV, Nerve Conduction Velocity; NR, No Response; Stim, Stimulation.

Table 2.

Electromyography (EMG) Findings Summary.

Muscle	Vastus lateralis	Gastrocnemius medial head	Peroneus longus	Tibialis anterior	Abductor hallucis	Extensor digitorum brevis
Side	L	L	L	L	L	L
Insertion activity	Normal		Decreased	Decreased	Decreased	Decreased
Fibrillations			0	+1		0
Positive waves	+1		+2	+2		+2
Fasciculations
Normal motor unit potentials			+1	+1
Polyphasia	N		++	++	++	+1
Low amplitude	0		0	0	0	+1
High amplitude	0		0	0	0	0
Duration	Long		Long	Long	Long	Long
Recruitment	Reduce		Reduce	Reduce	Reduce	No activation
Interference pattern	Reduce		Reduce	Reduce	Descret	No activation

After a few days she confided that she had been using “whippets” with her friends for about 7 months prior to the hospitalization. Patient admitted to inhaling about 50 canisters every 2 weeks.

Despite ongoing treatment with intramuscular Vitamin B12 at a dose of 1000 µg and symptomatic treatment for neuropathic pain, she did not achieve satisfactory improvement. She then received intravenous immunoglobulin followed by plasmapheresis for a tentative diagnosis of an immune mediated neuropathy, which may have co-existed with the neuropathy related to use of the whippets. After the second round of plasmapheresis, patient was able to actively extend and flex lower extremities without assistance but relapsed after the third round. During the second week of admission, we were notified of a positive finding from the genetic panel, which showed a heterozygous deletion of entire coding sequence of the PMP22 gene, consistent with a diagnosis of Charcot-Marie Tooth/Hereditary Neuropathy with Liability to Pressure Palsies (HNPP). In addition to pharmacologic therapies, the patient received inpatient physical rehabilitation therapy throughout her hospitalization. Physical therapy plan was tailored to the patient’s needs to avoid direct nerve compression, repetitive stereotyped movements, overextension or overflexion of the extremities, given her final diagnosis of HNPP.

At discharge, the patient continued to have proximal muscle weakness in upper and lower extremities, with improved tolerance to standing and trunk stability. She was unable to stand without assistance and unable to take steps, so was prescribed ankle-foot orthosis (AFOs), braces, and outpatient physical therapies. At 1-year follow-up, she was able to ambulate without AFOs, resumed work and obtained her high school diploma.

Discussion

Nitrous oxide (N₂O) is a chemically inert, odorless, bacteriostatic gas with an anti-anxiety effect initially synthesized by Joseph Priestley in 1775 to be used as an anesthetic. Since the Victorian times, it has also been used as an inhalant drug known as “laughing gas parties”, or more recently, “Hippy crack.” It is easily available as inexpensive cartridges or whipped cream canisters called “whippets”. ¹

In the United States, the lifetime prevalence of N₂O use is approximately 29%. ² The percentage of inhalant users aged 12 or older increased from .6 percent (or 1.7 million people) in 2016 to .8 percent (or 2.1 million people) in 2019. ³

N₂O inhalation produces a euphoric and hallucinogenic effect lasting from seconds to a few minutes. ¹ Adverse events are dose-dependent, with a variety of symptoms from nausea to urinary retention, painful erection, decreased libido, delusions, anxiety, to even death. ⁴ With long-term use of 10-100 doses per session, individuals are at risk of developing neurologic complications. ⁵ N₂O induces a neurotoxic effect by causing a functional vitamin B12 deficiency. By inactivating vitamin B12, methionine synthase is blocked, resulting in impaired DNA synthesis and myelin production.

The typical clinical picture is a sensorimotor polyneuropathy with combined lateral and posterior cord involvement signs. Peripheral nerve pathology can be either axonal or demyelinating or both. ⁶ Patients may present with numbness, tingling, weakness, ataxia and incontinence. There are no tests to detect N₂O toxicity. Although vitamin B12 level may be low, normal or elevated, methylmalonic acid and homocysteine precursors remain elevated. The pathophysiology of N₂O -induced axonal injury has not been determined. However, a high homocysteine level leads to oxidative stress injury causing mitochondrial dysfunction and neuronal necrosis. ⁷ The diagnostic approach aims to rule out other potential etiologies such as heavy metal toxicity, cord compression, electrolyte imbalances, autoimmune and hematology-oncology pathologies.^4,8,9 Among medications, vincristine is known to cause peripheral neuropathy and has been observed to worsen or reveal underlying hereditary neuropathy, such as Charcot Marie Tooth disease and HNPP. ¹⁰ Metals cause peripheral nerve damage by catalyzing redox reactions that interfere with cellular respiration, metabolism, and neurotransmitter synthesis. There is evidence that early life exposure to metals may cause epigenetic processes affecting gene expression and program later life adult disease phenotypes. ¹¹

Cessation of substance abuse and Vitamin B12 supplementation are the mainstay of treatment of N₂O -induced neuropathy. There is no standardized regimen for vitamin B12 supplementation. The most common used is 1000 µg intramuscular for 5 days and then intermittently until symptoms resolve. However, other interventions may be required depending on the severity of the presentation. Symptoms do not always resolve, and some functional impairment may be permanent. ⁸

In our case, the adolescent was also noted to have a heterozygous deletion in PMP22, consistent with a diagnosis of HNPP. HNPP is an autosomal dominant disorder with focal sensory-motor neuropathy with usual onset during adolescence. Mechanical stress applied on peripheral nerves or repetitive movements of extremities may aggravate patient focal deficits. PMP22 is an integral membrane glycoprotein expressed in the myelin of the peripheral nervous system and is involved in maintaining axonal integrity. ¹² The pathophysiology of this condition is related to limited reserve in the affected nerve fibers to nontraumatic compression or stretch. Even minimal compression may result in demyelination of the affected fibers and subsequent reduction in nerve conduction velocity distal to the point of compression. ¹² The diagnosis is established in a patient with suggestive clinical and electrophysiologic findings and confirmed with a genetic test showing the presence of a 1.5Mb deletion (80%) or novel sequence variant (20%) of the PMP22 gene. ¹² This gene, which codes for the peripheral myelin protein 22, maintains and stabilizes the lipid membrane and its membrane-membrane contact in the myelin sheath. Reduced copy numbers allow for normal signal transduction but limit the resilience of the myelin sheath membrane, leading to transient demyelination. ¹²

We hypothesize that, in our case, the chronic abuse of nitrous oxide arrested myelin production in the peripheral nerves -in the setting of an underlying demyelinating neuropathy. This may explain the severe clinical presentation, the relentless course of the disease, and the combination of demyelinating and axonal pathology noted on electromyography. Peripheral neuropathies induced by vitamin B12 deficiency ¹³ and N₂O mostly present with axonal motor dysfunction and rarely with demyelinating damage. ¹⁴ Conversely, HNPP typically presents with increased distal motor latencies, prolonged F-wave latencies, and focal slowing of conduction velocities only at sites of compression. ¹⁵ These findings are consistent with demyelinating neuropathy and are not typically found in peripheral neuropathies induced by vitamin B12 deficiency and N₂O toxicity. The diagnostic process is often stopped when a potential explanation is found for a given set of symptoms. More than 1 possible explanation may exist, like in our case. A broad differential should be entertained to ensure a comprehensive evaluation, especially when the neurophysiological findings are atypical for the disease process being considered.

ORCID iD

Giovanni Castellucci https://orcid.org/0000-0002-3031-5113